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

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-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.

Novel Model of Constrictive Pericarditis Associated With Autoimmune Heart Disease in Interferon-γ–Knockout Mice

“…8 The fibrogenic role of IL-4 and IL-13 has been demonstrated with the use of Schistosoma mansoni-induced fibrotic hepatic disease, 8,17 and blocking IL-4 prevented collagen deposition and fibrosis in a mouse model of scleroderma. 18 In vitro studies have further confirmed the stimulatory effects of IL-4 and suppressive effects of IFN-␥ on fibroblast proliferation and collagen deposition. 19,20 It is therefore likely that Th2 cytokines are important for the development of fibrosis in the pericardium in EAM.…”

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

“…Recently, the pivotal role of CD4 + T cells in the progression of renal fibrosis was discovered using severe combined immunodeficient mice and a depleting anti-CD4 antibody. 21 Furthermore, numerous studies in cytokinedeficient mice and using neutralizing antibodies have demonstrated that the development of the CD4 + Th2 cell response, including the local production of IL-4 and IL-13, is strongly associated with liver fibrosis, 22,23 scleroderma, 24 and pulmonary fibrosis. [25][26][27] Stimulation of cultured fibroblasts with IL-4 or IL-13 triggers upregulation of the expression of the extracellular matrix proteins type I and III collagen.…”

Th2‐oriented profile of male offspring T cells present in women with systemic sclerosis and reactive with maternal major histocompatibility complex antigens

“…Both SSc and cGVHD are characterized by skin, lung, and esophageal involvement and intense fibrosis (1,2). Immunologic similarities include lymphocytic infiltration of affected tissues, the presence of Scl-70 and PM-Scl serum autoantibodies, and up-regulation of a series of cytokines (1,2,(5)(6)(7)(8). Moreover, several reports have indicated that IL-4 production by CD4ϩ T cells infiltrating SSc and cGVHD lesions is prominent in both animal models and humans, suggesting a Th2-polarized phenotype of the specific immune response in both conditions (5)(6)(7)(8)10,11).…”

“…The selected CD4ϩ T cell population derived from fetal cell engraftment may be at least partially included in the population of T cells expressing IL-4 that are found in the skin of patients with SSc (5), and it is probably responsible for the enhanced levels of IL-4 in the biologic fluids of these patients (6)(7)(8). Thus, although the results of this study need further investigation, they provide support for the hypothesis that a fetal antimaternal cGVHD may be an immunopathogenic mechanism in the development of SSc in some women.…”

“…We and other investigators have reported the existence of a predominant activation of IL-4-producing Th2-like T cells in patients with SSc, which may account for the major alterations that occur in this disease (5)(6)(7)(8).…”