IL-4 up-regulates the expression of tissue inhibitor of metalloproteinase-2 in dermal fibroblasts via the p38 mitogen-activated protein kinase dependent pathway.
Tissue inhibitor of metalloproteinase-2 (TIMP-2) is a potent inhibitor of activated matrix metalloproteinases such as gelatinase and collagenase, and thus helps to control extracellular matrix metabolism and deposition by connective tissue cells. We examined the responsiveness of the expression of TIMP-2 to various cytokines in dermal fibroblasts and studied the regulatory and signaling mechanisms of the response. TIMP-2 protein and mRNA expression was induced by IL-4 in a dose- and time-dependent manner, but not by TGF-beta, oncostatin M, or IL-6. IL-4 induction of TIMP-2 expression was dependent upon transcription. The p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 suppressed IL-4-induced TIMP-2 expression, suggesting the involvement of p38 MAP kinase in the signaling of IL-4 leading to TIMP-2 expression. Immunoblotting analysis using a specific Ab against phosphorylated p38 MAP kinase (Thr(180)/Tyr(182)) showed that IL-4 induced phosphorylation of p38 MAP kinase in human dermal fibroblasts. Furthermore, the p38 MAP kinase assay showed that IL-4 induces p38 MAPK activation in human dermal fibroblasts. The expression of the dominant-negative mutant p38 MAPK represses the IL-4-induced TIMP-2 expression in human dermal fibroblasts. Thus, IL-4 can potentially alter the dermal matrix metabolism by regulating TIMP-2.
Ihn
Hironobu
H
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan. in-der@h.u-tokyo.ac.jp
Yamane
Kenichi
K
Asano
Yoshihide
Y
Kubo
Masahide
M
Tamaki
Kunihiko
K
D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D015847:Interleukin-4; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole