Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma

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Abstract
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‐IL‐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.