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. 1992 Oct;90(4):1479–1485. doi: 10.1172/JCI116015

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

A E Postlethwaite 1, M A Holness 1, H Katai 1, R Raghow 1
PMCID: PMC443194  PMID: 1401080

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aycock R. S., Raghow R., Stricklin G. P., Seyer J. M., Kang A. H. 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] [Google Scholar]
  2. Chu M. L., Myers J. C., Bernard M. P., Ding J. F., 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. doi: 10.1093/nar/10.19.5925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Claman H. N. Mast cells and fibrosis. The relevance to scleroderma. Rheum Dis Clin North Am. 1990 Feb;16(1):141–151. [PubMed] [Google Scholar]
  4. Coffman R. L., Ohara J., Bond M. W., Carty J., Zlotnik A., Paul W. E. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol. 1986 Jun 15;136(12):4538–4541. [PubMed] [Google Scholar]
  5. 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. doi: 10.1084/jem.163.6.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Graze P. R., Gale R. P. Chronic graft versus host disease: a syndrome of disordered immunity. Am J Med. 1979 Apr;66(4):611–620. doi: 10.1016/0002-9343(79)91171-9. [DOI] [PubMed] [Google Scholar]
  7. Howard M., Farrar J., Hilfiker M., Johnson B., Takatsu K., Hamaoka T., Paul W. E. Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med. 1982 Mar 1;155(3):914–923. doi: 10.1084/jem.155.3.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Isakson P. C. Antiimmunoglobulin-treated B cells respond to a B cell differentiation factor for IgG1. J Exp Med. 1986 Jul 1;164(1):303–308. doi: 10.1084/jem.164.1.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Lee F., Yokota T., Otsuka T., Meyerson P., Villaret D., Coffman R., Mosmann T., Rennick D., Roehm N., Smith C. 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. doi: 10.1073/pnas.83.7.2061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lowenthal J. W., Castle B. E., 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] [Google Scholar]
  11. Melton D. A., Krieg P. A., Rebagliati M. R., Maniatis T., Zinn K., Green M. R. 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. doi: 10.1093/nar/12.18.7035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Monroe J. G., Haldar S., Prystowsky M. B., Lammie P. Lymphokine regulation of inflammatory processes: interleukin-4 stimulates fibroblast proliferation. Clin Immunol Immunopathol. 1988 Nov;49(2):292–298. doi: 10.1016/0090-1229(88)90119-5. [DOI] [PubMed] [Google Scholar]
  13. Needleman B. W., Wigley F. M., Stair R. W. 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. doi: 10.1002/art.1780350111. [DOI] [PubMed] [Google Scholar]
  14. Noelle R., Krammer P. H., Ohara J., Uhr J. W., Vitetta E. S. 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. doi: 10.1073/pnas.81.19.6149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Noma Y., Sideras P., Naito T., Bergstedt-Lindquist S., Azuma C., Severinson E., Tanabe T., Kinashi T., Matsuda F., Yaoita Y. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature. 1986 Feb 20;319(6055):640–646. doi: 10.1038/319640a0. [DOI] [PubMed] [Google Scholar]
  16. Ohara J., Paul W. E. Receptors for B-cell stimulatory factor-1 expressed on cells of haematopoietic lineage. Nature. 1987 Feb 5;325(6104):537–540. doi: 10.1038/325537a0. [DOI] [PubMed] [Google Scholar]
  17. Park L. S., Friend D., Sassenfeld H. M., Urdal D. L. Characterization of the human B cell stimulatory factor 1 receptor. J Exp Med. 1987 Aug 1;166(2):476–488. doi: 10.1084/jem.166.2.476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Postlethwaite A. E., Seyer J. M. 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. doi: 10.1172/JCI115247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Postlethwaite A. E., Smith G. N., Mainardi C. L., Seyer J. M., Kang A. H. 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] [Google Scholar]
  20. Raghow R., Gossage D., Kang A. H. 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] [Google Scholar]
  21. Raghow R., Gossage D., Seyer J. M., Kang A. H. 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] [Google Scholar]
  22. Roehm N. W., Leibson H. J., Zlotnik A., Kappler J., Marrack P., Cambier J. C. Interleukin-induced increase in Ia expression by normal mouse B cells. J Exp Med. 1984 Sep 1;160(3):679–694. doi: 10.1084/jem.160.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Roumm A. D., Whiteside T. L., Medsger T. A., Jr, Rodnan G. P. Lymphocytes in the skin of patients with progressive systemic sclerosis. Quantification, subtyping, and clinical correlations. Arthritis Rheum. 1984 Jun;27(6):645–653. doi: 10.1002/art.1780270607. [DOI] [PubMed] [Google Scholar]
  24. Sideras P., Bergstedt-Lindqvist S., Severinson E. Partial biochemical characterization of IgG1-inducing factor. Eur J Immunol. 1985 Jun;15(6):593–598. doi: 10.1002/eji.1830150612. [DOI] [PubMed] [Google Scholar]
  25. Thomas P. S. Hybridization of denatured RNA transferred or dotted nitrocellulose paper. Methods Enzymol. 1983;100:255–266. doi: 10.1016/0076-6879(83)00060-9. [DOI] [PubMed] [Google Scholar]
  26. Van Boxel J. A., Paget S. A. Predominantly T-cell infiltrate in rheumatoid synovial membranes. N Engl J Med. 1975 Sep 11;293(11):517–520. doi: 10.1056/NEJM197509112931101. [DOI] [PubMed] [Google Scholar]
  27. Vath R. R., Alexander C. B., Fulmer J. D. The lymphocytic infiltrative lung diseases. Clin Chest Med. 1982 Sep;3(3):619–634. [PubMed] [Google Scholar]
  28. Vitetta E. S., Brooks K., Chen Y. W., Isakson P., Jones S., Layton J., Mishra G. C., Pure E., Weiss E., Word C. T-cell-derived lymphokines that induce IgM and IgG secretion in activated murine B cells. Immunol Rev. 1984 Apr;78:137–157. doi: 10.1111/j.1600-065x.1984.tb00480.x. [DOI] [PubMed] [Google Scholar]
  29. Wood D. D., Bayne E. K., Goldring M. B., Gowen M., Hamerman D., Humes J. L., Ihrie E. J., Lipsky P. E., Staruch M. J. The four biochemically distinct species of human interleukin 1 all exhibit similar biologic activities. J Immunol. 1985 Feb;134(2):895–903. [PubMed] [Google Scholar]
  30. Yokota T., Otsuka T., Mosmann T., Banchereau J., DeFrance T., Blanchard D., De Vries J. E., 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. doi: 10.1073/pnas.83.16.5894. [DOI] [PMC free article] [PubMed] [Google Scholar]

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