Regulation of fibroblast function in systemic sclerosis
Description
Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by altered fibroblast function, the result of which is disfiguring and debilitating fibrosis of the skin and internal organs. The hallmarks of SSc include (i) overproduction of collagen by fibroblasts, (ii) vascular injury, and (iii) immune dysregulation. We have identified hallmarks which distinguish dermal fibroblasts in clinically affected skin of five SSc patients from dermal fibroblasts in unaffected skin of the same patients and of two healthy donors. Results demonstrate that affected SSc fibroblasts are distinct from unaffected and control fibroblasts with respect to several hallmarks: (1) affected SSc fibroblasts elaborate into their medium factor(s) which stimulate procollagen production and to which affected fibroblasts are differentially sensitive; (2) affected fibroblasts produce statistically significant levels of c-myc and c-myb mRNA without stimulation; (3) affected fibroblasts constitutively secrete up to thirtyfold more immunoreactive and biologically active interleukin-6 (IL-6) into their medium; (4) elevated production of IL-6 by SSc fibroblasts is due, in part, to increased steady-state levels of IL-6 mRNA and abundant constitutive binding of sequence-specific DNA-binding proteins to positive regulatory elements in the IL-6 promoter; and (5) levels of IL-6 receptor mRNA in affected SSc fibroblasts do not correlate with IL-6 mRNA levels. We have also examined the response of dermal fibroblasts to cytokines, such as IL-4 and IL-6, which are elaborated in the scleroderma lesions. Our data demonstrate that exogenously added IL-4 results in induction of dermal fibroblast proliferation and IL-6 production. The response of dermal fibroblasts to IL-4 is both dose- and time-dependent and may require the presence of an intermediate factor. Dermal fibroblasts also respond positively to exogenously added IL-6 by upregulating IL-6 gene expression. In view of the important and multiple physiological functions of IL-6, and in view of the inherent elevated production of IL-6 by intralesional fibroblasts, the response of dermal fibroblasts to exogenous IL-6 suggests the presence of an autocrine response mechanism which may play an important role in the perpetuation of immune dysregulation in the scleroderma lesion and in the alteration of fibroblast function