Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 116, Issue 1, Pages 136-143Publisher
BLACKWELL SCIENCE INC
DOI: 10.1046/j.1523-1747.2001.00217.x
Keywords
emphysema; interleukin-4R; transforming growth factor-beta sclerosis; tight skin
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Funding
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI024671, Z01AI000493, ZIAAI000493] Funding Source: NIH RePORTER
- NIAID NIH HHS [P01AI24671-12] Funding Source: Medline
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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-beta 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-4R alpha or transforming growth factor-beta genes. The breeding failed to produce TSK/+ transforming growth factor-beta-/- mice so analysis of the role of transforming growth factor-beta was limited to TSK/+ transforming growth factor-beta+/- mice. We observed that TSK/+ interleukin-4R alpha-/- did not develop dermal thickening, and deletion of one allele of the transforming growth factor-beta gene resulted in diminished dermal thickness compared with TSK/+ mice; however, the deletion of interleukin-4R alpha or transforming growth factor-beta 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-4R alpha-/- 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-4R alpha or one allele of transforming growth factor-beta 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-beta 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.
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