A pharmacological protein kinase D inhibitor ameliorates experimental arthritis. (THER6P.850)

Abstract

Abstract While the factors that initiate and perpetuate inflammation in rheumatoid arthritis (RA) are not well understood, it is thought that RA may be initiated in part by signaling through Toll-like receptors (TLRs). Disruption of the TLR signaling pathway may provide an opportunity to halt the RA process in the earliest stages of development. We previously found that protein kinase D1 (PKD1) is essential for proinflammatory responses mediated by MyD88-dependent TLRs. Here, we investigated whether PKD1 is involved in exaggerated proinflammatory responses seen in RA patients, and in the development of experimental arthritis. PKD1 was constitutively hyperactivated in synoviocytes of RA patients, and was rapidly activated in synoviocytes of normal donors and RA patients in response to TLR/IL-1R ligands. Silencing PKD1 expression in RA synoviocytes resulted in substantial inhibition of both spontaneous and TLR/IL-1R-mediated expression of cytokines/chemokines. Suppression of PKD1 expression also resulted in inhibition of TLR/IL-1R-mediated cytokine production in IL-1R antagonist-deficient (IL-1rn-/-) macrophages. In addition, daily treatment with a PKD inhibitor substantially reduced the incidence and severity of spontaneously occurring inflammatory arthritis in IL-1rn-/- mice, and collagen-induced arthritis in humanized HLA-DR1 mice. This implies that PKD1 might be one of the key regulatory factors that modulate proinflammatory responses in RA, and can be a therapeutic target for RA.