Lack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the interleukin-4R alpha and transforming growth factor-beta genes.
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.
McGaha
T
T
Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Saito
S
S
Phelps
R G
RG
Gordon
R
R
Noben-Trauth
N
N
Paul
W E
WE
Bona
C
C
D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D003433:Crosses, Genetic; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D019948:Receptors, Interleukin-4 / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000235:genetics; D012867:Skin / Q000473:pathology*; D012868:Skin Abnormalities / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015291:Transforming Growth Factors / Q000235:genetics*
D019948:Receptors, Interleukin-4; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D015291:Transforming Growth Factors; D003094:Collagen