Tacrolimus down-regulates chemokine expressions on rheumatoid synovial fibroblasts: screening by a DNA microarray.

Objective: Although the effects of tacrolimus on T cells are well-known, direct effects on rheumatoid synovial fibroblasts (RSF) remain unclear. We studied the effects of tacrolimus on RSF by a DNA microarray analysis.

Materials And Methods: Tacrolimus and interleukin (IL)-1β were added to cultured RSF. Total RNA was prepared from the cells and the gene expression profile was analyzed by a DNA microarray screening system. mRNA expressions influenced by tacrolimus in the screening system were confirmed by real-time PCR. The effects of tacrolimus on nuclear translocation of nuclear factor-κB (NF-κB) were also examined.

Results: The mRNA expressions of CCL3, CCL4, and CXCL8 were up-regulated by IL-1β and down-regulated by tacrolimus. The levels of these IL-1β-induced chemokines in culture supernatant were decreased by a therapeutic concentration of tacrolimus. Tumor necrosis factor-α as well as IL-1β induced these chemokines, while tacrolimus inhibited their production and mRNA expression. Chemotaxis of polymorphonuclear cells in response to IL-1β was also inhibited by tacrolimus. Nuclear translocation of p50 and p65 NF-κB in response to IL-1β was decreased by tacrolimus.

Conclusion: IL-1β-induced chemokine expressions were down-regulated by tacrolimus, suggesting that tacrolimus exerts its anti-inflammatory effect partly through inhibiting chemokine production by RSF.