Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma.
The tight-skin (Tsk/+) mutant mouse, a putative murine model of scleroderma, is characterized primarily by the excessive deposition of collagen and other extracellular matrix molecules in the dermis, and also by a developmentally acquired defect in pulmonary architecture. Passive transfer experiments have suggested an etiologic role for the immune system in Tsk/+ dermal pathology. In addition, CD4+ T lymphocytes have been shown to be required for the excessive accumulation of dermal collagen in these mice. As IL-4, a product of differentiated CD4+ T cells, is capable of regulating the synthesis of various matrix molecules (including type I collagen) by fibroblasts in vitro, we investigated the potential role of IL-4 in mediating Tsk/+ dermal fibrosis. Confirming that Tsk/+ cells are capable of responding to IL-4, we found receptors for this cytokine on Tsk/+ embryonic fibroblasts and a dermal fibroblast cell line derived from these mice. Furthermore, IL-4 receptors on Tsk/+ fibroblasts were functional since IL-4 stimulation in vitro increased type I collagen secretion from these cells. These results demonstrated the potential for IL-4 to be directly involved in the excessive deposition of dermal collagen in Tsk/+ mice. Critical insight into the role played by IL-4 in mediating the dermal phenotype, however, was obtained following the administration of neutralizing anti-lL-4 antibodies to Tsk/+ mice. This treatment prevented the development of dermal fibrosis, leading to normalization of dermal collagen content. Given the requirement for CD4+ T cells in Tsk/+ dermal fibrosis, our results suggest that Th2 cells and/or factors elaborated by this T cell subset may play a key role in regulating dermal collagen content in this strain.
Ong
C
C
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Wong
C
C
Roberts
C R
CR
Teh
H S
HS
Jirik
F R
FR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D015847:Interleukin-4 / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D012595:Scleroderma, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D012867:Skin / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015847:Interleukin-4; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase