Skip to main content
  • Poster presentation
  • Open access
  • Published:

Regulation of macrophage-mediated chronic inflammation by JAK inhibitors

Small molecule inhibitors of the Janus kinases (JAK) have been developed as anti-inflammatory and immunosuppressive agents and are currently subjects of clinical trials. Tofacitinib/CP-690,550 (more potent in inhibiting JAK3 and JAK1) and Ruxolitinib/INCB-018424 (selective inhibitor of JAK1/2) have demonstrated clinical efficacy in rheumatoid arthritis (RA), however, the exact mechanisms that mediate the inhibitory effects of these compounds are not known.

In this study, we examined the effects of CP-690,550 (CP) and INCB-018424 (INCB) on inflammatory responses in human macrophages (hMΦs). In our study, we used long term exposure to TNF as a model of chronic inflammation to investigate mechanisms regulating hMΦ activation and functions, and have shown that TNF can activate an IFN-JAK-STAT-dependent autocrine loop that regulates expression of pro-inflammatory chemokines and interferon stimulated genes (ISGs), followed by an increase of NFATc1, that regulates osteoclastogenesis.

As expected, both inhibitors abrogated TNF-induced STAT1 activation and expression of genes encoding inflammatory chemokines (CXCL9, 10, 11 and CCL5) and ISGs (IFIT1 and 2, IRF7). Interestingly, both compounds attenuated a late wave of IL-1 induction and nuclear expression of NF-κB subunits. Furthermore, ex vivo treatment with inhibitors decreased IL-1 and IL-6 expression in synovial MΦs isolated from the patients with arthritis. Next, we analyzed the effects of JAK inhibitors on TNF-induced osteoclastogenesis and discovered that both compounds augmented nuclear levels of NFATc1 and cJun, followed by increased formation of TRAP positive multinuclear cells. Lastly, we examined an in vivo effect of CP on innate immune response in arthritis using K/BxN serum transfer arthritis model and found that CP treatment significantly inhibited inflammation and joint swelling. Taken together, our data suggest that JAK inhibitors can affect inflammatory responses in hMΦs and thus, can target both acquired and innate immunity in RA and other chronic inflammatory diseases.

Author information

Authors and Affiliations

Authors

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article

Yarilina, A., Xu, K., Chan, C. et al. Regulation of macrophage-mediated chronic inflammation by JAK inhibitors. Arthritis Res Ther 14 (Suppl 1), P78 (2012). https://doi.org/10.1186/ar3679

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/ar3679

Keywords