Constitutive collagenase-1 synthesis through MAPK pathways is mediated, in part, by endogenous IL-1alpha during fibrotic repair in corneal stroma.

Abstract

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.

• Authors: Jae-Chang Jung, Man-Il Huh, M Elizabeth Fini
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 102 Issue 2 Pg. 453-62 (Oct 01 2007) ISSN: 0730-2312 [Print] United States
• PMID: 17455222 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Flavonoids
• Imidazoles
• Interleukin-1alpha
• Pyridines
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Collagenases
• collagenase 1
• SB 203580
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Cells, Cultured
• Collagenases (biosynthesis)
• Corneal Stroma (drug effects, metabolism, pathology)
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Fibroblasts (drug effects, metabolism)
• Fibrosis
• Flavonoids (pharmacology)
• Imidazoles (pharmacology)
• Interleukin-1alpha (metabolism)
• Pyridines (pharmacology)
• Rabbits
• Signal Transduction
• Wound Healing
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)