Constitutive collagenase-1 synthesis through MAPK pathways is mediated, in part, by endogenous IL-1alpha during fibrotic repair in corneal stroma.
Collagenase-1 is a protease expressed by active fibroblasts that is involved in remodeling of the extracellular matrix (ECM). In this study, we characterize the intracellular signaling mechanism of collagenase-1 production by IL-1alpha in subcultured normal fibroblasts (NF) from uninjured normal corneas, compared to that in repair wound fibroblasts (WF). In NF, collagenase-1 was induced specifically after the exogenous addition of IL-1alpha via activation of ERK and p38MAPK. Collagenase-1 expression was strongly suppressed upon treatment with either a MEK or p38MAPK inhibitor. In contrast, repair WF constitutively synthesized both IL-1alpha and collagenase-1. Combined treatment with both mitogen-activated protein kinase (MAPK) inhibitors dramatically reduced collagenase-1 synthesis, while individual MEK1 or p38 inhibitors weakly modulated the collagenase-1 level. The results indicate that both pathways are crucial in the regulation of collagenase-1 synthesis. Furthermore, an IL-1alpha receptor antagonist (IL-1ra) could not abolish constitutive collagenase-1 synthesis, even at high doses, suggesting that other cytokines/factors are additionally involved in this process. We propose that induction of collagenase-1 by IL-1alpha in both WF and NF depends on a unique combination of cell type-specific signaling pathways.
Jung
Jae-Chang
JC
Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Korea. jcjung@mail.knu.ac.kr
Huh
Man-Il
MI
Fini
M Elizabeth
ME
D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis*; D003319:Corneal Stroma / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction; D014945:Wound Healing; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D005419:Flavonoids; D007093:Imidazoles; D053582:Interleukin-1alpha; D011725:Pyridines; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; C417249:collagenase 1; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one