INTERLEUKIN-1 (IL-1) RECEPTOR ANTAGONIST AND SOLUBLE IL-1 RECEPTOR INHIBIT IL-1-INDUCED GLYCOSAMINOGLYCAN PRODUCTION IN CULTURED HUMAN ORBITAL FIBROBLASTS FROM PATIENTS WITH GRAVES OPHTHALMOPATHY

An accumulation of glycosaminoglycans (GAG) is a feature characteristi c of orbital connective tissues from patients with Graves' ophthalmopa thy (GO) that leads directly to the clinical expressions of the diseas e. Interleukin-1 (IL-1), produced by macrophages and fibroblasts withi n the diseased orbit, stimulates GAG synthesis by orbital fibroblasts. We designed the current study to determine whether particular agents might block this effect and thus be useful in the treatment of GO. Orb ital fibroblast cultures were grown to confluence and incubated for 48 h with IL-1 (1-10 U/mL) alone or IL-1 (10 U/mL) in combination with I L-1 receptor antagonist (IL-1ra; 1-40 ng/mL) or soluble IL-1 receptor (sIL-1R; 0.25-10 mu g/mL). Cells were labeled with [H-3]glucosamine an d processed for GAG quantitation. The addition of IL-1 alone stimulate d GAG synthesis by 73-176%(mean, 104%; P < 0.05). Significant inhibiti on of IL-1-stimulated GAG synthesis was observed after treatment of no rmal fibroblasts with IL-1ra at a concentration of 5 ng/mL (12.5-fold molar excess; mean, 33%; P < 0.05); essentially complete inhibition wa s achieved at 40 ng/mL (100-fold molar excess; mean, 86%; P < 0.05). S ignificant inhibition of GAG synthesis by sIL-1R was observed at a con centration of 0.5 mu g/mL (720-fold molar excess; mean, 79%; P < 0.05) , and inhibition was essentially complete at 1 mu g/mL (1440-fold mola r excess; mean, 89%; P < 0.05). IL-1ra and sIL-1R are potent inhibitor s of IL-1-induced GAG production by cultured human orbital fibroblasts . Our results suggest that these two compounds, shown in early trials to be safe when administered parenterally, may be useful in the preven tion or treatment of GO.