Orbital fibroblast chemokine modulation: effects of dexamethasone and cyclosporin A

摘要

AIM—Orbital inflammation is common, but the mechanisms underlying leucocytic infiltration of orbital tissue are poorly understood. Human orbital fibroblasts (OF) express chemokines, interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1), when exposed to proinflammatory cytokines. The effects of dexamethasone (DEX) and cyclosporin A (CSA) on OF IL-8 and MCP-1 were examined.
METHODS—Cultured human OF were incubated with recombinant interleukin 1β (rIL-1β; 0.2, 2.0, 20 ng/ml) alone or incubated with rIL-1β and DEX (10^-8, 10^-7, 10^-6 M) or CSA (3, 30, 300 ng/ml) for 24 hours. ELISA and northern blot analyses were performed to determine OF IL-8 and MCP-1 protein secretion and mRNA expression, respectively.
RESULTS—OF lacked constitutive IL-8 or MCP-1 expression, but secreted significant amounts of these chemokines and expressed substantial steady state mRNA for both chemokines upon rIL-1β stimulation. DEX caused dose dependent inhibition of IL-1 induced IL-8 (p<0.001) and MCP-1 (p<0.05) secretion and mRNA expression at all concentrations of rIL-1β. CSA enhanced IL-1 induced OF IL-8 (p<0.001) and suppressed rIL-1β induced OF MCP-1 (p<0.05) secretion when lower doses of rIL-1β were used. These effects on secreted chemokines at different concentrations of rIL-1β and immunomodulating 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 effectiveness in human orbital diseases that respond to corticosteroids.

Keywords: orbital fibroblasts; chemokines; dexamethasone; cyclosporin A