In addition to clearing extracellular matrices in inflammatory lesions, MMP-8 is thought to assist neutrophil (PMN) migration and tissue infiltration by degrading collagen. Paradoxically, our recent collaborative studies with Carlos Lopez-Otin using MMP8 −/− mice revealed an unexpected phenotype (1). The absence of MMP-8 strongly increased the incidence of skin tumors in male MMP-8 −/− mice, these mice also had abnormalities in the inflammatory response induced by carcinogens. Following an initial lag of delayed PMN infiltration upon challenge a massive PMN accumulation then ensued indicating that MMP-8 may control PMN cell chemotaxis in vivo in a homeostatic feedback loop that is perturbed in the knock-out mouse. We have screened the CXC-R2 chemokines for processing by MMP-8 and a panel of MMPs by analysis on Tris-tricine gel ectrophoresis and electrospray mass spectrometry. We found that LIX (1-92) was N-and C- terminally cleaved by MMP-8 generating LIX (5-92) and (5-79), and at the N-terminal by MMP-1, -2, -9, -13 but not -14. Processing of ENA (1-78) by MMP-8 generating ENA (5-78) and (8-78), as well as by MMP-2 and -1 (ENA 6-78, 7-78) was observed. A novel MMP cleavage site of IL-8 was identified IL-8 (6-77) by MMP-8 and -13 that differs from the known MMP-9 cleavage site IL-8 (7-77) (2), which was also generated by MMP-1 processing. The processed chemokines were still able to bind proteoglycan glycosaminoglycan chains and showed enhanced in vitro chemotactic potential to PMNs. However using an in vivo model of inflammation in the MMP-8 −/− mouse, the lack of MMP-8 processing and induced activation of LIX was shown to be responsible for the delayed PMN recruitment to the injury site. This data indicates that MMPs regulate PMN function by processing of the CXC R2 chemokines- a novel concept with important implications for the regulation of inflammation and cancer. 1. Balbin et al. (2003) Nature Genetics 35: 252-257. 2. Van den Steen et al. (2000) Blood 96: 2673-2681.
[Proc Amer Assoc Cancer Res, Volume 45, 2004]