Lack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the interleukin-4Rα and transforming factor-β genes

Tracy McGaha, Shinichiro Saito, Robert G. Phelps, Ronald Gordon, Nancy Noben-Trauth, William E. Paul, Constantin Bona

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106 Scopus citations


Scleroderma is a disorder characterized by fibrosis of the skin and internal organs and autoimmunity. Whereas the cause is unknown, interleukin-4 and transforming growth factor-β have been postulated to play a major part in the fibrosis. To investigate the part played by these cytokines, we prepared TSK/+ mice with a targeted mutation in the interleukin-4Rα or transforming growth factor-β genes. The breeding failed to produce TSK/+ transforming growth factor-β-/- mice so analysis of the role of transforming growth factor-β was limited to TSK/+ transforming growth factor-β +/- mice. We observed that TSK/+ interleukin-4Rα-/- did not develop dermal thickening, and deletion of one allele of the transforming growth factor-β gene resulted in diminished dermal thickness compared with TSK/+ mice; however, the deletion of interleukin-4Rα or transforming growth factor-β had no effect on lung emphysema, which is another characteristic of TSK syndrome. Electron microscopic analysis of skin showed that the collagen fibrils in TSK/+ interleukin-4Rα-/- mice exhibit normal periodicity but have a smaller diameter than the fibers found in C57BL/6 mice. Analysis of skin and serum samples showed that the deletion of interleukin-4Rα or one allele of transforming growth factor-β prevented the increase of skin thickness paralleled with a decrease in the dermal hydroxyproline content and development of autoantibodies associated with TSK syndrome. These results demonstrate the importance of interleukin-4 and transforming growth factor-β for the development of cutaneous fibrosis in vivo and suggest an important part for these cytokines in wound healing and connective tissue maintenance in general.

Original languageEnglish (US)
Pages (from-to)136-143
Number of pages8
JournalJournal of Investigative Dermatology
Issue number1
Publication statusPublished - Jan 1 2001



  • Emphysema
  • Interleukin-4R
  • Tight skin
  • Transforming growth factor-β sclerosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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