Gene interactions and pathways from curated databases and text-mining
J Immunol 2002, PMID: 11823524

IL-4 up-regulates the expression of tissue inhibitor of metalloproteinase-2 in dermal fibroblasts via the p38 mitogen-activated protein kinase dependent pathway.

Ihn, Hironobu; Yamane, Kenichi; Asano, Yoshihide; Kubo, Masahide; Tamaki, Kunihiko

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.

Diseases/Pathways annotated by Medline MESH: MAP Kinase Signaling System
Document information provided by NCBI PubMed

Text Mining Data

IL-4 → IL-6: " 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 → oncostatin M: " 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 "

TIMP-2 → IL-4: " IL-4 induction of TIMP-2 expression was dependent upon transcription "

TIMP-2 → IL-4: " 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 "

p38 → IL-4: " Furthermore, the p38 MAP kinase assay showed that IL-4 induces p38 MAPK activation in human dermal fibroblasts "

MAPK → IL-4: " Furthermore, the p38 MAP kinase assay showed that IL-4 induces p38 MAPK activation in human dermal fibroblasts "

TIMP-2 ⊣ MAPK: " The expression of the dominant negative mutant p38 MAPK represses the IL-4 induced TIMP-2 expression in human dermal fibroblasts "

TIMP-2 → IL-4: " The expression of the dominant negative mutant p38 MAPK represses the IL-4 induced TIMP-2 expression in human dermal fibroblasts "

Manually curated Databases

  • OpenBEL Selventa BEL large corpus: MAPK14 → IL4 (increases, IL4 Activity)
    Evidence: 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.
  • OpenBEL Selventa BEL large corpus: MAPK14 → IL4 (increases)
    Evidence: 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.
  • OpenBEL Selventa BEL large corpus: MAPK14 → MAPK14 (directlyIncreases, MAPK14 Activity)
    Evidence: 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.