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Increased Induction of HLA-DR by Interferon- in Cultured Fibroblasts Derived from Patients with Graves’ Ophthalmopathy and Pretibial Dermopathy^*

Division of Endocrinology, Department of Medicine, Mayo Clinic/Foundation Rochester, Minnesota 55905
The Division of Molecular and Cellular Medicine, Department of Medicine, Albany Medical College and Veterans Administration Medical Center Albany, New York 12208

Address all correspondence and requests for reprints to: R. S. Bahn, M.D., Division of Endocrinology, Mayo Clinic, Rochester, Minnesota 55905.

We investigated the effects of several cytokines on HLA-DR expression in cultured fibroblasts derived from retroocular connective tissue and pretibial and abdominal skin of patients with Graves’ ophthalmopathy (GO) and pretibial dermopathy (PTD), as well as from normal individuals. We hypothesized that differences in response to cytokines between fibroblasts from various anatomical areas might play a role in the site-selective involvement of the extrathyroidal manifestations of Graves’ disease. HLA-DR expression in fibroblasts was quantitated by scanning densitometry of whole cell lysates subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Direct immunofluorescence of cell monolayers was also performed. We hypothesize that unique characteristics of these fibroblasts may play a role in GO and PTD.

Cultured retroocular, pretibial, and abdominal fibroblasts from patients with Graves’ disease as well as from normal individuals did not express HLA-DR spontaneously. Treatment in vitro with interferon- (IFN; 100 U/mL) for 5 days induced HLA-DR by 50- to 80-fold (P < 0.0001) in fibroblasts from all sites and subjects studied. However, IFN-induced HLA-DR expression was significantly greater in retroocular (P < 0.005) and pretibial (P < 0.0005) fibroblasts from patients with GO and PTD than in fibroblasts obtained from the same anatomical sites of normal individuals. Further, retroocular and pretibial fibroblasts from patients with GO and PTD responded to IFN more vigorously than did abdominal fibroblasts from these same patients (P < 0.0001). IFN-induced HLA-DR expression was enhanced by concomitant treatment with tumor necrosis factor- (100 U/mL). In contrast, treatment of retroocular fibroblasts with transforming growth factor-β (10 ng/mL), epidermal growth factor (1 ng/mL), or interleukin-6 (IL-6; 100 U/mL) significantly attenuated IFN-induced HLA-DR reactivity by 40–59% (P < 0.05). Incubation of retroocular fibroblasts with tumor necrosis factor-, IL-1 (10 U/mL), IL-2 (10 U/mL), IL-6, granulocyte-macrophage colony-stimulating factor (100 U/mL), epidermal growth factor, and transforming growth factor-β alone did not affect HLA-DR expression.

These results indicate that several cytokines can influence HLA-DR expression in cultured fibroblasts. The enhanced induction of HLA-DR by IFN in retroocular and pretibial fibroblasts compared with that in abdominal fibroblasts may partially explain the selective involvement of the retroocular connective tissue and pretibial skin in fully expressed Graves disease.

^* This work was supported in part by a postdoctoral grant from Deutsche Forschungsgemeinschaft (He 1485/2–1) and the Research Service of the V.A.

Received December 10, 1990.

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