Regular article
Human recombinant interleukin-4 induces proliferation and interleukin-6 production by cultured human skin fibroblasts

https://doi.org/10.1016/0090-1229(92)90011-CGet rights and content

Abstract

The effect of human recombinant interleukin-4 (hrIL-4) on normal human adult dermal fibroblasts in terms of proliferation and IL-6 production was studied. Fibroblasts were exposed to different concentrations of IL-4 for various periods of time. Proliferation was measured using a [3H]thymidine incorporation assay. IL-6 production was measured at the transcriptional, protein, and functional levels by Northern blot analysis, radioimmunoassay, and B9 bioassay, respectively. Our results show that hrIL-4 significantly stimulated (two- to fivefold) fibroblasts to increase the incorporation of [3H]thymidine in a dose- and time-dependent manner. However, hrIL-1, hrIL-2, hrIL-5, or hrTNFα, at the same concentration (100 U/ml) and for the same time period (4 days), did not. In addition, IL-4 significantly induced (four- to eightfold) the production of immunoreactive and biologically functional IL-6. However, IL-4 was not as potent an inducer of IL-6 as IL-1. The IL-4-induced IL-6 production was dose and time dependent and was due, at least in part, to a dramatic increase in the steady-state levels of IL-6 mRNA. This is the first report describing the ability of IL-4 to activate human dermal fibroblasts in terms of proliferation and IL-6 production.

References (49)

  • T. Geppert

    Clinical features, pathogenic mechanisms, and new developments in the treatment of systemic sclerosis

    Amer. J. Med. Sci.

    (1990)
  • J. Le et al.

    Interleukin-6: A multifunctional cytokine regulating immune reactions and the acute phase protein response

    Lab. Invest.

    (1989)
  • S.B. Mizel

    The interleukins

    FASEB J

    (1989)
  • J. Van Snick

    Interleukin-6: An overview

    Annu. Rev. Immunol.

    (1990)
  • J. Krueger et al.

    Expression and function of interleukin-6 in epithelial cells

    J. Cell. Biochem.

    (1991)
  • P.B. Sehgal et al.

    Regulation of the acute phase and immune responses: Interleukin-6

    Ann. N.Y. Acad. Sci.

    (1989)
  • P.B. Sehgal

    Interleukin-6: Molecular pathophysiology

    J. Invest. Dermatol.

    (1990)
  • M. Howard et al.

    Identification of a T cell-derived B cell growth factor distinet from interleukin 2

    J. Exp. Med.

    (1982)
  • M.C.J. Wolvekamp et al.

    Interleukin-6. Historical background, genetics and biological significance

    Immunol. Lett.

    (1990)
  • L.S. Park et al.

    Characterization of the human B cell stimulatory factor 1 receptor

    J. Exp. Med.

    (1987)
  • T. Yokota et al.

    Molecular biology of interleukin 4 and interleukin 5 genes and biology of their products that stimulate B cells, T cells and hemopoietic cells

    Immunol. Rev.

    (1988)
  • R. Henschler et al.

    Interleukin-4 regulates mRNA accumulation of macrophage colony-stimulating factor by fibroblasts: Synergism with interleukin-1β

    Br. J. Haematol.

    (1990)
  • S. Brantschen et al.

    Regulatory effect of recombinant interleukin (IL)3 and IL4 on cytokine gene expression of bone marrow and peripheral blood mononuclear cells

    Eur. J. Immunol.

    (1989)
  • R. Essner et al.

    IL-4 down-regulates IL-1 and TNF gene expression in human monocytes

    J. Immunol.

    (1989)
  • Cited by (58)

    • Systemic sclerosis biomarkers detection in the secretome of TGFβ1-activated primary human lung fibroblasts

      2021, Journal of Proteomics
      Citation Excerpt :

      In this regard, the IL4 and IL13 signaling pathways are of interest since both interleukins have elevated serum levels in SSc patients [33], both can stimulate fibroblast proliferation and differentiation as well as regulate the expression of collagen and other fibrosis-associated genes, and stimulate macrophages to secrete macrophage-derived insulin-like growth factor-I (IGF1), which protects myofibroblasts from apoptosis and perpetuates fibrosis [34]. Furthermore, IL-4 can induce IL-6 production [35], a known pro-fibrotic factor overexpressed in SSc [36]. Additionally, perturbation of the “trafficking and processing of endosomal TLR” pathway is also relevant to SSc-PF and idiopathic pulmonary fibrosis (IPF) [37,38].

    • Mast cells in airway diseases and interstitial lung disease

      2016, European Journal of Pharmacology
      Citation Excerpt :

      These observations suggest that interactions between mast cells and smooth muscle and/or myofibroblasts may play a role in matrix deposition and fibrosis in interstitial lung diseases. Indeed, mast cell mediators such as histamine, bFGF and TGFβ promote fibroblast proliferation in humans (Boucek and Noble, 1973; Feghali et al., 1992; Hetzel et al., 2005; Jordana et al., 1988) and mast cells adhere strongly to fibroblasts in coculture (Moiseeva et al., 2013b; Trautmann et al., 1997; Wygrecka et al., 2013). Mast cells play an important role in the pathogenesis of asthma and this role most likely depends upon the microlocalisation of mast cells, providing a niche to support mast cell growth, survival and activation through cell-to-cell contact.

    • The adipose cell lineage is not intrinsically insulin resistant in polycystic ovary syndrome

      2007, Metabolism: Clinical and Experimental
      Citation Excerpt :

      We also investigated the possibility that cultured PCOS skin fibroblasts with constitutive increase in serine phosphorylation of IR (IR ser+) could secrete an insulin resistance–inducing factor. Cultured human skin fibroblasts have the capacity to synthesize several growth factors and cytokines [43] including IL-6 [44]. However, neither growth in IR ser+ conditioned media nor coculture with IR ser+ fibroblasts altered insulin responsiveness in control preadipocytes, indicating that factors secreted by PCOS skin fibroblasts that act via a paracrine mechanism are not implicated in the selective insulin resistance of these cells [15].

    • Role of cytokines in scleroderma: Use of animal models

      2006, Clinical and Applied Immunology Reviews
      Citation Excerpt :

      IL-6, also a type 2 cytokine, was shown to stimulate the synthesis of collagen and glycosaminoglycans [84]. In vitro studies have shown that IL-4 induces the production of IL-6 by human skin fibroblasts [85], which suggests that these cytokines are able to amplify the stimulating effects of collagen synthesis in fibroblasts. Elevated IL-6 levels are also frequently found in sera of SSc patients [75].

    • Cytokine regulation of pulmonary fibrosis in scleroderma

      2003, Cytokine and Growth Factor Reviews
    View all citing articles on Scopus
    View full text