• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Oct 1992; 90(4): 1479–1485.
PMCID: PMC443194

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

Abstract

Interleukin 4 (also known as "B cell stimulatory factor-1"), 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 beta-actin mRNA. Quantitative analysis of the levels of Pro alpha 1(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 alpha 1(I) collagen transcripts. Nuclear run-off transcription experiments indicated that IL-4 stimulated the rates of mRNA biogenesis. Based on these observations we conclude that IL-4 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 IL-4 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.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Howard M, Farrar J, Hilfiker M, Johnson B, Takatsu K, Hamaoka T, Paul WE. Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med. 1982 Mar 1;155(3):914–923. [PMC free article] [PubMed]
  • Vitetta ES, Brooks K, Chen YW, Isakson P, Jones S, Layton J, Mishra GC, Pure E, Weiss E, Word C, et al. T-cell-derived lymphokines that induce IgM and IgG secretion in activated murine B cells. Immunol Rev. 1984 Apr;78:137–157. [PubMed]
  • Sideras P, Bergstedt-Lindqvist S, Severinson E. Partial biochemical characterization of IgG1-inducing factor. Eur J Immunol. 1985 Jun;15(6):593–598. [PubMed]
  • Lee F, Yokota T, Otsuka T, Meyerson P, Villaret D, Coffman R, Mosmann T, Rennick D, Roehm N, Smith C, et al. Isolation and characterization of a mouse interleukin cDNA clone that expresses B-cell stimulatory factor 1 activities and T-cell- and mast-cell-stimulating activities. Proc Natl Acad Sci U S A. 1986 Apr;83(7):2061–2065. [PMC free article] [PubMed]
  • Noma Y, Sideras P, Naito T, Bergstedt-Lindquist S, Azuma C, Severinson E, Tanabe T, Kinashi T, Matsuda F, Yaoita Y, et al. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature. 1986 Feb 20;319(6055):640–646. [PubMed]
  • Isakson PC. Antiimmunoglobulin-treated B cells respond to a B cell differentiation factor for IgG1. J Exp Med. 1986 Jul 1;164(1):303–308. [PMC free article] [PubMed]
  • Coffman RL, Ohara J, Bond MW, Carty J, Zlotnik A, Paul WE. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol. 1986 Jun 15;136(12):4538–4541. [PubMed]
  • Roehm NW, Leibson HJ, Zlotnik A, Kappler J, Marrack P, Cambier JC. Interleukin-induced increase in Ia expression by normal mouse B cells. J Exp Med. 1984 Sep 1;160(3):679–694. [PMC free article] [PubMed]
  • Noelle R, Krammer PH, Ohara J, Uhr JW, Vitetta ES. Increased expression of Ia antigens on resting B cells: an additional role for B-cell growth factor. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6149–6153. [PMC free article] [PubMed]
  • Ohara J, Paul WE. Receptors for B-cell stimulatory factor-1 expressed on cells of haematopoietic lineage. Nature. 1987 Feb 5;325(6104):537–540. [PubMed]
  • Park LS, Friend D, Sassenfeld HM, Urdal DL. Characterization of the human B cell stimulatory factor 1 receptor. J Exp Med. 1987 Aug 1;166(2):476–488. [PMC free article] [PubMed]
  • Lowenthal JW, Castle BE, Christiansen J, Schreurs J, Rennick D, Arai N, Hoy P, Takebe Y, Howard M. Expression of high affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic and nonhemopoietic cells. J Immunol. 1988 Jan 15;140(2):456–464. [PubMed]
  • Monroe JG, Haldar S, Prystowsky MB, Lammie P. Lymphokine regulation of inflammatory processes: interleukin-4 stimulates fibroblast proliferation. Clin Immunol Immunopathol. 1988 Nov;49(2):292–298. [PubMed]
  • Postlethwaite AE, Seyer JM. Fibroblast chemotaxis induction by human recombinant interleukin-4. Identification by synthetic peptide analysis of two chemotactic domains residing in amino acid sequences 70-88 and 89-122. J Clin Invest. 1991 Jun;87(6):2147–2152. [PMC free article] [PubMed]
  • Wood DD, Bayne EK, Goldring MB, Gowen M, Hamerman D, Humes JL, Ihrie EJ, Lipsky PE, Staruch MJ. The four biochemically distinct species of human interleukin 1 all exhibit similar biologic activities. J Immunol. 1985 Feb;134(2):895–903. [PubMed]
  • Grabstein K, Eisenman J, Mochizuki D, Shanebeck K, Conlon P, Hopp T, March C, Gillis S. Purification to homogeneity of B cell stimulating factor. A molecule that stimulates proliferation of multiple lymphokine-dependent cell lines. J Exp Med. 1986 Jun 1;163(6):1405–1414. [PMC free article] [PubMed]
  • Yokota T, Otsuka T, Mosmann T, Banchereau J, DeFrance T, Blanchard D, De Vries JE, Lee F, Arai K. Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5894–5898. [PMC free article] [PubMed]
  • Postlethwaite AE, Smith GN, Mainardi CL, Seyer JM, Kang AH. Lymphocyte modulation of fibroblast function in vitro: stimulation and inhibition of collagen production by different effector molecules. J Immunol. 1984 May;132(5):2470–2477. [PubMed]
  • Raghow R, Gossage D, Kang AH. Pretranslational regulation of type I collagen, fibronectin, and a 50-kilodalton noncollagenous extracellular protein by dexamethasone in rat fibroblasts. J Biol Chem. 1986 Apr 5;261(10):4677–4684. [PubMed]
  • Raghow R, Gossage D, Seyer JM, Kang AH. Transcriptional regulation of type I collagen genes in cultured fibroblasts by a factor isolated from thioacetamide-induced fibrotic rat liver. J Biol Chem. 1984 Oct 25;259(20):12718–12723. [PubMed]
  • Aycock RS, Raghow R, Stricklin GP, Seyer JM, Kang AH. Post-transcriptional inhibition of collagen and fibronectin synthesis by a synthetic homolog of a portion of the carboxyl-terminal propeptide of human type I collagen. J Biol Chem. 1986 Oct 25;261(30):14355–14360. [PubMed]
  • Thomas PS. Hybridization of denatured RNA transferred or dotted nitrocellulose paper. Methods Enzymol. 1983;100:255–266. [PubMed]
  • Chu ML, Myers JC, Bernard MP, Ding JF, Ramirez F. Cloning and characterization of five overlapping cDNAs specific for the human pro alpha 1(I) collagen chain. Nucleic Acids Res. 1982 Oct 11;10(19):5925–5934. [PMC free article] [PubMed]
  • Melton DA, Krieg PA, Rebagliati MR, Maniatis T, Zinn K, Green MR. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 1984 Sep 25;12(18):7035–7056. [PMC free article] [PubMed]
  • Claman HN. Mast cells and fibrosis. The relevance to scleroderma. Rheum Dis Clin North Am. 1990 Feb;16(1):141–151. [PubMed]
  • Vath RR, Alexander CB, Fulmer JD. The lymphocytic infiltrative lung diseases. Clin Chest Med. 1982 Sep;3(3):619–634. [PubMed]
  • Van Boxel JA, Paget SA. Predominantly T-cell infiltrate in rheumatoid synovial membranes. N Engl J Med. 1975 Sep 11;293(11):517–520. [PubMed]
  • Roumm AD, Whiteside TL, Medsger TA, Jr, Rodnan GP. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984 Jun;27(6):645–653. [PubMed]
  • Graze PR, Gale RP. Chronic graft versus host disease: a syndrome of disordered immunity. Am J Med. 1979 Apr;66(4):611–620. [PubMed]
  • Needleman BW, Wigley FM, Stair RW. Interleukin-1, interleukin-2, interleukin-4, interleukin-6, tumor necrosis factor alpha, and interferon-gamma levels in sera from patients with scleroderma. Arthritis Rheum. 1992 Jan;35(1):67–72. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...