Ibudilast Inhibits Chemokine Expression in Rheumatoid Arthritis Synovial Fibroblasts and Exhibits Immunomodulatory Activity in Experimental Arthritis

Abstract

Ibudilast is a well-tolerated, orally available phosphodiesterase 4 (PDE4) inhibitor used to treat asthma and stroke. Since PDE4 inhibition suppresses inflammatory mediator production and cell proliferation in leukocytes, ibudilast may be a valuable therapy for the treatment of inflammatory autoimmune diseases such as rheumatoid arthritis (RA). This study was undertaken to assess the therapeutic potential of ibudilast by measuring its capacity to modulate inflammation in human leukocytes and RA synovial fibroblasts (RASFs) and in experimental arthritis. Using standard curve quantitative polymerase chain reaction, the effect of ibudilast on gene expression in activated human leukocytes and RASFs was measured. Ibudilast was used to treat DBA/1 mice with collagen-induced arthritis, and an adoptive transfer model was used to assess its tolerogenic capacity. Ibudilast inhibited the expression of TNF, IL12A, and IL12B and the secretion of tumor necrosis factor (TNF) and interleukin-12 (IL-12)/23p40 from leukocytes, and reduced the expression of CCL5 and CCL3 in activated RASFs. Treatment of experimental arthritis with ibudilast resulted in a reduction in IL-17-producing cells and inhibition of disease progression. When combined with a TNF inhibitor, ibudilast caused marked suppression of active disease. Exposure of leukocytes from type II collagen-immunized DBA/1 mice to ibudilast in vitro attenuated their ability to adoptively transfer arthritis to DBA/1J-PrkdcSCID mice, providing evidence of an immunomodulatory effect. Our findings indicate that ibudilast reduces the expression and/or secretion of inflammatory mediators from activated human leukocytes and RASFs, inhibits Th17 cell responses in vivo, and improves established arthritis. Given the established safety profile of ibudilast in humans, its clinical evaluation in RA, either alone or in combination with a TNF inhibitor, should be considered.