Inducible nitric oxide synthase (iNOS) metabolizes L-arginine to produce NO that was originally identified in myeloid cells as a host defense mechanism against pathogens. Recent studies, however, have revealed that iNOS is often induced in both tumor and myeloid cells in the tumor microenvironment. More intriguingly, compelling experimental data have shown that iNOS promotes tumor development in certain cellular context and suppress tumor development under other cellular conditions. The molecular mechanisms underlying this contrasting function of iNOS is unknown. Because iNOS is often induced by inflammatory signals, it is therefore likely that the opposite functions of iNOS might be controlled by the inflammatory signaling pathways. We show here that proinflammatory IFN-γ and NF-κB signals synergistically induce iNOS expression in human colon cancer cells. We further demonstrated that NF-κB directly binds to the NOS2 promoter to regulate iNOS expression. Although the IFN-γ signaling pathway or the NF-κB signaling pathway alone is insufficient to induce iNOS expression in myeloid cells, IFN-γ and NF-κB synergistically induce iNOS expression in myeloid cells. Furthermore, we determined that IFN-γ up-regulates IRF8 expression to augment NF-κB induction of iNOS expression. More interestingly, we observed that the p65/p65 and p50/p50 homodimers, not the canonical p65/p50 heterodimer, directly binds to the nos2 promoter to regulate iNOS expression in myeloid cells. Our results thus determine that the IFN-γ-induced IRF8 acts in concert with the NF-κB p65/p65 and p50/p50 homodimers to regulate iNOS expression.

Citation Format: Priscilla Simon, Sarah Sharman, Chunwan Lu, Dafeng Yang, Amy Paschall, Kebin Liu. The NF-κB p65 and p50 homodimer cooperate with pSTAT1 to synergistically activate iNOS transcription. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B86.