Inhibitory effect of pentoxifylline on HLA-DR expression and glycosaminoglycan synthesis by retrobulbar fibroblasts

Objective. Glycosaminoglycan (GAG) production by retroocular fibroblasts (REF) is increased in patients with thyroid-associated ophthalmopathy (TAO). Various cytokines stimulate REFs to proliferate and elaborate GAG, free oxygen radicals as well as induce HLA-DR expression on these cells. Pentoxifyllin (Ptx) regulates the production of several cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and, interferon gamma (IFN-gamma). We wished in this study to determine whether Ptx modified the spontaneous and cytokine-induced GAG synthesis by REF and IFN-gamma induced HLA-DR expression. Design. REF derived from extraocular muscles of healthy subjects were cultured without and with cytokines (IFN-gamma, TNF alpha and IL-1) and the effect of Ptx on the production of GAG by REF and HLA-DR expression was determined. Measurements. Glycosaminoglycan was measured by incorporation of (H-3) glycosamine into GAG. HLA-DR expression was analyzed by fluorescence activated cell sorter. Results. Both spontaneous and cytokine induced GAG synthesis by REF was inhibited by Ptx (100, 500 and 1000 mg/l, respectively). IFN-gamma (50, 100 and 500 U/ml) induced a dose-dependent increase in the expression of HLA-DR molecules by REF. Ptx, which was not toxic to REF, inhibited HLA-DR expression on those cells dose-dependently. Conclusions. Our in vitro results suggest that Ptx reduces cytokine-induced GAG production and HLA-DR expression by REF. It thus has potential as a therapeutic agent which regulates the function of lymphocytes infiltrating the retro-orbital tissues, and which are instrumental in TAO.