Regulation of Inflammatory Responses in Tumor Necrosis Factor-activated and Rheumatoid Arthritis Synovial Macrophages by JAK Inhibitors

Overview

Journal Arthritis Rheum

Specialty Rheumatology

Date 2012 Sep 4

PMID 22941906

Citations 52

Authors

Anna Yarilina

Kai Xu

Chunhin Chan

Lionel B Ivashkiv

Affiliations

Soon will be listed here.

Abstract

Objective: JAK inhibitors have been developed as antiinflammatory and immunosuppressive agents and are currently undergoing testing in clinical trials. The JAK inhibitors CP-690,550 (tofacitinib) and INCB018424 (ruxolitinib) have demonstrated clinical efficacy in rheumatoid arthritis (RA). However, the mechanisms that mediate the beneficial actions of these compounds are not known. The purpose of this study was to examine the effects of both JAK inhibitors on inflammatory and tumor necrosis factor (TNF) responses in human macrophages.

Methods: In vitro studies were performed using peripheral blood macrophages derived from healthy donors and treated with TNF and using synovial fluid macrophages derived from patients with RA. Levels of activated STAT proteins and other transcription factors were detected by Western blotting, and gene expression was measured by real-time polymerase chain reaction analysis. The in vivo effects of JAK inhibitors were evaluated in the K/BxN serum-transfer model of arthritis.

Results: JAK inhibitors suppressed the activation and expression of STAT-1 and downstream inflammatory target genes in TNF-stimulated and RA synovial macrophages. In addition, JAK inhibitors decreased nuclear localization of NF-κB subunits in TNF-stimulated and RA synovial macrophages. CP-690,550 significantly decreased the expression of interleukin-6 in synovial macrophages. JAK inhibitors augmented nuclear levels of NF-ATc1 and cJun, followed by increased formation of osteoclast-like cells. CP-690,550 strongly suppressed K/BxN serum-transfer arthritis, which is dependent on macrophages, but not lymphocytes.

Conclusion: Our findings demonstrate that JAK inhibitors suppress macrophage activation and attenuate TNF responses and further suggest that suppression of cytokine/chemokine production and innate immunity contribute to the therapeutic efficacy of JAK inhibitors.

Citing Articles

Evaluation of gecacitinib vs hydroxyurea in patients with intermediate-2 or high-risk myelofibrosis: final analysis results from a randomized phase 3 study.

Zhang Y, Zhou H, Suo S, Zhuang J, Yang L, He A Blood Cancer J. 2024; 14(1):216.

PMID: 39695117 PMC: 11655548. DOI: 10.1038/s41408-024-01202-8.

JAK Inhibitors for the Treatment of Axial Spondyloarthritis.

Klavdianou K, Papagoras C, Baraliakos X Mediterr J Rheumatol. 2023; 34(2):129-138.

PMID: 37654636 PMC: 10466367. DOI: 10.31138/mjr.34.2.129.

Case report: JAK inhibition as promising treatment option of fatal RVCLS due to mutation (pVAL235Glyfs6).

Ufer F, Ziegler S, Altfeld M, Friese M Front Neurol. 2023; 14:1118369.

PMID: 36895907 PMC: 9989011. DOI: 10.3389/fneur.2023.1118369.

JAK inhibitors disrupt T cell-induced proinflammatory macrophage activation.

Nyirenda M, Nijjar J, Frleta-Gilchrist M, Gilchrist D, Porter D, Siebert S RMD Open. 2023; 9(1).

PMID: 36599629 PMC: 9815080. DOI: 10.1136/rmdopen-2022-002671.

A novel selective spleen tyrosine kinase inhibitor SKI-O-703 (cevidoplenib) ameliorates lupus nephritis and serum-induced arthritis in murine models.

Cho S, Jang E, Yoon T, Hwang H, Youn J Clin Exp Immunol. 2022; 211(1):31-45.

PMID: 36346114 PMC: 9993459. DOI: 10.1093/cei/uxac096.

References

Hogan P, Chen L, Nardone J, Rao A . Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003; 17(18):2205-32. DOI: 10.1101/gad.1102703. View

Ghoreschi K, Laurence A, OShea J . Janus kinases in immune cell signaling. Immunol Rev. 2009; 228(1):273-87. PMC: 2782696. DOI: 10.1111/j.1600-065X.2008.00754.x. View

Feldmann M . Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol. 2002; 2(5):364-71. DOI: 10.1038/nri802. View

Takayanagi H, Sato K, Takaoka A, Taniguchi T . Interplay between interferon and other cytokine systems in bone metabolism. Immunol Rev. 2005; 208:181-93. DOI: 10.1111/j.0105-2896.2005.00337.x. View

Paniagua R, Si M, Flores M, Rousvoal G, Zhang S, Aalami O . Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. Transplantation. 2005; 80(9):1283-92. DOI: 10.1097/01.tp.0000177643.05739.cd. View

Kim S, Koga T, Isobe M, Kern B, Yokochi T, Chin Y . Stat1 functions as a cytoplasmic attenuator of Runx2 in the transcriptional program of osteoblast differentiation. Genes Dev. 2003; 17(16):1979-91. PMC: 196253. DOI: 10.1101/gad.1119303. View

Yamaoka K, Tanaka Y . Jak inhibitor ; possibility and mechanism as a new disease modifying anti-rheumatic drug. Nihon Rinsho Meneki Gakkai Kaishi. 2009; 32(2):85-91. DOI: 10.2177/jsci.32.85. View

Yarilina A, DiCarlo E, Ivashkiv L . Suppression of the effector phase of inflammatory arthritis by double-stranded RNA is mediated by type I IFNs. J Immunol. 2007; 178(4):2204-11. DOI: 10.4049/jimmunol.178.4.2204. View

Ji H, Pettit A, Ohmura K, Ortiz-Lopez A, Duchatelle V, Degott C . Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis. J Exp Med. 2002; 196(1):77-85. PMC: 2194010. DOI: 10.1084/jem.20020439. View

10.

Hu X, Chakravarty S, Ivashkiv L . Regulation of interferon and Toll-like receptor signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol Rev. 2009; 226:41-56. PMC: 2630590. DOI: 10.1111/j.1600-065X.2008.00707.x. View

11.

Rosengren S, Corr M, Firestein G, Boyle D . The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis. 2011; 71(3):440-7. DOI: 10.1136/ard.2011.150284. View

12.

Gordon R, Grigoriev G, Lee A, Kalliolias G, Ivashkiv L . The interferon signature and STAT1 expression in rheumatoid arthritis synovial fluid macrophages are induced by tumor necrosis factor α and counter-regulated by the synovial fluid microenvironment. Arthritis Rheum. 2012; 64(10):3119-28. PMC: 3449023. DOI: 10.1002/art.34544. View

13.

Conklyn M, Andresen C, Changelian P, Kudlacz E . The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. J Leukoc Biol. 2004; 76(6):1248-55. DOI: 10.1189/jlb.0504282. View

14.

Bezbradica J, Medzhitov R . Integration of cytokine and heterologous receptor signaling pathways. Nat Immunol. 2009; 10(4):333-9. DOI: 10.1038/ni.1713. View

15.

Hamilton J, Tak P . The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases. Arthritis Rheum. 2009; 60(5):1210-21. DOI: 10.1002/art.24505. View

16.

Parganas E, Wang D, Stravopodis D, Topham D, Marine J, Teglund S . Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998; 93(3):385-95. DOI: 10.1016/s0092-8674(00)81167-8. View

17.

Korganow A, Ji H, Mangialaio S, Duchatelle V, Pelanda R, Martin T . From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity. 1999; 10(4):451-61. DOI: 10.1016/s1074-7613(00)80045-x. View

18.

van der Pouw Kraan T, van Gaalen F, Kasperkovitz P, Verbeet N, Smeets T, Kraan M . Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum. 2003; 48(8):2132-45. DOI: 10.1002/art.11096. View

19.

McInnes I, Schett G . The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011; 365(23):2205-19. DOI: 10.1056/NEJMra1004965. View

20.

Rodig S, Meraz M, White J, Lampe P, Riley J, Arthur C . Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998; 93(3):373-83. DOI: 10.1016/s0092-8674(00)81166-6. View