Laminin α3 LG4 Module Induces Matrix Metalloproteinase-1 through Mitogen-activated Protein Kinase Signaling

Abstract The LG4 module of the laminin α3 chain (α3 LG4), a component of epithelial-specific laminin-5, has cell attachment activity and binds syndecan (Utani, A., Nomizu, M., Matsuura, H., Kato, K., Kobayashi, T., Takeda, U., Aota, S., Nielsen, P. K., and Shinkai, H. (2001) J. Biol. Chem. 276, 28779–28788). Here, we show that recombinant α3 LG4 and a 19-mer synthetic peptide (A3G756) within α3 LG4 active for syndecan binding increased the expression of matrix metalloproteinase-1 (MMP-1) in keratinocytes and fibroblasts. This induction was inhibited by heparin and required de novo synthesis of proteins. In keratinocytes, A3G756 up-regulated interleukin (IL)-1β and MMP-1 expression and an IL-1 receptor antagonist thoroughly inhibited A3G756-mediated induction of MMP-1. A3G756 also activated p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-related kinase (Erk). Studies with specific inhibitors of MAPKs showed that p38 MAPK activation was necessary for both IL-1β and MMP-1 induction, but Erk activation was required only for MMP-1 induction. In fibroblasts, IL-1 receptor antagonist did not block A3G756-mediated induction of MMP-1. These results indicated that induction of MMP-1 by α3 LG4 is mediated through the IL-1β autocrine loop in keratinocytes but the mechanism of the induction in fibroblasts is different. Our study suggests that the laminin α3 LG4 module may play an important role in tissue remodeling by inducing MMP-1 expression during wound healing.