Interleukin-13 Stimulates the Transcription of the Human α2(I) Collagen Gene in Human Dermal Fibroblasts

Abstract

Interleukin (IL)-13 is a novel lymphokine produced by activated Type 2 helper cells. In this study, we examined the target genes of IL-13 by the cDNA microarray analysis in human dermal fibroblasts. We focused on the human ␣2(I) collagen gene, which was one of the IL-13-induced genes by the microarray analysis. IL-13 induced type I collagen protein as well as mRNA in a dose-dependent manner. Actinomycin D, an RNA synthesis inhibitor, significantly blocked the IL-13-mediated up-regulation of ␣2(I) collagen mRNA expression, whereas cycloheximide, a protein synthesis inhibitor, did not block this up-regulation. In addition, IL-13 treatment induced the promoter activity of ␣2(I) collagen by nuclear run-on transcription assay and chloramphenicol acetyltransferase assay. IL-13-mediated transcriptional activation of ␣2(I) collagen gene or type I collagen protein up-regulation was inhibited by the treatment of fibroblasts with a selective phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or STAT6 antisense oligonucleotide, but not by PD98059, a specific inhibitor of MEK/ERK, or SB202190 or SB203580, specific inhibitors of p38 MAPK; IL-13 induced the phosphorylation of PI3K p85 regulatory subunit and STAT6. These results suggest that IL-13 may play a role in the regulation of extracellular matrix and indicate the possible therapeutic value of the blockade of IL-13 signaling pathways via PI3K and STAT6 in fibrosis.

Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells

“…In hepatic stellate cells, basal collagen IA1 mRNA levels were decreased by LY294002 [7]. IL-13-induced collagen IA2 upregulation also depended on PI3K in dermal fibroblasts [33]. We have shown the importance of Akt activation in matrix generation in response to mechanical stress [5] and observed that overexpression of active Akt (AktDD) led to increased collagen I secretion by unstimulated mesangial cells [5].…”

Systemic sclerosis: a prototypic multisystem fibrotic disorder

“…Expression of IL-4 protein and mRNA is markedly elevated in SSc lesional skin and cultured fibroblasts (86). The profibrotic activities of IL-13 involve both direct fibroblast activation and indirect mechanisms due to stimulation of TGF-β (87,88). Although levels of IL-13 are elevated in the serum of patients with SSc, its role in inducing and maintaining tissue fibrosis in SSc remains to be determined.…”

Fibroblasts stimulated via HLA-II molecules produce prostaglandin E2 and regulate cytokine production from helper T cells

“…[50][51][52][53][54] IL-4 and IL-13 exploit the same IL-4Ra/Stat6 signaling pathways 55 to induce the incremental transcriptional activity of COL1A2 gene expression and type I collagen protein synthesis. 56 In this study, as IL-4 was not detected in the supernatants of activated Th cells following MLR culture with DQ-sup (data not shown), IL-13 is found to be the most probable facilitator of collagen synthesis in fibroblasts. TGF-b1 is also a key cytokine in the mechanisms of fibrosis, whereby TGF-b1 production is induced by IL-13 stimulation via IL-13Ra2 in fibroblasts.…”