Proteolytic Switch from Defense to Repair

Abstract

Wound healing requires the coordinated action of multiple signals acting on several different cell types to ensure that antimicrobial processes initiated by leukocytes do not prevent survival and proliferation of neighboring epithelial cells. Zhu et al. describe a signaling system that appears to function as a switch that may promote a transition from a predominant innate immune response to a situation favoring epithelial cell proliferation and wound healing. They discovered that the anti-inflammatory agent secretory leukocyte protease inhibitor (SLPI) interacted with the protein proepithelin (PEPI, also called progranulin, PC-cell-derived growth factor, or acrogranin) in a yeast two-hybrid assay and in extracellular fluids from humans. PEPI is thought to promote wound healing as an epithelial cell growth factor and can be proteolytically cleaved to form epithelins (EPIs). Zhu et al. provide evidence that the interaction of SLPI with PEPI acts in two ways to prevent cleavage of PEPI. SLPI directly inhibits elastase, which appears to be a key mediator of conversion of PEPI to EPI, and binding to SLPI to PEPI appears to block access of elastase and other proteases that might cleave PEPI. PEPI had anti-inflammatory effects, inhibiting signaling by tumor necrosis factor in neutrophils. In contrast, its cleavage product EPI promoted inflammation by inhibiting growth of epithelial cells and promoting secretion of the neutrophil attractant interleukin 8. Mice lacking SLPI have impaired wound healing, but the defect was overcome by application of exogenous PEPI. Thus, SLPI appears to have an important biological role in balancing conversion of PEPI to EPI, which may serve as biological switch that regulates progression of a wound from an inflammatory response to a state more conducive to healing. J. Zhu, C. Nathan, W. Jin, D. Sim, G. S. Ashcroft, S. M. Wahl, L. Lacomis, H. Erdjument-Bromage, P. Tempst, C. D. Wright, A. Ding, Conversion of proepithelin to epithelins: Roles of SLPI and elastase in host defense and wound repair. Cell 111 , 867-878 (2002). [Online Journal]