A pharmacological protein kinase C/D inhibitor Go6976 ameliorates collagen-induced arthritis

Abstract Toll-like receptor (TLR) signaling has been implicated with the initiation and progression of rheumatoid arthritis (RA). Disruption of TLR signaling at early stages of RA might thereby provide an opportunity to halt the RA progression and ameliorate outcomes. We previously found that protein kinase D1 (PKD1) is essential for proinflammatory responses mediated by MyD88-dependent TLRs, and TLR-dependent PKD1 activation is inhibited by Gö6976. However, it is currently unknown whether PKD1 plays a role in pathogenesis of RA and whether Gö6976 has ameliorating effects on arthritis. Here, we investigated whether PKD1 contributes to the TLR-mediated proinflammatory responses in human synovial cells, and to development and progression of type II collagen (CII)-induced arthritis (CIA; an experimental animal model for human RA). We found that PKD1 is constitutively hyperactivated in synoviocytes of RA patients, and is rapidly activated 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. Although Gö6976 had no effect on the TCR-induced cell proliferation and cytokine production, synergistic effects of TCR and TLR2, as well as TLR2 alone, on the spleen cell cytokine production and proliferation were significantly inhibited in the presence of Gö6976. In addition, daily treatment with Gö6976 significantly reduced serum levels of IFNg and anti-CII IgG, and the incidence and severity of arthritis in humanized HLA-DR1 transgenic mice immunized with CII. Our data suggest that PKD1 might play an important role in proinflammatory responses in RA and CIA, and could be a therapeutic target for arthritis.