Laminin alpha 3 LG4 module induces matrix metalloproteinase-1 through mitogen-activated protein kinase signaling.
The LG4 module of the laminin alpha 3 chain (alpha 3 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 alpha 3 LG4 and a 19-mer synthetic peptide (A3G756) within alpha 3 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)-1 beta 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-1 beta 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 alpha 3 LG4 is mediated through the IL-1 beta autocrine loop in keratinocytes but the mechanism of the induction in fibroblasts is different. Our study suggests that the laminin alpha 3 LG4 module may play an important role in tissue remodeling by inducing MMP-1 expression during wound healing.
Utani
Atsushi
A
Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. utani@derma01.m.chiba-u.ac.jp
Momota
Yutaka
Y
Endo
Hideharu
H
Kasuya
Yoshitoshi
Y
Beck
Konrad
K
Suzuki
Nobuharu
N
Nomizu
Motoyoshi
M
Shinkai
Hiroshi
H
D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D007797:Laminin / Q000737:chemistry*; D020935:MAP Kinase Signaling System; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D053669:Syndecan-2; D053671:Syndecan-4; D053667:Syndecans; D013997:Time Factors; D015854:Up-Regulation; D014945:Wound Healing; D048051:p38 Mitogen-Activated Protein Kinases
D018076:DNA, Complementary; D007375:Interleukin-1; D007797:Laminin; D008562:Membrane Glycoproteins; D010455:Peptides; D011509:Proteoglycans; D011994:Recombinant Proteins; C508245:SDC2 protein, human; C508304:SDC4 protein, human; D053671:Syndecan-4; D053667:Syndecans; D053669:Syndecan-2; C095567:laminin alpha 3; D003094:Collagen; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1