Ameliorating effects of Gö6976, a pharmacological agent that inhibits protein kinase D, on collagen-induced arthritis

• Published in: PloS one 2019-12, Vol.14 (12), p.e0226145
• Main Authors: Yoon, Tae Won, Kim, Young-In, Cho, Hongsik, Brand, David D, Rosloniec, Edward F, Myers, Linda K, Postlethwaite, Arnold E, Hasty, Karen A, Stuart, John M, Yi, Ae-Kyung
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Apoptosis; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - enzymology; Arthritis, Experimental - immunology; Biochemistry; Biology and Life Sciences; Biomedical engineering; Bone surgery; Cancer therapies; Carbazoles - administration & dosage; Carbazoles - pharmacology; Cell activation; Cell cycle; Cell proliferation; Cells, Cultured; Chemokines; Collagen; Collagen (type II); Collagen Type II - adverse effects; Cytokines; Deoxyribonucleic acid; Disease; Disruption; DNA; DNA damage; Human behavior; Humans; Immunization; Immunoglobulin G; Immunology; Inflammation; Interleukin 1 receptors; Kinases; Ligands; Lymphocytes T; Macrophages; Medicine; Medicine and Health Sciences; Mice; MyD88 protein; Orthopedics; Pathogenesis; Pediatrics; Protein kinase; Proteins; Receptors, Interleukin-1 - metabolism; Research and Analysis Methods; Serum levels; Signal transduction; Signaling; Spleen; Synergistic effect; Synoviocytes; Synoviocytes - drug effects; Synoviocytes - enzymology; Synoviocytes - immunology; T cell receptors; T-cell receptor; Therapeutic applications; Toll-like receptors; Toll-Like Receptors - metabolism; TRPP Cation Channels - antagonists & inhibitors; Veterans
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0226145

Toll-like receptor (TLR) signaling can contribute to the pathogenesis of arthritis. Disruption of TLR signaling at early stages of arthritis might thereby provide an opportunity to halt the disease progression and ameliorate outcomes. We previously found that Gö6976 inhibits TLR-mediated cytokine production in human and mouse macrophages by inhibiting TLR-dependent activation of protein kinase D1 (PKD1), and that PKD1 is essential for proinflammatory responses mediated by MyD88-dependent TLRs. In this study, we investigated whether PKD1 contributes to TLR-mediated proinflammatory responses in human synovial cells, and whether Gö6976 treatment can suppress the development and progression of type II collagen (CII)-induced arthritis (CIA) in mouse. We found that TLR/IL-1R ligands induced activation of PKD1 in human fibroblast-like synoviocytes (HFLS). TLR/IL-1R-induced expression of cytokines/chemokines was substantially inhibited in Gö6976-treated HFLS and PKD1-knockdown HFLS. In addition, serum levels of anti-CII IgG antibodies, and the incidence and severity of arthritis after CII immunization were significantly reduced in mice treated daily with Gö6976. Synergistic effects of T-cell receptor and TLR, as well as TLR alone, on spleen cell proliferation and cytokine production were significantly inhibited in the presence of Gö6976. Our results suggest a possibility that ameliorating effects of Gö6976 on CIA may be due to its ability to inhibit TLR/IL-1R-activated PKD1, which might play an important role in proinflammatory responses in arthritis, and that PKD1 could be a therapeutic target for inflammatory arthritis.