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

• Published in: European journal of immunology Vol. 28; no. 9; pp. 2619 - 2629
• Main Authors: Ong, Christopher, Wong, Connie, Roberts, Clive R., Teh, Hung‐Sia, Jirik, Frank R.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY‐VCH Verlag GmbH 01.09.1998
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Collagen; Collagen - antagonists & inhibitors; Collagen - metabolism; Disease Models, Animal; IL‐4; immune deviation; Interleukin-4 - immunology; Mice; Mice, Mutant Strains; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - immunology; Scleroderma; Scleroderma, Systemic - genetics; Scleroderma, Systemic - immunology; Scleroderma, Systemic - metabolism; Skin - immunology; Skin - metabolism; T-Lymphocytes - immunology; Tsk
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/(SICI)1521-4141(199809)28:09<2619::AID-IMMU2619>3.0.CO;2-M

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.