Requirement of hydrogen peroxide generation in TGF-β1 signal transduction in human lung fibroblast cells: Involvement of hydrogen peroxide and Ca2+ in TGF-β1-induced IL-6 expression

E. Junn, Nyung Lee Kee Nyung Lee, Ran Ju Hyang Ran Ju, Hyun Han Seung Hyun Han, Young Im Joo Young Im, Sik Kang Hyung Sik Kang, Ho Lee Tae Ho Lee, Soo Bae Yun Soo Bae, Soo Ha Kwon Soo Ha, Won Lee Zee Won Lee, Goo Rhee Sue Goo Rhee, I. Choi

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131 Scopus citations

Abstract

Stimulation of human lung fibroblast cells with TGF-β1 resulted in a transient burst of reactive oxygen species with maximal increase at 5 min after treatment. This reactive oxygen species increase was inhibited by the antioxidant, N-acetyl-L-cysteine (NAC). TGF-β1 treatment stimulated IL-6 gene expression and protein synthesis in human lung fibroblast cells. Antioxidants including NAC, glutathione, and catalase reduced TGF-β1-induced IL-6 gene expression, and direct H2O2 treatment induced IL-6 expression in a dose-dependent manner. NAC also reduced TGF-β1-induced AP-1 binding activity, which is involved in IL-6 gene expression. It has been reported that Ca2+ influx is stimulated by TGF-β1 treatment. EGTA suppressed TGF- β1- or H2O2- induced IL-6 expression, and ionomycin increased IL-6 expression, with simultaneously modulating AP-1 activity in the same pattern. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase/extracellular signal-related kinase kinase 1, suppressed TGF-β1- or H2O2-induced IL-6 and AP-1 activation. In addition, TGF-β1 or H2O2 increased MAPK activity which was reduced by EGTA and NAC, suggesting that MAPK is involved in TGF-β1-induced IL-6 expression. Taken together, these results indicate that TGF-β1 induces a transient increase of intracellular H2O2 production, which regulates downstream events such as Ca2+ influx, MAPK, and AP-1 activation and IL-6 gene expression.

Original languageEnglish
Pages (from-to)2190-2197
Number of pages8
JournalJournal of Immunology
Volume165
Issue number4
DOIs
StatePublished - 15 Aug 2000

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