Human fibroblasts synthesize elevated levels of extracellular matrix proteins in response to interleukin 4.

Abstract

Interleukin 4 (also known as "B cell stimulatory factor-l"), a cytokine product of T lymphocytes and mast cells, stimulates synthesis of the extracellular matrix proteins, types I and III collagen and fibronectin, by human dermal fibroblasts in vitro. Stimulation of collagen by human recombinant (hr)IL-4 was also demonstrated in several fibroblastic synovial cell lines obtained from patients with rheumatoid arthritis and osteoarthritis. The stimulatory effect of hrIL-4 on fibroblast collagen synthesis was specifically neutralized by rabbit anti-hrIL-4 Ig. IL-4 specifically increased the steady-state levels of types I and III procollagen and fibronectin mRNAs, with no effect on cytoplasmic fl-actin mRNA. Quantitative analysis of the levels of Pro al (I) collagen transcripts in IL-4-treated fibroblast cultures was also corroborated by antisense RNA-mRNA hybridization and RNAse resistant hybrids which showed that IL-4-treated fibroblasts expressed higher levels of Pro al (I) collagen transcripts. Nuclear run-off transcription experiments indicated that IL4 stimulated the rates of mRNA biogenesis. Based on these observations we conclude that IL4 exerts its effect on collagen and fibronectin synthesis at the pretranslational level, resulting in synthesis of these extracellular matrix proteins. These and other data suggest that IL4 may be a "fibrogenic cytokine" that could be important in promoting biogenesis of extracellular matrix proteins in normal wound healing and in pathological fibrosis in which mast cells and T lymphocytes play a central role. (J. Clin. Invest. 1992.

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

“…TGF-␤, IL-4, and oncostatin M up-regulate collagen synthesis (12,20,30), whereas tumor necrosis factor-␣, interferon-␥, basic fibroblast growth factor, and IL-10 down-regulate collagen production (31)(32)(33). In this study, IL-13 was shown to induce the expression of type I collagen protein at the same extent as IL-4.…”

Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts

“…In addition to IL-6 and MCP-1, we attempted to deduce other potential candidate genes for Stat6 transcriptional regulation in ®broblasts by identifying downstream transcriptional targets common to both PDGF and IL-4 pathways. In fact, inspection of PDGF and IL-4 e ects on ®broblasts revealed that both regulate the transcription of genes encoding extracellular matrix proteins (Owen et al, 1982;Postlethwaite et al, 1992). To date, we have been unable to observe a di erential e ect in the expression of several extracellular matrix proteins in wild-type compared to Stat6 7/7 ®broblasts (P Kriebel and WJ LaRochelle, unpublished observation) although compensatory transcriptional activators cannot be excluded.…”

“…In addition to proliferative and di erentiation e ects (Conrad et al, 1987;Noelle et al, 1984), IL-4 also increases IL-4R expression on lymphocytes (Ohara and Paul, 1988). In ®broblasts, IL-4 modulates functional responses such as extracellular matrix production (Postlethwaite et al, 1992) and chemotaxis (Postlethwaite and Seyer, 1991), rather than inducing pronounced proliferative e ects (Postlethwaite et al, 1992). IL-4R activation (Wang et al, 1992) results in tyrosine phosphorylation of many signaling molecules including Jak1, Jak3 (Johnston et al, 1994;Witthuhn et al, 1994), IRS-1 (Wang et al, 1993b), IRS-2/4PS (Wang et al, 1993a), and Stat6 (Hou et al, 1994;Kotanides and Reich, 1993;Quelle et al, 1995;Schindler and Darnell, 1995).…”

Oncostatin M Stimulates the Growth of Dermal Fibroblasts Via a Mitogen-Activated Protein Kinase-Dependent Pathway

“…Transient fibroblast activation is likely regulated by a variety of cytokines produced by infiltrating platelets, monocytes, T lymphocytes, and other inflammation-associated cells (1). Numerous in vitro and in vivo studies have suggested that some cytokines such as TGF-␣ and -␤, platelet-derived growth factor, epidermal growth factor, IL-1␣ and -␤, TNF-␣ and -␤, IL-4, and IL-6 regulate dermal fibroblast proliferation and extracellular matrix deposition (2)(3)(4)(5)(6)(7)(8)(9). Dermal fibroblasts derived from patients with systemic sclerosis or keloid appear to be persistently activated and produce elevated levels of extracellular matrix components in tissue culture.…”