ORBITAL FIBROBLAST CHEMOKINE MODULATION - EFFECTS OF DEXAMETHASONE AND CYCLOSPORINE-A

Aim-Orbital inflammation is common, but the mechanisms underlying leuc ocytic infiltration of orbital tissue are poorly understood. Human orb ital fibroblasts (OF) express chemokines, interleukin 8 (IL-8) and mon ocyte chemotactic protein 1 (MCP-1), when exposed to proinflammatory c ytokines. The effects of dexamethasone (DEX) and cyclosporin A (CSA) o n OF IL-8 and MCP-1 were examined. Methods-Cultured human OF were incu bated with recombinant interleukin 1 beta (rIL-1 beta; 0.2, 2.0, 20 ng /ml) alone or incubated with rIL-1 beta and DEX (10(-8), 10(-7), 10(-6 ) M) or CSA (3, 30, 300 ng/ml) for 24 hours. ELISA and northern blot a nalyses were performed to determine OF IL-8 and MCP-1 protein secretio n and mRNA expression, respectively. Results-OF lacked constitutive IL -8 or MCP-1 expression, but secreted significant amounts of these chem okines and expressed substantial steady state mRNA for both chemokines upon rIL-1 beta stimulation. DEX caused dose dependent inhibition of IL-1 induced IL-8 (p<0.001) and MCP-1 (p<0.05) secretion and mRNA expr ession at all concentrations of rIL-1 beta. CSA enhanced IL-1 induced OF IL-8 (p<0.001) and suppressed rIL-1 beta induced OF MCP-1 (p<0.05) secretion when lower doses of rIL-1 beta were used. These effects on s ecreted chemokines at different concentrations of rIL-1 beta and immun omodulating agents were corroborated by steady state OF IL-8 and MCP-1 mRNA expression. Conclusions-DEX is a potent inhibitor of OF IL-8 and MCP-1. In contrast, CSA enhances IL-1 induced OF IL-8 and suppresses OF MCP-1. These observations may explain the relative lack of CSA effe ctiveness in human orbital diseases that respond to corticosteroids.