IFNs are cytokines with important antiproliferative activity and exhibit key roles in immune surveillance against malignancies. Early work initiated over three decades ago led to the discovery of IFN receptor activated Jak–Stat pathways and provided important insights into mechanisms for transcriptional activation of IFN-stimulated genes (ISG) that mediate IFN biologic responses. Since then, additional evidence has established critical roles for other receptor-activated signaling pathways in the induction of IFN activities. These include MAPK pathways, mTOR cascades, and PKC pathways. In addition, specific miRNAs appear to play a significant role in the regulation of IFN signaling responses. This review focuses on the emerging evidence for a model in which IFNs share signaling elements and pathways with growth factors and tumorigenic signals but engage them in a distinctive manner to mediate antiproliferative and antiviral responses. Mol Cancer Res; 12(12); 1691–703. ©2014 AACR.

Because of their antineoplastic, antiviral, and immunomodulatory properties, recombinant IFNs have been used extensively in the treatment of various diseases in humans (1). IFNs have clinical activity against several malignancies and are actively used in the treatment of solid tumors such as malignant melanoma and renal cell carcinoma; and hematologic malignancies, such as myeloproliferative neoplasms (MPN; ref. 1). In addition, IFNs play prominent roles in the treatment of viral syndromes, such as hepatitis B and C (2). In contrast to their beneficial therapeutic properties, IFNs have also been implicated in the pathophysiology of certain diseases in humans. In many cases, this involvement reflects abnormal activation of the endogenous IFN system, which has important roles in various physiologic processes. Diseases in which dysregulation of the type I IFN system has been implicated as a pathogenetic mechanism include autoimmune disorders such as systemic lupus erythematosus (3), Sjogren syndrome (3, 4), dermatomyositis (5), and systemic sclerosis (3, 4). In addition, type II IFN (IFNγ) overproduction has been implicated in bone marrow failure syndromes, such as aplastic anemia (6). There is also recent evidence for opposing actions of distinct IFN subtypes in the pathophysiology of certain diseases. For instance, a recent study demonstrated that there is an inverse association between IFNβ and IFNγ gene expression in human leprosy, consistent with opposing functions between type I and II IFNs in the pathophysiology of this disease (7). Thus, differential targeting of components of the IFN system, to either promote or block induction of IFN responses depending on the disease context, may be useful in the therapeutic management of various human illnesses. The emerging evidence for the complex regulation of the IFN system underscores the need for a detailed understanding of the mechanisms of IFN signaling to target IFN responses effectively and selectively.

It took over 35 years from the original discovery of IFNs in 1957 to the discovery of Jak–Stat pathways (8). The identification of the functions of Jaks and Stats dramatically advanced our understanding of the mechanisms of IFN signaling and had a broad impact on the cytokine research field as a whole, as it led to the identification of similar pathways from other cytokine receptors (8). Subsequently, several other IFN receptor (IFNR)-regulated pathways were identified (9). As discussed below, in recent years, there has been accumulating evidence that beyond Stats, non-Stat pathways play important and essential roles in IFN signaling. This has led to an evolution of our understanding of the complexity associated with IFN receptor activation and how interacting signaling networks determine the relevant IFN response.

IFNs and their functions

The IFNs are classified in three major categories, type I (α, β, ω, ϵ, τ, κ, ν); type II (γ), and type III IFNs (λ1, λ2, λ3; refs. 1, 9, 10). The largest IFN gene family is the group of type I IFNs. This family includes 14 IFNα genes, one of which is a pseudogene, resulting in the expression of 13 IFNα protein subtypes (1, 9). There are 3 distinct IFNRs that are specific for the three different IFN types. All type I IFN subtypes bind to and activate the type I IFNR, while type II and III IFNs bind to and activate the type II and III IFNRs, respectively (9–11). It should be noted that although all the different type I IFNs bind to and activate the type I IFNR, differences in binding to the receptor may account for specific responses and biologic effects (9). For instance, a recent study provided evidence that direct binding of mouse IFNβ to the Ifnar1 subunit, in the absence of Ifnar2, regulates engagement of signals that control expression of genes specifically induced by IFNβ, but not IFNα (12). This recent discovery followed original observations from the 1990s that revealed differential interactions between the different subunits of the type I IFN receptor in response to IFNβ binding as compared with IFNα binding and partially explained observed differences in functional responses between different type I IFNs (9).

A common property of all IFNs, independent of type and subtype, is the induction of antiviral effects in vitro and in vivo (1). Because of their potent antiviral properties, IFNs constitute an important element of the immune defense against viral infections. There is emerging information indicating that specificity of the antiviral response is cell type–dependent and/or reflects specific tissue expression of certain IFNs. As an example, a recent comparative analysis of the involvement of the type I IFN system as compared with the type III IFN system in antiviral protection against rotavirus infection of intestinal epithelial cells demonstrated an almost exclusive requirement for IFNλ (type III IFN; ref. 13). The antiviral effects of IFNα have led to the introduction of this cytokine in the treatment of hepatitis C and B in humans (2) and different viral genotypes have been associated with response or failure to IFN therapy (14).

Most importantly, IFNs exhibit important antineoplastic effects, reflecting both direct antiproliferative responses mediated by IFNRs expressed on malignant cells, as well as indirect immunomodulatory effects (15). IFNα and its pegylated form (peg IFNα) have been widely used in the treatment of several neoplastic diseases, such as hairy cell leukemia (HCL), chronic myeloid leukemia (CML), cutaneous T-cell lymphoma (CTCL), renal cell carcinoma, malignant melanoma, and myeloproliferative neoplasms (MPN; refs. 1, 16). Although the emergence of new targeted therapies and more effective agents have minimized the use of IFNs in the treatment of diseases like HCL and CML, IFNs are still used extensively in the treatment of melanoma, CTCL and MPNs (1, 16, 17). Notably, recent studies have provided evidence for long lasting molecular responses in patients with polycythemia vera, essential thrombocytosis and myelofibrosis who were treated with IFNα (16). Beyond their inhibitory properties on malignant hematopoietic progenitors, IFNs are potent regulators of normal hematopoiesis (9) and contribute to the regulation of normal homeostasis in the human bone marrow (18). Related to its effects in the central nervous system, IFNβ has clinical activity in multiple sclerosis and has been used extensively for the treatment of patients with multiple sclerosis (19). The immunoregulatory properties of type I IFNs include key roles in the control of innate and adaptive immune responses, as well as positive and negative effects on the activation of the inflammasome (15). Dysregulation of the type I IFN response is seen in certain autoimmune diseases, such as Aicardi–Goutières syndrome (20). In fact, self-amplifying type I IFN production is a key pathophysiologic mechanism in autoimmune syndromes (21). There is also emerging evidence that IFNλ may contribute to the IFN signature in autoimmune diseases (3).

Jak–stat pathways

Jak kinases and DNA-binding Stat complexes.

Tyrosine kinases of the Janus family (Jaks) are associated in unique combinations with different IFNRs and their functions are essential for IFN-inducible biologic responses. Stats are transcriptional activators whose activation depends on tyrosine phosphorylation by Jaks (8, 9). In the case of the type I IFN receptor, Tyk2 and Jak1 are constitutively associated with the IFNAR1 and IFNAR2 subunits, respectively (refs. 8, 9; Fig. 1). For the type II IFN receptor, Jak1 and Jak2 are associated with the IFNGR1 and IFNGR2 receptor subunits, respectively (refs. 8, 9; Fig. 1). Finally, in the case of the type III IFNR, Jak1 and Tyk2 are constitutively associated with the IFNλR1 and IL10R2 receptor chains, respectively (ref. 10; Fig. 1). Upon engagement of the different IFNRs by the corresponding ligands, the kinase domains of the associated Jaks are activated and phosphorylate tyrosine residues in the intracellular domains of the receptor subunits that serve as recruitmenst sites for specific Stat proteins. Subsequently, the Jaks phosphorylate Stat proteins that form unique complexes and translocate to the nucleus where they bind to specific sequences in the promoters of IFN-stimulated genes (ISG) to initiate transcription. A major Stat complex in IFN signaling is the IFN-stimulated gene factor 3 (ISGF3) complex. This IFN-inducible complex is composed or Stat1, Stat2, and IRF9 and regulates transcription by binding to IFN-stimulated response elements (ISRE) in the promoters of a large group of ISGs (refs. 8, 9). ISGF3 complexes are induced during engagement of the type I and III IFN receptors, but not in response to activation of type II IFN receptors (refs. 8–10; Table 1). Beyond ISGF3, several other Stat complexes involving different Stat homodimers or heterodimers are activated by IFNs and bind to IFNγ-activated (GAS) sequences in the promoters of groups of ISGs (8, 9). Such GAS-binding complexes are induced by all different IFNs (I, II, and III), although there is variability in the engagement and utilization of different Stats by the different IFN receptors (Table 1). It should also be noted that engagement of certain Stats, such as Stat4 and Stat6, is cell type–specific and may be relevant for tissue-specific functions (9). The significance of different Stat-binding complexes in the induction of type I and II IFN responses was in part addressed in a study in which Stat1 cooperative DNA binding was disrupted by generating knock-in mice expressing cooperativity-deficient STAT1 (22). As expected, type II IFN-induced gene transcription and antibacterial responses were essentially lost in these mice, but type I IFN-dependent recruitment of Stat1 to ISRE elements and antiviral responses were not affected (22), demonstrating the existence of important differences in Stat1 cooperative DNA binding between type I and II IFN signaling.

Figure 1.

Type I, II, III IFN receptor subunits, associated kinases of the Janus family, and effector Stat pathways. Note: Stat:Stat reflects multiple potential Stat:Stat complexes, as outlined in Table 2.

Figure 1.

Type I, II, III IFN receptor subunits, associated kinases of the Janus family, and effector Stat pathways. Note: Stat:Stat reflects multiple potential Stat:Stat complexes, as outlined in Table 2.

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Table 1.

Different Stat–DNA binding complexes induced by type I, II, and III IFNs

IFN typeStat complexes
Type I Stat1: Stat2: IRF9, Stat1:Stat1, Stat1:Stat2, Stat1:Stat3, Stat2:Stat3, Stat3:Stat3, Stat4:Stat4, Stat1:Stat4, Stat1:Stat5, Stat5:Stat5, Stat5:Stat6, CrkL:Stat5 
Type II Stat1:Stat1, Stat1:Stat3, Stat3:3, 
Type III Stat1:Stat2: IRF9, Stat1:1 
IFN typeStat complexes
Type I Stat1: Stat2: IRF9, Stat1:Stat1, Stat1:Stat2, Stat1:Stat3, Stat2:Stat3, Stat3:Stat3, Stat4:Stat4, Stat1:Stat4, Stat1:Stat5, Stat5:Stat5, Stat5:Stat6, CrkL:Stat5 
Type II Stat1:Stat1, Stat1:Stat3, Stat3:3, 
Type III Stat1:Stat2: IRF9, Stat1:1 

Serine phosphorylation of Stats.

The nuclear translocation of Stat proteins occurs after their activation, following phosphorylation on specific sites by Jak kinases (8, 9). It is well established that phosphorylation on tyrosine 701 is required for activation of Stat1 and phosphorylation on tyrosine 705 is required for activation of Stat3 (8, 9). Beyond tyrosine phosphorylation, phosphorylation on serine 727 in the Stat1 and Stat3 transactivation domains is required for full and optimal transcriptional activation of ISGs (8, 9). There is evidence that serine phosphorylation occurs after the phosphorylation of Stat1 on tyrosine 701 and that translocation to the nucleus and recruitment to the chromatin are essential in order for Stat1 to undergo serine 727 phosphorylation (23). Several IFN-dependent serine kinases for Stat1 have been described, raising the possibility that this phosphorylation occurs in a cell type–specific manner. After the original demonstration that protein kinase C (PKC) delta (PKCδ) is a serine kinase for Stat1 and is required for optimal transcriptional activation in response to IFNα (24), extensive work has confirmed the role of this PKC isoform in the regulation of serine 727 phosphorylation in Stat1 and has been extended to different cellular systems (refs. 25–29; Table 2). In the type II IFN system five different serine kinases for the transactivation domain (TAD) of Stat1/phosphorylation on serine 727 have been demonstrated in different cell systems. These include PKCδ (30, 31), calmodulin-dependent kinase II (CAMKII; ref. 32), PKCϵ (33), PKCα (34), Erk (35), and cyclin-dependent kinase 8 (CDK8; ref. 36; Table 2). Thus, it appears that in the type I IFN system, PKCδ is the predominant kinase that regulates phosphorylation of Stat1 on serine 727 (Table 2), while in the type II IFN system several serine kinases appear to play roles in different cell types (Table 2). It remains to be determined whether the diversity of serine kinases in the type II IFN system reflects differences in cellular expression patterns or is context-dependent, possibly influenced by parallel signaling events. It should also be noted that it is likely that, beyond phosphorylation on serine 727 in the TAD, phosphorylation on other serine residues in Stats may be important for transcriptional activity and the generation of IFN responses. For instance, phosphorylation of serine 708 in Stat1 by the kinase IKKϵ is important for transcriptional activation of a subset of ISGs (37). Thus, it appears that our current understanding of the role of serine phosphorylation of Stats is incomplete and future studies may uncover other serine phosphorylation sites and corresponding kinases relevant to Stat activity.

Table 2.

Serine kinases demonstrated to regulate phosphorylation of Stat1 on serine 727 in response to different IFNs

IFN typePutative kinases for TAD/serine 727
Type I PKCδ 
Type II PKCδ, PKCϵ, PKCα, CAMKII, Erk, JNK, CDK8 
Type III Unknown 
IFN typePutative kinases for TAD/serine 727
Type I PKCδ 
Type II PKCδ, PKCϵ, PKCα, CAMKII, Erk, JNK, CDK8 
Type III Unknown 

Regulatory effects of phosphatases on Jak–Stat signaling.

After undergoing tyrosine phosphorylation by Jaks and translocation to the nucleus to regulate ISG transcription by binding to specific promoter elements, nuclear Stats are deactivated by dephosphorylation. Several phosphatases have been identified as regulators of IFN signaling pathways (Table 3). In the type I IFN system, it has been shown that the tyrosine phosphatase TC-PTP modulates Stat1 activity in BCR-ABL–transformed leukemia cells (38). TC-PTP is involved in dephosphorylation of Stat1 in the type II IFN system and pharmacologic inhibition of its activity has been shown to enhance IFNγ signaling (39). In the type I IFN system, SHP1 is associated with the Tyk2 tyrosine kinase (40), while it has been shown to dephosphorylate IFNγ tyrosine phosphorylated Stat1 in brain microglia and astrocytes (41). In addition, interaction of tyrosine phosphorylated SHP-2 (pY-SHP-2) with cytosolic STAT1 has been shown to prevent recruitment of Stat1 to the type II IFNR and to inhibit Stat1-mediated signaling (42). The protein tyrosine phosphatase PTPN1 has been implicated in both type I (43) and type II (44) IFN signaling. Moreover, there is evidence that PTPN1 and TC-PTP have nonoverlapping roles in type II IFN signaling (44). Finally, recent studies have shown the negative regulator of JAK kinases, phosphatase CD45 exhibits regulatory effects on IFN signaling (45). Thus, the coordinated function of distinct tyrosine phosphatases at different important check points of IFN-activated signaling cascades accounts for control of tyrosine phosphorylation-mediated signaling events and optimal balancing of IFN responses.

Table 3.

Protein tyrosine phosphatases with regulatory effects on Jak–Stat pathways in IFN signaling

IFN typeTyrosine phosphatases
Type I TC-PTP, PTPN1, SHP1, CD45 
Type II TC-PTP, PTPN1, SHP1, SHP2 
Type III Not known 
IFN typeTyrosine phosphatases
Type I TC-PTP, PTPN1, SHP1, CD45 
Type II TC-PTP, PTPN1, SHP1, SHP2 
Type III Not known 

Other modifications of Stat activity

There has been accumulating evidence over the last decade that events unrelated to Stat phosphorylation have important regulatory roles on the functions of Stats. IFN-inducible unphosphorylated Stat1 (U-Stat1) appears to increase or maintain the expression of a subset of ISGs independently of tyrosine-phosphorylated Stat1 (46). Remarkably, this regulation can also occur by the formation of a complex with unphosphorylated Stat2 and IRF9, suggesting the existence of an unphosphorylated ISGF3 complex (8). U-Stat2 has also recently been shown to play important regulatory roles in transcriptional activation of a set of ISGs (47). Although the physiologic and pathophysiologic relevance of unphosphorylated Stat functions remain to be precisely defined, it has been suggested that some of the genes regulated by the unphosphorylated ISGF3 complex (8) may be mediators of resistance of tumor cells to DNA damage, to chemotherapy and/or radiation. Other events that appear to modulate IFN-dependent Stat activity include SUMO conjugation (48, 49) and interaction with histone deacetylases (50). A recent study demonstrated that a complex involving the ATP-binding RVB proteins (RVB1 and RVB2) is required for type I, but not type II, IFN-dependent transcription of ISGs (51). In that study, it was shown that RVB1 and RVB2 interact with the transactivation domain of STAT2 after type I IFN treatment (51), suggesting a mechanism by which their effects occur and underscoring the complexity of events required for optimal ISG transcriptional activation. It should be noted that IFN-inducible Jak–Stat signaling is tightly regulated by additional negative regulators. Beyond the factors described above, suppressors of cytokine signaling (SOCS) and protein inhibitors of activated Stats (PIAS) have been associated with negatively regulating IFN inducible Jak–Stat signaling (reviewed in ref. 52). In addition, the IFN-inducible ubiqutitin carboxyterminal hydrolase 18 (USP18)/ubiquitin-specific protease, UBP43, can displace Jak1 from the associated IFNAR2 subunit, thereby affecting Jak–Stat signaling (reviewed in ref. 52).

Map kinase pathways

Mitogen activated protein (Map) kinases control key effector pathways in cytokine signaling and play important roles in the control of various important cellular processes (9). Map kinase pathways are involved in the regulation of innate immunity (53) and have important roles in the pathophysiology of malignancies, a fact that makes them attractive therapeutic targets for the treatment of certain tumors (54). All three major classes of Map kinases (p38 MAPK, Erk, and JNK) have been shown to participate in the induction of IFN responses via distinct cellular signaling events, as outlined below.

p38 Map kinase pathways.

There is extensive evidence that the p38 Map kinase signaling pathway acts as an auxiliary cascade for Jak–Stat pathways and that its function is required for optimal transcriptional activation of ISGs (9, 18). This pathway has been shown to be engaged by the type I (9, 55–60), type II (60, 61), and type III (62) IFN receptors. The functional relevance of this signaling cascade in the type I IFN system was established some time ago, when it was demonstrated that p38 MAP kinase engagement is essential for type I IFN-dependent suppression of normal and leukemic hematopoiesis (9, 60). There is also recent evidence implicating the p38 MAPK in the induction of type I IFN-dependent antiproliferative and/or proapoptotic responses in T-cell leukemia cells (58) and primary malignant hematopoietic progenitors from patients with polycythemia vera expressing the JAK2-V617F mutation (63). Not surprisingly, as the function of the p38 MAP kinase pathway is required for IFN-inducible expression of ISG protein products, its engagement is essential for IFN responses against different viruses (9, 57, 64). However, there is also evidence for selectivity in the IFN responses controlled by the p38 MAPK, suggesting differential regulation of target genes by p38 signals. For instance, the neuroprotective effect of IFNβ against mitochondrial toxicity occurs via modulation of Stat1 activity, but it seems to be p38 MAPK independent (65).

Because of the importance of this pathway in the generation of IFN responses, extensive work has been conducted to identify the mechanisms by which its activation is regulated and to define downstream signaling effectors. The engagement of the p38 MAPK by the type I IFN receptor occurs via activation of an upstream cellular pathway that involves the Vav proto-oncogene and/or other guanine exchange factors, the small G-protein Rac1, and/or other GTPases, a yet to be defined MAPKKK and then MMK3/6 (9) (Fig. 2). Several downstream effectors of the type I IFN-activated p38 MAPK have been identified. These include the kinases MapKapK2/3 (55, 57), the nucleosomal kinase Msk1 (57), and the transcription factor ATF-2 (56). Although the precise mechanisms by which the p38 MAPK pathway regulates gene transcription in the IFN system remain to be identified, it is possible that Msk1 plays a role by modifying nuclear histone phosphorylation (9). It is also possible that the involvement of p38 MAPK in the generation of type I IFN growth inhibitory responses involves transcriptional regulation of members of gene families with growth inhibitory properties, such as Schlafen (Slfn) genes (66). Notably, malignant transformation by BCR-ABL has been shown to involve suppression of type I IFN-dependent gene transcription, via inhibition of both p38 MAPK activity and Stat-activation (67), underscoring the relevance of the p38 MAPK in immune surveillance against cancer. A novel function of the p38 MAPK was recently established by Fuchs and colleagues (68). Evidence was provided for ligand-independent PKR-like endoplasmic reticulum kinase (PERK) - mediated p38 MAPK activation that regulates priming phosphorylation of IFNAR1, facilitating ubiquitination and degradation of this receptor subunit (68).

Figure 2.

Map kinase pathways in type I IFN signaling. GEF, guanine exchange factor; RGT, regulation of gene transcription; RMT, regulation of mRNA translation; PTRGE, posttranscriptional regulation of gene expression.

Figure 2.

Map kinase pathways in type I IFN signaling. GEF, guanine exchange factor; RGT, regulation of gene transcription; RMT, regulation of mRNA translation; PTRGE, posttranscriptional regulation of gene expression.

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Although a functional p38 MAPK is required for type I IFN transcriptional activation via ISRE or GAS elements (55, 57), it does not appear to play a major role in type II IFN-induced Stat-dependent ISG transcription (57). However, the p38 MAPK pathway is activated by the type II IFN receptor and/or plays important roles in the generation of type II IFN biologic responses in several different cell types (34, 60, 61, 69). There is also evidence for what appears to be cell type–specific regulation of expression of genes required for the innate immune response (70). As the p38 MAPK is a mediator of the suppressive effects of IFNγ on normal hematopoiesis (60), its pharmacologic inhibition may be relevant in diseases in which there is overproduction of IFNγ-associated suppressed hematopoiesis. Indeed, there is evidence that inhibition of p38 MAPK activity can enhance hematopoietic progenitor colony formation in vitro from bone marrows of patients with aplastic anemia (60), anemia of chronic disease (71), and myelodysplastic syndromes (71, 72).

The roles of the p38 Map kinase in the type III IFN system is less well defined compared with the type I and II IFN systems, primarily because of the relatively recent discovery of the IFNλ family compared with other IFNs. Nevertheless, it has been shown that IFNλ induces activation of the p38 MAPK pathway and that, as is the case for type I IFN signaling, p38 activity is required for ISG transcription (62). Future studies should define the effectors of the p38 MAPK pathway in the type III IFN system and determine whether there are type III IFN-specific effectors or unique type III IFN-dependent engagement of downstream pathways. Viewed altogether, the p38 MAPK pathway plays a prominent role in signaling for all three different classes of IFNs and its function is central for the biologic effects of IFNs.

Erk kinase pathways.

There is considerable evidence that the Mek/Erk kinase pathway is also activated by IFNs. Since the original demonstration that type I IFNs activate Erk (reviewed in 9), a substantial amount of data have defined the relevance of Mek/Erk signaling to the generation of IFN responses. This activation appears to be Jak1-dependent and to involve upstream Raf1 activation (ref. 9; Fig. 2). Recent evidence reveals that type I IFN-dependent activation of Erk occurs in several different cell types, including hepatocytes (73), endometrial epithelial cells (74), gastric carcinoma cells (75) and adrenal chromaffin cells (76). Type I IFN-activated Erk has been shown to regulate phosphorylation of tyrosine hydroxylase on serine 31 (76) and to mediate IFNα-induced apoptosis (77). Importantly, a recent study demonstrated that engagement of the MEK/Erk pathway is critical for IFNα-induced phosphodiesterase 4 (PDE4) activation and repression of cAMP in Treg cells (78). This study provided evidence for a novel type I IFN-induced, Erk-mediated, function, involving inhibition of the suppressive effects of Tregs on CD4+ T cells and NK cells (78).

In addition to effects on transcriptional activation of ISGs, the Mek/Erk pathway has an important role in mRNA translation of ISGs via activation of at least two distinct effectors. One pathway involves engagement of the kinase Mnk1 and downstream phosphorylation of the eukaryotic initiation factor 4E (eIF4E; ref. 79). Although Mnk kinases can be activated downstream of either p38 MAPK or Erk in response to stress signals (80), it appears that in the type I IFN system, this activation occurs selectively downstream of the Mek/Erk, but not the p38 MAPK pathway (79). Studies using cells from mice with targeted deletion of Mnk1 and Mnk2 have established that the Mnk pathway is essential for mRNA translation of the Isg15 and Isg54 genes and that its function is required for the generation of the inhibitory effects of type I IFNs in normal hematopoietic progenitors (79). A recent study (81) showed that the Mnk pathway is an essential mediator of the antineoplastic effects of IFNα on malignant hematopoietic progenitors from patients with myeloproliferative neoplasms. The key role for Mnk in these responses (81) has provided important clues on the mechanisms by which type I IFNs generate their antitumor effects against Jak2V617F malignancies. Other studies have shown that Sprouty (Spry) proteins are stabilized/upregulated downstream of type I IFN-dependent Mnk kinases and exert negative feedback regulatory roles on the activation of the p38 MAPK and Erk kinase pathways (82). These proteins have negative regulatory roles in the generation of antiviral and antileukemic effects of type I IFNs (82). Another effector of the MEK/Erk pathway in the type I IFN system is the kinase RSK1 (83). This kinase regulates type I IFN-dependent eIF4B phosphorylation in hematopoietic cells and is required for induction of type I IFN-dependent antileukemic responses (83).

The Mek/Erk pathway is also activated during engagement of the type II IFN receptor (35, 70, 84, 85) and is required for optimal gene transcription via IFNγ-activated site (GAS) elements (35) and IFNγ-activated transcriptional elements (GATE; ref. 86). Effectors of the pathway, such as Mnk1, are also engaged downstream of MEK/Erk activation by the type I IFN receptor (87). The MEK/Erk pathway has been shown to mediate diverse responses following engagement of the type II IFN receptor, including suppressive effects on normal hematopoiesis (87), IFNγ-dependent death of oligodendroglial progenitor cells (84), and bacterial internalization by gut epithelia (85). There is also evidence that the MEK/Erk pathway is activated by the type III IFN receptor and mediates IFNλ-dependent activation of the kinase RSK1 and downstream upregulation of p21WAF1/CIP1, suggesting a mechanism for the generation of IFNλ-inducible growth inhibitory responses (88).

JNK kinase pathways.

The JNK family of Map kinases is composed of three distinct isoforms (JNK1, JNK2, and JNK3) (53). In recent years, there has been accumulating evidence that the members of this family participate directly in IFN signaling and mediate IFN biological responses. Type I IFNs have been reported to activate JNK1 (27, 56, 77), although this activation appears to be weaker than the activation of other MAPK pathways by the type I IFNR. Two reports (27, 77) have suggested a unique mechanism of activation of the JNK pathway by the type I IFN receptor, involving PKCδ-dependent activation of JNK1 (Fig. 2). This sequential activation was found to be essential for type I IFN-induced apoptosis of malignant cells (27, 77). Other studies have shown that sequential IFNα-dependent activation of PKCδ and JNK is required for IFN-induced expression of IFIT4 (89) and induction of phospholipid scramblase 1 (PLSCR1) which promotes proapoptotic and antiviral activities (26).

The JNK kinase pathway is also activated during engagement of the type II IFN receptor (70, 90, 91) and mediates important biologic and biochemical responses, including transcriptional activation of genes involved in antigen presentation (70), differentiation of neural progenitor cells (91), upregulation of B7-DC, and antitumor immunity (90). Similarly, the JNK pathway is engaged by the type III IFN receptor, albeit in a cell type–restricted manner, and appears to participate in type III IFN gene induction (62).

mTOR pathways

The ability of the mTOR pathway to regulate initiation of mRNA translation is critical for important functions in normal cells, including cell proliferation and survival, cell division and motility, lipid synthesis, glycolysis, and autophagy (92). Because of these roles in important cellular functions, dysregulation of the mTOR pathway has been implicated in the pathogenesis and/or pathophysiology of diverse diseases and syndromes, including malignancies, obesity, diabetes, neurodegenerative diseases, cognitive defects, and depression (92). As dysregulation of mTOR signaling is particularly important in promoting malignant transformation and neoplastic cell proliferation, there has been an intense interest leading to extensive efforts to target mTOR pathways for the treatment of cancer (93).

mTOR exists in at least two distinct complexes with unique elements and downstream effectors, namely mTORC1 and mTORC2 (92, 93). mTORC1 is a protein complex of mTOR with Deptor, mLST8, and Raptor, whereas the mTORC2 complex includes Deptor, mLST8, Sin1, and Rictor (refs. 92, 93; Fig. 3). mTORC1 signals are important for the initiation of mRNA translation, whereas mTORC2 is critical for the activation of survival cellular pathways via engagement of the AGC family of kinases, which include AKT, SGK, and PKCα (92, 93). mTOR pathways are activated during engagement of the type I and II IFN receptors and play important roles in mRNA translation of ISGs (9). The first evidence implicating mTOR in IFN signaling emerged about 10 years ago, when it was demonstrated that type I IFN treatment of cells results in phosphorylation/activation of the p70 S6 kinase and its downstream effector, S6 ribosomal protein, as well as the translational repressor, 4E-BP1 (94). At that time it was also shown that engagement of mTORC1-dependent signals is defective in cells with targeted disruption of the p85α and p85β regulatory subunits of the PI3K (94). In subsequent studies, evidence was also provided that mTOR pathways are activated during engagement of the type II IFN (IFNγ) receptor (95). Later studies identified upstream effectors and regulators of the mTOR pathway in the IFN system as the PI3K (96) and the AKT kinase (97). These kinases are sequentially activated in an IFN-dependent manner and act as positive upstream effectors of mTORC1 activity (96, 97) (Fig. 3). On the other hand, TSC1/2 act as negative upstream effectors of IFN-activated mTORC1 (98). Several of the downstream effectors of the mTOR pathway during engagement of the IFN receptors have been identified and their functions defined. The translational repressor 4E-BP1 is phosphorylated on multiple sites by IFN-activated mTOR, resulting in its dissociation from the eukaryotic initiation factor 4E (eIF4E), to allow for initiation of cap-dependent mRNA translation (94, 98). Induction of expression of type I and II IFN-inducible proteins and IFN antiviral responses are enhanced in cells with targeted disruption of the 4e-bp1 gene (98). Other studies have shown a key role for the S6K effector, eIF4B, in the generation of IFN responses (83). IFN-dependent phosphorylation of eIF4B promotes the interaction of the protein with eIF3A (p170/eIF3A) and results in increased associated ATPase activity (83). In addition, the IFN-activated form of S6K was shown to phosphorylate the tumor suppressor protein, programmed cell death 4 (PDCD4), on Ser67, resulting in the interaction of PDCD4 with the ubiquitin ligase β-TRCP (β-transducin repeat-containing protein) and its subsequent degradation (99). This degradation of PDCD4 results in increased IFN-induced eukaryotic translation initiation factor 4A (eIF4A) activity and binding to translation initiation factor eIF4G and increased cap-dependent translation (99). Other studies have shown that mTORC2 complexes are engaged by the type I IFN receptor and regulate expression of ISGs (100). Remarkably, these complexes appear to selectively regulate an Akt/mTORC1 axis in response to engagement by the type I IFN receptor, but not in response to growth factor receptors or oncogenic signals, suggesting the existence of an IFN-specific mTORC2/mTORC1 modification and function (100). Altogether, the mTOR pathway exerts important roles in type I IFN-dependent responses (96–98, 101, 102) and antineoplastic effects (77). Importantly, the mTOR pathway is also required for type I IFN production by plasmacytoid dendritic cells (103), suggesting the existence of a positive feedback regulatory loop for the induction of IFN responses. There is also some evidence for engagement of mTOR by the type III IFN receptor (10), suggesting important roles for this signaling cascade in responses to each of the IFN types.

Figure 3.

mTOR pathways in type I IFN signaling. ISP, signals regulating transcription independent of Stat pathways; STP, Stat pathways.

Figure 3.

mTOR pathways in type I IFN signaling. ISP, signals regulating transcription independent of Stat pathways; STP, Stat pathways.

Close modal

miRNAs and the IFN response

IFN-inducible JAK–STAT, MAPK, and mTOR signaling cascades are also regulated potentially by microRNAs (miRs). miRs are important regulators of post-transcriptional events, leading to inhibition of mRNA translation or mRNA degradation (104). In recent years, it has become apparent that the direct regulation of STAT activity by mIRs has profound effects on consequent gene expression, specifically in the context of cytokine-inducible events (105). Pertinent for this review of IFN-inducible STAT activation, miR145, miR146A, and miR221/222 target STAT1 and miR221/222 target STAT2 (105). Numerous studies describe different miRs that target STAT3: miR17, miR17-5p, mIR17-3p, mIR18a, miR19b, mIR92-1, miR20b, Let7a, miR106a, miR106-25, miR106a-362, and miR125b (ref. 105; Fig. 4). miR132, miR212, and miR200a have been implicated in negatively regulating STAT4 expression in human NK cells (106) and miR222 has been shown to regulate STAT5 expression (107). In addition, JAK–STAT signaling is affected by miR targeting of suppressors of cytokine signaling (SOCS) proteins. miR122 and miR155 targeting of SOCS1 releases the inhibition of STAT1 (and STAT5a/b; refs. 108–110), and miR19a regulation of SOCS1 and SOCS3 effectively prolongs activation of both STAT1 and STAT3 (111). There is also evidence that miR155 targets the inositol phosphatase SHIP1, effectively prolonging/inducing IFNγ expression (112). Much of the evidence associated with miRs prolonging JAK–STAT activation relates to cancer studies, where tumor-secreted miRs promote cell migration and angiogenesis by prolonging JAK–STAT activation (113). miR145 targeting of SOCS7 affects nuclear translocation of STAT3 and has been associated with enhanced IFNβ production (114). Beyond inhibition of SOCS proteins, miRs may influence the expression of other inhibitory factors associated with JAK–STAT signaling, and miR301a and miR18a have been shown to inhibit PIAS3, a negative regulator of STAT3 activation (115). There is also the potential for STATS to directly regulate miR gene expression. STAT5 suppresses expression of miR15/16 (116) and there is evidence that there are potential STAT3 binding sites in the promoters of about 200 miRs (117). Viewed altogether, there is compelling evidence for miR–STAT interactions, yet few studies have considered the contributions of miRs to IFN-inducible JAK–STAT signaling.

Figure 4.

Targeting and regulation of various proteins known to be involved in IFN signaling by different miRNAs.

Figure 4.

Targeting and regulation of various proteins known to be involved in IFN signaling by different miRNAs.

Close modal

Given the accumulating evidence for a miR network that regulates JAK–STAT activation, additional miR networks that directly contribute to signaling output and biologic responses induced by the different IFNs, associated with the other IFN signaling cascades, must operate. Analogous to miR networks that may affect IFN-inducible JAK–STAT signaling, there is a paucity of direct data linking miRs to IFN-inducible mTOR or MAPK signaling cascades. As above, we will identify miRs that potentially may interact with IFN-inducible signaling effectors. A number of studies have focused on miR inhibition of PI3K/mTOR signaling. Similar to investigations related to miR interactions with STATs, the majority of the miR-PI3K/mTOR studies have been conducted in the context of cancers. The catalytic subunit of PI3K, p110, is the target of miR124 (118). mTOR is a direct target for miR199a, miR99a, miR144, miR100, miR520c, and miR373 (refs. 119–122; Fig. 4). When considering MAPK signaling, studies reveal that miR124 targets and miR128 suppress p38a transcripts (123). Moreover, there is some evidence that IFN-β inducible miR431 targets intermediates in the MAPK pathway in cells sensitive to its growth inhibitory effects (124).

Not surprisingly, miRs have been identified that target IFNs and IFN-inducible genes. The expression of multiple IFNα species can be directly inhibited by miR466I, through their 3′ untranslated region (125). miR22, associated with the transition from cell quiescence to proliferation, suppresses type I IFN gene expression by targeting high mobility group box-1 and IRF5, preventing IRF3 and NFκB activation (126). This effectively blocks the antiproliferative response of type I IFNs. miR203, an IFN-inducible miR, targets IFIT1, effectively providing an inhibitory feedback loop following IFN gene activation (127). miR548 targets the 3′ untranslated region of IFNλ1, affecting IFNλ1 expression and the expression of a number of ISGs, including the human MxA protein and 2′5′-oligoadenylate synthetase-1 (OAS1; ref. 128). SOCS1 targeting by miR122 in liver Huh7 cells significantly increases type I IFN expression (108). miR29 targets IFNγ mRNA and the transcription factors T-bet and Eomes, inhibiting IFNγ production (129, 130). In addition, using miR databases, at least 17 miRs have been identified that potentially target IFNγ, including miR29 (131). Undeniably, the contributions of miRs to an IFN response are profound, contextual, and involve a network of interactions, affecting both the production of IFNs and the sustainability of the signaling responses they invoke.

Evolution of our understanding of IFN signals and future perspectives

A substantial amount of knowledge has accumulated since the original discovery of the Jak–Stat pathway in the early 1990s. It is now clear that several key signaling cascades are essential for the induction of type I, II, and III IFN responses. The original view that IFN signals can be transmitted from the cell surface to the nucleus in two simple steps involving tyrosine phosphorylation of Stat proteins (8) now appears somewhat simplistic, as it has been established that modifications of Jak–Stat signals by other pathways and/or simultaneous engagement of other essential complementary cellular cascades is essential for induction of ISG transcriptional activation, mRNA translation, protein expression, and subsequent induction of IFN responses. Such pathways include PKC and MAP kinase pathways and mTORC1 and mTORC2-dependent signaling cascades.

Over the next decade, our understanding of the mechanisms by which IFN signals are induced will likely continue to evolve, with the anticipated outcome that it will be possible exploit this new knowledge for translational therapeutic purposes. For instance, selective targeting of kinase elements of the IFN pathway with kinase inhibitors may be useful in the treatment of autoimmune diseases where dysregulated/excessive type I IFN production contributes to the pathophysiology of disease. On the other hand, efforts to promote the induction of specific IFN signals, may lead to novel, less toxic, therapeutic interventions for a variety of viral infectious diseases and neoplastic disorders.

No potential conflicts of interest were disclosed.

1.
Borden
EC
,
Sen
GC
,
Uze
G
,
Silverman
RH
,
Ransohoff
RM
,
Foster
GR
, et al
Interferons at age 50: past, current and future impact on biomedicine
.
Nat Rev Drug Discov
2007
;
6
:
975
90
.
2.
Hofmann
WP
,
Zeuzem
S
. 
A new standard of care for the treatment of chronic HCV infection
.
Nat Rev Gastroenterol Hepatol
2011
;
8
:
257
64
.
3.
Rönnblom
L
,
Eloranta
ML
. 
The interferon signature in autoimmune diseases
.
Curr Opin Rheumatol
2013
;
25
:
248
53
.
4.
Wahren-Herlenius
M
,
Dörner
T
. 
Immunopathogenic mechanisms of systemic autoimmune disease
.
Lancet
2013
;
382
:
819
31
.
5.
Baechler
EC
,
Bilgic
H
,
Reed
AM
. 
Type I interferon pathway in adult and juvenile dermatomyositis
.
Arthritis Res Ther
2011
;
13
:
249
.
6.
Young
NS
,
Calado
RT
,
Scheinberg
P
. 
Current concepts in the pathophysiology and treatment of aplastic anemia
.
Blood
2006
;
108
:
2509
19
.
7.
Teles
RM
,
Graeber
TG
,
Krutzik
SR
,
Montoya
D
,
Schenk
M
,
Lee
DJ
, et al
Type I interferon suppresses type II interferon-triggered human anti-mycobacterial responses
.
Science
2013
;
339
:
1448
53
.
8.
Stark
GR
,
Darnell
JE
 Jr
. 
The JAK-STAT pathway at twenty
.
Immunity
2012
;
36
:
503
14
.
9.
Platanias
LC
. 
Mechanisms of type-I- and type-II-interferon-mediated signalling
.
Nat Rev Immunol
2005
;
5
:
375
86
.
10.
Kotenko
SV
. 
IFN-λs
.
Curr Opin Immunol
2011
;
23
:
583
90
.
11.
Kaur
S
,
Platanias
LC
. 
IFNβ-specific signaling via a unique IFNAR1 interaction
.
Nat Immunol
2013
;
14
:
884
5
.
12.
de Weerd
NA
,
Vivian
JP
,
Nguyen
TK
,
Mangan
NE
,
Gould
JA
,
Braniff
SJ
, et al
Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1
.
Nat Immunol
2013
;
14
:
901
7
.
13.
Pott
J
,
Mahlakõiv
T
,
Mordstein
M
,
Duerr
CU
,
Michiels
T
,
Stockinger
S
, et al
IFN-{lambda} determines the intestinal epithelial antiviral host defense
.
Proc Natl Acad Sci USA
2011
;
108
:
7944
9
.
14.
Wong
VW
,
Sung
JJ
. 
Diagnosis and personalized management of hepatitis B including significance of genotypes
.
Curr Opin Infect Dis
2012
;
25
:
570
7
.
15.
González-Navajas
JM
,
Lee
J
,
David
M
,
Raz
E
. 
Immunomodulatory functions of type I interferons
.
Nat Rev Immunol
2012
;
12
:
125
35
.
16.
Stauffer Larsen
T
,
Iversen
KF
,
Hansen
E
,
Mathiasen
AB
,
Marcher
C
,
Frederiksen
M
, et al
Long term molecular responses in a cohort of Danish patients with essential thrombocythemia, polycythemia vera and myelofibrosis treated with recombinant interferon alpha
.
Leuk Res
2013
;
37
:
1041
5
.
17.
Kaufman
HL
,
Kirkwood
JM
,
Hodi
FS
,
Agarwala
S
,
Amatruda
T
,
Bines
SD
,
Clark
JI
, et al
The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma
.
Nat Rev Clin Oncol
2013
;
10
:
588
98
.
18.
Platanias
LC
. 
Map kinase signaling pathways and hematologic malignancies
.
Blood
2003
;
101
:
4667
79
.
19.
Killestein
J
,
Polman
CH
. 
Determinants of interferon β efficacy in patients with multiple sclerosis
.
Nat Rev Neurol
2011
;
7
:
221
8
.
20.
Rice
GI
,
Kasher
PR
,
Forte
GM
,
Mannion
NM
,
Greenwood
SM
,
Szynkiewicz
M
, et al
Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature
.
Nat Genet
2012
;
44
:
1243
8
.
21.
Hall
JC
,
Rosen
A
. 
Type I interferons: crucial participants in disease amplification in autoimmunity
.
Nat Rev Rheumatol
2010
;
6
:
40
9
.
22.
Begitt
A
,
Droescher
M
,
Meyer
T
,
Schmid
CD
,
Baker
M
,
Antunes
F
, et al
STAT1 cooperative DNA binding distinguishes between type-1 and type-2 interferon signaling
.
Nat Immunol
2014
;
15
:
168
76
.
23.
Sadzak
I
,
Schiff
M
,
Gattermeier
I
,
Glinitzer
R
,
Sauer
I
,
Saalmüller
A
, et al
Recruitment of Stat1 to chromatin is required for interferon-induced serine phosphorylation of Stat1 transactivation domain
.
Proc Natl Acad Sci USA
2008
;
105
:
8944
9
.
24.
Uddin
S
,
Sassano
A
,
Deb
DK
,
Verma
A
,
Majchrzak
B
,
Rahman
A
, et al
Protein kinase C-δ (PKC-δ) is activated by type I interferons and mediates phosphorylation of Stat1 on serine 727
.
J Biol Chem
2002
;
277
:
14408
16
.
25.
Kaur
S
,
Parmar
S
,
Smith
J
,
Katsoulidis
E
,
Li
Y
,
Sassano
A
, et al
Role of protein kinase C-delta (PKC-delta) in the generation of the effects of IFN-alpha in chronic myelogenous leukemia cells
.
Exp Hematol
2005
;
33
:
550
7
.
26.
Zhao
KW
,
Li
D
,
Zhao
Q
,
Huang
Y
,
Silverman
RH
,
Sims
PJ
, et al
Interferon-alpha-induced expression of phospholipid scramblase 1 through STAT1 requires the sequential activation of protein kinase Cdelta and JNK
.
J Biol Chem
2005
;
280
:
42707
14
.
27.
Yanase
N
,
Hayashida
M
,
Kanetaka-Naka
Y
,
Hoshika
A
,
Mizuguchi
J
. 
PKC-δ mediates interferon-α-induced apoptosis through c-Jun NH2-terminal kinase activation
.
BMC Cell Biol
2012
;
13
:
7
.
28.
Chen
J
,
Wu
M
,
Zhang
X
,
Zhang
W
,
Zhang
Z
,
Chen
L
, et al
Hepatitis B virus polymerase impairs interferon-α-induced STAT activation through inhibition of importin-α5 and protein kinase C-δ
.
Hepatology
2013
;
57
:
470
82
.
29.
Hald
A
,
Andrés
RM
,
Salskov-Iversen
ML
,
Kjellerup
RB
,
Iversen
L
,
Johansen
C
. 
STAT1 expression and activation is increased in lesional psoriatic skin
.
Br J Dermatol
2013
;
168
:
302
10
.
30.
Deb
DK
,
Sassano
A
,
Lekmine
F
,
Majchrzak
B
,
Verma
A
,
Kambhampati
S
, et al
Activation of protein kinase C δ by IFN-γ
.
J Immunol
2003
;
171
:
267
73
.
31.
Kwon
MJ
,
Yao
Y
,
Walter
MJ
,
Holtzman
MJ
,
Chang
CH
. 
Role of PKCdelta in IFN-gamma-inducible CIITA gene expression
.
Mol Immunol
2007
;
44
:
2841
9
.
32.
Nair
JS
,
DaFonseca
CJ
,
Tjernberg
A
,
Sun
W
,
Darnell
JE
Jr,
Chait
BT
, et al
Requirement of Ca2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-γ
.
Proc Natl Acad Sci USA
2002
;
99
:
5971
6
.
33.
Choudhury
GG
. 
A linear signal transduction pathway involving phosphatidylinositol 3-kinase, protein kinase C-ϵ, and MAPK in mesangial cells regulates interferon-γ-induced STAT1α transcriptional activation
.
J Biol Chem
2004
;
279
:
27399
409
.
34.
Hardy
PO
,
Diallo
TO
,
Matte
C
,
Descoteaux
A
. 
Roles of phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase in the regulation of protein kinase C-alpha activation in interferon-gamma-stimulated macrophages
.
Immunology
2009
;
128
(
1 Suppl
):
e652
60
.
35.
Li
N
,
McLaren
JE
,
Michael
DR
,
Clement
M
,
Fielding
CA
,
Ramji
DP
. 
ERK is integral to the IFN-γ-mediated activation of STAT1:the expression of key genes implicated in atherosclerosis, and the uptake of modified lipoproteins by human macrophages
.
J Immunol
2010
;
185
:
3041
8
.
36.
Bancerek
J
,
Poss
ZC
,
Steinparzer
I
,
Sedlyarov
V
,
Pfaffenwimmer
T
,
Mikulic
I
, et al
CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response
.
Immunity
2013
;
38
:
250
62
.
37.
Tenoever
BR
,
Ng
SL
,
Chua
MA
,
McWhirter
SM
,
García-Sastre
A
,
Maniatis
T
. 
Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity
.
Science
2007
;
315
:
1274
8
.
38.
Nishiyama-Fujita
Y
,
Shimizu
T
,
Sagawa
M
,
Uchida
H
,
Kizaki
M
. 
The role of TC-PTP (PTPN2) in modulating sensitivity to imatinib and interferon-α in CML cell line, KT-1 cells
.
Leuk Res
2013
;
37
:
1150
5
.
39.
Chen
Z
,
Sun
X
,
Shen
S
,
Zhang
H
,
Ma
X
,
Liu
J
, et al
Wedelolactone, a naturally occurring coumestan, enhances interferon-γ signaling through inhibiting STAT1 protein dephosphorylation
.
J Biol Chem
2013
;
288
:
14417
27
.
40.
Yetter
A
,
Uddin
S
,
Krolewski
JJ
,
Jiao
H
,
Yi
T
,
Platanias
LC
. 
Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase
.
J Biol Chem
1995
;
270
:
18179
82
.
41.
Kim
JH
,
Choi
DJ
,
Jeong
HK
,
Kim
J
,
Kim
DW
,
Choi
SY
, et al
DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1:in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1
.
Neurobiol Dis
2013
;
60
:
1
10
.
42.
Wu
X
,
Guo
W
,
Wu
L
,
Gu
Y
,
Gu
L
,
Xu
S
, et al
Selective sequestration of STAT1 in the cytoplasm via phosphorylated SHP-2 ameliorates murine experimental colitis
.
J Immunol
2012
;
189
:
3497
507
.
43.
García-Ruiz
I
,
Solís-Muñoz
P
,
Gómez-Izquierdo
E
,
Muñoz-Yagüe
MT
,
Valverde
AM
,
Solís-Herruzo
JA
. 
Protein-tyrosine phosphatases are involved in interferon resistance associated with insulin resistance in HepG2 cells and obese mice
.
J Biol Chem
2012
;
287
:
19564
73
.
44.
Heinonen
KM
,
Bourdeau
A
,
Doody
KM
,
Tremblay
ML
. 
Protein tyrosine phosphatases PTP-1B and TC-PTP play nonredundant roles in macrophage development and IFN-gamma signaling
.
Proc Natl Acad Sci USA
2009
;
106
:
9368
72
.
45.
Porcu
M
,
Kleppe
M
,
Gianfelici
V
,
Geerdens
E
,
DeKeersmaecker
K
,
Tartaglia
M
, et al
Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia
.
Blood
2012
;
119
:
4476
9
.
46.
Cheon
H
,
Stark
GR
. 
Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes
.
Proc Natl Acad Sci USA
2009
;
106
:
9373
8
.
47.
Testoni
B
,
Völlenkle
C
,
Guerrieri
F
,
Gerbal-Chaloin
S
,
Blandino
G
,
Levrero
M
. 
Chromatin dynamics of gene activation and repression in response to interferon alpha (IFNα) reveal new roles for phosphorylated and unphosphorylated forms of the transcription factor STAT2
.
J Biol Chem
2011
;
286
:
20217
27
.
48.
Tahk
S
,
Liu
B
,
Chernishof
V
,
Wong
KA
,
Wu
H
,
Shuai
K
. 
Control of specificity and magnitude of NF-kappa B and STAT1-mediated gene activation through PIASy and PIAS1 cooperation
.
Proc Natl Acad Sci USA
2007
;
104
:
11643
8
.
49.
Begitt
A
,
Droescher
M
,
Knobeloch
KP
,
Vinkemeier
U
. 
SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ
.
Blood
2011
;
118
:
1002
7
.
50.
Au-Yeung
N
,
Mandhana
R
,
Horvath
CM
. 
Transcriptional regulation by STAT1 and STAT2 in the interferon JAK-STAT pathway
.
JAKSTAT
2013
;
2
:
e23931
.
51.
Gnatovskiy
L
,
Mita
P
,
Levy
DE
. 
The human RVB complex is required for efficient transcription of type I interferon-stimulated genes
.
Mol Cell Biol
2013
;
33
:
3817
25
.
52.
Ivashkiv
LB
,
Donlin
LT
. 
Regulation of type I interferon responses
.
Nature Rev Immunol
2014
;
14
:
36
49
.
53.
Arthur
JS
,
Ley
SC
. 
Mitogen-activated protein kinases in innate immunity
.
Nat Rev Immunol
2013
;
13
:
679
92
.
54.
Wagner
EF
,
Nebreda
AR
. 
Signal integration by JNK and p38 MAPK pathways in cancer development
.
Nat Rev Cancer
2009
;
9
:
537
49
.
55.
Uddin
S
,
Majchrzak
B
,
Woodson
J
,
Arunkumar
P
,
Alsayed
Y
,
Pine
R
, et al
Activation of the p38 Map kinase by type I interferons
.
J Biol Chem
1999
;
274
:
30127
31
.
56.
Zhao
LJ
,
Hua
X
,
He
SF
,
Ren
H
,
Qi
ZT
. 
Interferon alpha regulates MAPK and STAT1 pathways in human hepatoma cells
.
Virol J
2011
;
8
:
157
.
57.
Li
Y
,
Sassano
A
,
Majchrzak
B
,
Deb
DK
,
Levy
DE
,
Gaestel
M
, et al
Role of p38alpha Map kinase in Type I interferon signaling
.
J Biol Chem
2004
;
279
:
970
9
.
58.
Lee
WH
,
Liu
FH
,
Lee
YL
,
Huang
HM
. 
Interferon-alpha induces the growth inhibition of human T-cell leukaemia line Jurkat through p38alpha and p38beta
.
J Biochem
2010
;
147
:
645
50
.
59.
Verma
A
,
Deb
DK
,
Sassano
A
,
Uddin
S
,
Varga
J
,
Wickrema
A
, et al
Activation of the p38 mitogen-activated protein kinase mediates the suppressive effects of type I interferons and transforming growth factor-beta on normal hematopoiesis
.
J Biol Chem
2002
;
277
:
7726
35
.
60.
Verma
A
,
Deb
DK
,
Sassano
A
,
Kambhampati
S
,
Wickrema
A
,
Uddin
S
, et al
Cutting edge: activation of the p38 mitogen-activated protein kinase signaling pathway mediates cytokine-induced hemopoietic suppression in aplastic anemia
.
J Immunol
2002
;
168
:
5984
8
.
61.
Matsuzawa
T
,
Kim
BH
,
Shenoy
AR
,
Kamitani
S
,
Miyake
M
,
Macmicking
JD
. 
IFN-γ elicits macrophage autophagy via the p38 MAPK signaling pathway
.
J Immunol
2012
;
189
:
813
8
.
62.
Zhou
Z
,
Hamming
OJ
,
Ank
N
,
Paludan
SR
,
Nielsen
AL
,
Hartmann
R
. 
Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases
.
J Virol
2007
;
81
:
7749
58
.
63.
Lu
M
,
Zhang
W
,
Li
Y
,
Berenzon
D
,
Wang
X
,
Wang
J
, et al
Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway
.
Exp Hematol
2010
;
38
:
472
80
.
64.
Zorzitto
J
,
Galligan
CL
,
Ueng
JJ
,
Fish
EN
. 
Characterization of the antiviral effects of interferon-alpha against a SARS-like coronoavirus infection in vitro
.
Cell Res
2006
;
16
:
220
9
.
65.
Di Filippo
M
,
Tozzi
A
,
Tantucci
M
,
Arcangeli
S
,
Chiasserini
D
,
Ghiglieri
V
, et al
Interferon-β1a protects neurons against mitochondrial toxicity via modulation of STAT1 signaling: Electrophysiological evidence
.
Neurobiol Dis
2013
;
pii
:
S0969
9961
;
00281–7
.
66.
Katsoulidis
E
,
Carayol
N
,
Woodard
J
,
Konieczna
I
,
Majchrzak-Kita
B
,
Jordan
A
, et al
Role of Schlafen 2 (SLFN2) in the generation of interferon alpha-induced growth inhibitory responses
.
J Biol Chem
2009
;
284
:
25051
64
.
67.
Katsoulidis
E
,
Sassano
A
,
Majchrzak-Kita
B
,
Carayol
N
,
Yoon
P
,
Jordan
A
, et al
Suppression of interferon (IFN)-inducible genes and IFN-mediated functional responses in BCR-ABL-expressing cells
.
J Biol Chem
2008
;
283
:
10793
803
.
68.
Bhattacharya
S
,
Qian
J
,
Tzimas
C
,
Baker
DP
,
Koumenis
C
,
Diehl
JA
, et al
Role of p38 protein kinase in the ligand-independent ubiquitination and down-regulation of the IFNAR1 chain of type I interferon receptor
.
J Biol Chem
2011
;
286
:
22069
76
.
69.
Seo
JY
,
Kim
DY
,
Lee
YS
,
Ro
JY
. 
Cytokine production through PKC/p38 signaling pathways, not through JAK/STAT1 pathway, in mast cells stimulated with IFNg
.
Cytokine
2009
;
46
:
51
60
.
70.
Valledor
AF
,
Sánchez-Tilló
E
,
Arpa
L
,
Park
JM
,
Caelles
C
,
Lloberas
J
, et al
Selective roles of MAPKs during the macrophage response to IFN-gamma
.
J Immunol
2008
;
180
:
4523
9
.
71.
Katsoulidis
E
,
Li
Y
,
Yoon
P
,
Sassano
A
,
Altman
J
,
Kannan-Thulasiraman
P
,
Balasubramanian
L
, et al
Role of the p38 mitogen-activated protein kinase pathway in cytokine-mediated hematopoietic suppression in myelodysplastic syndromes
.
Cancer Res
2005
;
65
:
9029
37
.
72.
Navas
TA
,
Mohindru
M
,
Estes
M
,
Ma
JY
,
Sokol
L
,
Pahanish
P
, et al
Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors
.
Blood
2006
;
108
:
4170
7
.
73.
Chai
Y
,
Huang
HL
,
Hu
DJ
,
Luo
X
,
Tao
QS
,
Zhang
XL
, et al
IL-29 and IFN-α regulate the expression of MxA, 2′,5′-OAS and PKR genes in association with the activation of Raf-MEK-ERK and PI3K-AKT signal pathways in HepG2.2.15 cells
.
Mol Biol Rep
2011
;
38
:
139
43
.
74.
Banu
SK
,
Lee
J
,
Stephen
SD
,
Nithy
TK
,
Arosh
JA
. 
Interferon tau regulates PGF2alpha release from the ovine endometrial epithelial cells via activation of novel JAK/EGFR/ERK/EGR-1 pathways
.
Mol Endocrinol
2010
;
24
:
2315
30
.
75.
Qu
J
,
Zhao
M
,
Teng
Y
,
Zhang
Y
,
Hou
K
,
Jiang
Y
, et al
Interferon-α sensitizes human gastric cancer cells to TRAIL-induced apoptosis via activation of the c-CBL-dependent MAPK/ERK pathway
.
Cancer Biol Ther
2011
;
12
:
494
502
.
76.
Douglas
SA
,
Bunn
SJ
. 
Interferon-alpha signalling in bovine adrenal chromaffin cells: Involvement of signal-transducer and activator of transcription 1 and 2, extracellular signal-regulated protein kinases 1/2 and serine 31 phosphorylation of tyrosine hydroxylase
.
J Neuroendocrinol
2009
;
21
:
200
7
.
77.
Panaretakis
T
,
Hjortsberg
L
,
Tamm
KP
,
Björklund
AC
,
Joseph
B
,
Grandér
D
. 
Interferon alpha induces nucleus-independent apoptosis by activating extracellular signal-regulated kinase 1/2 and c-Jun NH2-terminal kinase downstream of phosphatidylinositol 3-kinase and mammalian target of rapamycin
.
Mol Biol Cell
2008
;
19
:
41
50
.
78.
Bacher
N
,
Raker
V
,
Hofmann
C
,
Graulich
E
,
Schwenk
M
,
Baumgrass
R
, et al
Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells
.
Cancer Res
2013
;
73
:
5647
56
.
79.
Joshi
S
,
Kaur
S
,
Redig
AJ
,
Goldsborough
K
,
David
K
,
Ueda
T
, et al
Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses
.
Proc Natl Acad Sci USA
2009
;
106
:
12097
102
.
80.
Joshi
S
,
Platanias
LC
. 
Mnk kinases in cytokine signaling and regulation of cytokine responses
.
Biomol Concepts
2012
;
3
:
127
39
.
81.
Mehrotra
S
,
Sharma
B
,
Joshi
S
,
Kroczynska
B
,
Majchrzak
B
,
Stein
BL
, et al
Essential role for the Mnk pathway in the inhibitory effects of type I interferons on myeloproliferative neoplasm (MPN) precursors
.
J Biol Chem
2013
;
288
:
23814
22
.
82.
Sharma
B
,
Joshi
S
,
Sassano
A
,
Majchrzak
B
,
Kaur
S
,
Aggarwal
P
, et al
Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses
.
J Biol Chem
2012
;
287
:
42352
60
.
83.
Kroczynska
B
,
Kaur
S
,
Katsoulidis
E
,
Majchrzak-Kita
B
,
Sassano
A
,
Kozma
SC
, et al
Interferon-dependent engagement of eukaryotic initiation factor 4B via S6 kinase (S6K)- and ribosomal protein S6K-mediated signals
.
Mol Cell Biol
2009
;
29
:
2865
75
.
84.
Horiuchi
M
,
Itoh
A
,
Pleasure
D
,
Itoh
T
. 
MEK-ERK signaling is involved in interferon-gamma-induced death of oligodendroglial progenitor cells
.
J Biol Chem
2006
;
281
:
20095
106
.
85.
Smyth
D
,
McKay
CM
,
Gulbransen
BD
,
Phan
VC
,
Wang
A
,
McKay
DM
. 
Interferon-gamma signals via an ERK1/2-ARF6 pathway to promote bacterial internalization by gut epithelia
.
Cell Microbiol
2012
;
14
:
1257
70
.
86.
Roy
SK
,
Hu
J
,
Meng
Q
,
Xia
Y
,
Shapiro
PS
,
Reddy
SP
, et al
MEKK1 plays a critical role in activating the transcription factor C/EBP-β-dependent gene expression in response to IFN-γ
.
Proc Natl Acad Sci USA
2002
;
99
:
7945
50
.
87.
Joshi
S
,
Sharma
B
,
Kaur
S
,
Majchrzak
B
,
Ueda
T
,
Fukunaga
R
, et al
Essential role for Mnk kinases in type II interferon (IFNgamma) signaling and its suppressive effects on normal hematopoiesis
.
J Biol Chem
2011
;
286
:
6017
26
.
88.
Kroczynska
B
,
Joshi
S
,
Eklund
EA
,
Verma
A
,
Kotenko
SV
,
Fish
EN
, et al
Regulatory effects of ribosomal S6 kinase 1 (RSK1) in IFNλ signaling
.
J Biol Chem
2011
;
286
:
1147
56
.
89.
Huang
X
,
Shen
N
,
Bao
C
,
Gu
Y
,
Wu
L
,
Chen
S
. 
Interferon-induced protein IFIT4 is associated with systemic lupus erythematosus and promotes differentiation of monocytes into dendritic cell-like cells
.
Arthritis Res Ther
2008
;
10
:
R91
.
90.
Deng
J
,
Qian
Y
,
Geng
L
,
Xie
H
,
Wang
Y
,
Jiang
G
, et al
Involvement of ERK and JNK pathways in IFN-γ-induced B7-DC expression on tumor cells
.
J Cancer Res Clin Oncol
2011
;
137
:
243
50
.
91.
Kim
SJ
,
Qian
Y
,
Geng
L
,
Xie
H
,
Wang
Y
,
Jiang
G
, et al
Interferon-gamma promotes differentiation of neural progenitor cells via the JNK pathway
.
Neurochem Res
2007
;
32
:
1399
406
.
92.
Laplante
M
,
Sabatini
DM
. 
mTOR signaling in growth control and disease
.
Cell
2012
;
149
:
274
93
.
93.
Benjamin
D
,
Colombi
M
,
Moroni
C
,
Hall
MN
. 
Rapamycin passes the torch: a new generation of mTOR inhibitors
.
Nat Rev Drug Discov
2011
;
10
:
868
80
.
94.
Lekmine
F
,
Uddin
S
,
Sassano
A
,
Parmar
S
,
Brachmann
SM
,
Majchrzak
B
, et al
Activation of the p70 S6 kinase and phosphorylation of the 4E-BP1 repressor of mRNA translation by type I interferons
.
J Biol Chem
2003
;
278
:
27772
80
.
95.
Lekmine
F
,
Sassano
A
,
Uddin
S
,
Smith
J
,
Majchrzak
B
,
Brachmann
SM
, et al
Interferon-gamma engages the p70 S6 kinase to regulate phosphorylation of the 40S S6 ribosomal protein
.
Exp Cell Res
2004
;
295
:
173
82
.
96.
Kaur
S
,
Sassano
A
,
Joseph
AM
,
Majchrzak-Kita
B
,
Eklund
EA
,
Verma
A
, et al
Dual regulatory roles of phosphatidylinositol 3-kinase in IFN signaling
.
J Immunol
2008
;
181
:
7316
23
.
97.
Kaur
S
,
Sassano
A
,
Dolniak
B
,
Joshi
S
,
Majchrzak-Kita
B
,
Baker
DP
, et al
Sassano A, Dolniak B, Joshi S, Majchrzak-Kita B, Baker DP, Role of the Akt pathway in mRNA translation of interferon-stimulated genes
.
Proc Natl Acad Sci USA
2008
;
105
:
4808
13
.
98.
Kaur
S
,
Lal
L
,
Sassano
A
,
Majchrzak-Kita
B
,
Srikanth
M
,
Baker
DP
, et al
Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling
.
J Biol Chem
2007
;
282
:
1757
68
.
99.
Kroczynska
B
,
Sharma
B
,
Eklund
EA
,
Fish
EN
,
Platanias
LC
. 
Regulatory effects of programmed cell death 4 (PDCD4) protein in interferon (IFN)-stimulated gene expression and generation of type I IFN responses
.
Mol Cell Biol
2012
;
32
:
2809
22
.
100.
Kaur
S
,
Sassano
A
,
Majchrzak-Kita
B
,
Baker
DP
,
Su
B
,
Fish
EN
, et al
Regulatory effects of mTORC2 complexes in type I IFN signaling and in the generation of IFN responses
.
Proc Natl Acad Sci USA
2012
;
109
:
7723
8
.
101.
Matsumoto
A
,
Ichikawa
T
,
Nakao
K
,
Miyaaki
H
,
Hirano
K
,
Fujimito
M
, et al
Interferon-alpha-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway
.
J Gastroenterol
2009
;
44
:
856
63
.
102.
Burke
JD
,
Sonenberg
N
,
Platanias
LC
,
Fish
EN
. 
Antiviral effects of interferon-β are enhanced in the absence of the translational suppressor 4E-BP1 in myocarditis induced by Coxsackievirus B3
.
Antivir Ther
2011
;
16
:
577
84
.
103.
Cao
W
,
Manicassamy
S
,
Tang
H
,
Kasturi
SP
,
Pirani
A
,
Murthy
N
, et al
Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway
.
Nat Immunol
2008
;
9
:
1157
64
.
104.
Kim
VN
. 
MicroRNA biogenesis: coordinated cropping and dicing
.
Nat Rev Mol Cell Biol
2005
;
6
:
376
85
.
105.
Kohanbash
G
,
Okada
H
. 
MicoRNAs and STAT interplay
.
Semin Cancer Biol
2012
;
22
:
70
5
.
106.
Huang
Y
,
Lei
Y
,
Zhang
H
,
Hou
L
,
Zhang
M
,
Dayton
AI
. 
MicroRNA regulation of STAT4 protein expression: rapid and sensitive modulation of IL-12 signaling in human natural killer cells
.
Blood
2011
;
118
:
6793
802
.
107.
Dentelli
P
,
Rosso
A
,
Orso
F
,
Olgasi
C
,
Taverna
D
,
Brizzi
MF
. 
microRNA-222 controls neovascularization by regulating signal transducer and activator of transcription 5A expression
.
Arterioscler Thromb Vasc Biol
2010
;
30
:
1562
8
.
108.
Li
A
,
Song
W
,
Qian
J
,
Li
Y
,
He
J
,
Zhang
Q
, et al
MiR-122 modulates type I interferon expression through locking suppressor of cytokine signaling 1
.
Int J Biochem Cell Biol
2013
;
45
:
856
65
.
109.
Su
C
,
Hou
Z
,
Zhang
C
,
Tian
Z
,
Zhang
J
. 
Ectopic expression of microRNA-155 enhances innate antiviral immunity against HBV infection in human hepatoma cells
.
Virol J
2011
;
8
:
354
.
110.
Yao
R
,
Ma
YL
,
Liang
W
,
Li
HH
,
Ma
ZJ
,
Yu
X
, et al
MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1
.
PLoS ONE
2012
;
7
:
e46082
.
111.
Collins
AS
,
McCoy
CE
,
Lloyd
AT
,
O'Farrelly
C
,
Stevenson
NJ
. 
miR-19a: an effective regulator of SOCS3 and enhancer of JAK-STAT signalling
.
PLoS ONE
2013
;
8
:
e69090
.
112.
Trotta
R
,
Chen
L
,
Ciarlariello
D
,
Josyula
S
,
Mao
C
,
Costinean
S
, et al
miR-155 regulates IFN-γ production in natural killer cells
.
Blood
2012
;
119
:
3478
85
.
113.
Zhuang
G
,
Wu
X
,
Jiang
Z
,
Kasman
I
,
Yao
J
,
Guan
Y
, et al
Tumor-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway
.
EMBO J
2012
;
31
:
3513
23
.
114.
Noguchi
S
,
Yamada
N
,
Kumazaki
M
,
Yasui
Y
,
Iwasaki
J
,
Naito
S
, et al
ssocs7, a target gene of microRNA-145:regulates interferon- induction through STAT3 nuclear translocation in bladder cancer cells
.
Cell Death Dis
2013
;
4
:
e482
.
115.
Mycko
MP
,
Cichalewska
M
,
Machlanska
A
,
Cwiklinska
H
,
Mariasiewicz
M
,
Selmaj
KW
. 
microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination
.
Proc Natl Acad Sci USA
2012
;
109
:
E1248
57
.
116.
Li
G
,
Miskimen
KL
,
Wang
Z
,
Xie
XY
,
Brenzovich
J
,
Ryan
JJ
, et al
STAT5 requires the N-domain for suppression of miR15/16:induction of bcl-2, and survival signaling in myeloproliferative disease
.
Blood
2010
;
115
:
1416
24
.
117.
Rozovski
U
,
Calin
GA
,
Setoyama
T
,
D'Abundo
L
,
Harris
DM
,
Li
P
, et al
Signal transducer and activator of transcription (STAT)-3 regulates microRNA gene expression in chronic lymphocytic leukemia cells
.
Mol Cancer
2013
;
12
:
50
.
118.
Lang
Q
,
Ling
C
. 
miR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PI3KCA
.
Biochem Biophys Res Commun
2012
;
426
:
247
52
.
119.
Oneyama
C
,
Ikeda
J
,
Okuzaki
D
,
Suzuki
K
,
Kanou
T
,
Shintani
Y
, et al
Micro-RNA-mediated downregulation of mTOR/FGFR3 controls tumor growth induced by Src-related oncogenic pathways
.
Oncogene
2011
;
30
:
3489
501
.
120.
Liu
P
,
Wilson
MJ
. 
miR-520c and miR-373 upregulate MMP9 expression by targeting mTOR and SIRT1, and activate the Ras/Raf/MEK/Erk signaling pathway and NF-kB factor in human fibrosarcoma cells
.
J Cell Physiol
2012
;
227
:
867
76
.
121.
Torres
A
,
Torres
K
,
Pesci
A
,
Ceccaroni
M
,
Paszkowski
T
,
Cassandrini
P
, et al
Deregulation of miR-100, mir-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma
.
BMC Cancer
2012
;
12
:
369
.
122.
Iwaya
T
,
Yokobori
T
,
Nishida
N
,
Kogo
R
,
Sudo
T
,
Tanaka
F
, et al
Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway
.
Carcinogenesis
2012
;
33
:
2391
7
.
123.
Lawson
SK
,
Dobrikova
EY
,
Shveygert
M
,
Gromeir
M
. 
p38a mitogen-activated protein kinase depletion and repression of signal transduction to translation machinery by miR-124 and -128 in neorons
.
Mol Cell Biol
2013
;
33
:
127
35
.
124.
Tanka
T
,
Sugaya
S
,
Kita
K
,
Arai
M
,
Kanda
T
,
Fujii
K
, et al
Inhibition of cell viability by human IFN-ß is mediated by microRNA-431
.
Int J Oncol
2012
;
40
:
1470
6
.
125.
Li
Y
,
Fan
X
,
He
X
,
Sun
H
,
Zou
Z
,
Yuan
H
, et al
MicroRNA-466I inhibits antiviral innate immune response by targeting interferon-alpha
.
Cell Mol Immunol
2012
;
9
:
497
502
.
126.
Polioudakis
D
,
Bhinge
AA
,
Killion
PJ
,
Lee
BK
,
Abell
NS
,
Iyer
VR
. 
A Myc-micro network promotes exit from quiescence by suppressing the interferon response and cell-cycle arrest genes
.
Nucleic Acids Res
2013
;
41
:
2239
54
.
127.
Buggele
WA
,
Horvath
CM
. 
MicroRNA profiling of Sendai-virus infected A549 cells identifies miR-203 as an interferon-inducible regulator of IFIT1/ISG56
.
J Virol
2013
;
87
:
9260
70
.
128.
Li
Y
,
Xie
J
,
Xu
X
,
Wang
J
,
Ao
F
,
Wan
Y
, et al
MicroRNA-548 down-regulates host antiviral response via direct targeting of IFN-λ1
.
Protein Cell
2013
;
4
:
130
41
.
129.
Ma
F
,
Xu
S
,
Liu
X
,
Zhang
Q
,
Xu
X
,
Liu
M
, et al
The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ
.
Nature Immunol
2011
;
12
:
861
9
.
130.
Steiner
DF
,
Thomas
MF
,
Hu
JK
,
Yang
Z
,
Babiarz
JE
,
Allen
CD
, et al
MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells
.
Immunity
2011
;
35
:
169
81
.
131.
Yamada
M
,
Gomez
JC
,
Chugh
PE
,
Lowell
CA
,
Dinauer
MC
,
Dittmer
DP
, et al
Interferon-γ production by neutrophils during bacterial pneumonia in mice
.
Am J Respir Crit Care Med
2011
;
183
:
1391
401
.