Effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate on experimentally induced autoimmune anterior uveitis.

PURPOSE: To determine the effect of pyrrolidine dithiocarbamate (PDTC), a nuclear factor (NF)-kappaB inhibitor, on chemokine and chemokine receptor expression and thus elucidate the role of NF-kappaB in the pathogenesis of experimental autoimmune anterior uveitis (EAAU).

METHODS

Uveitis was induced in Lewis rats with the injection of melanin-associated antigen into the footpad. PDTC (200 mg/kg and 100 mg/kg) was administered intraperitoneally daily, beginning 1 day after the immunization. The clinical inflammatory activity of the anterior chamber was recorded daily and scored. Immunohistochemical staining and an electrophoretic mobility shift assay assessed the effect of PDTC on NF-kappaB activation in the iris/ciliary body tissues. Gene expression profiles of chemokine and chemokine receptors were semiquantitatively examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Aqueous chemokine levels were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTS

PDTC significantly attenuated the clinical scores and monocyte/lymphocyte infiltration in rats with EAAU. PDTC effectively inhibited NF-kappaB activation in the iris and ciliary body, and markedly inhibited the expression of chemokine genes, including monocyte chemoattractant protein (MCP)-1, regulated-on-activation normal T-cell expressed and secreted (RANTES), and interleukin (IL)-8 and chemokine receptors genes including CCR2, CCR5, and CXCR3.

CONCLUSIONS

Activation of NF-kappaB appears to play an important role in the pathogenesis of EAAU, through transcriptional control of MCP-1, RANTES, and IL-8 gene expression. Blocking NF-kappaB reduces ocular inflammation and may be an effective strategy in the treatment of acute anterior uveitis.