? An important role for the balance between pro-inflammatory and anti-inflammatory cytokines in determining the severity and progression of rheumatoid arthritis (RA) is now well established. A key role for the inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) has been confirmed by the efficacy of new biological therapies that block TNF and IL-1 activity. RA synovitis is also characterized by the expression of the potent antiinflammatory cytokine IL-10. A key activity of IL-10 is the suppression of TNF and IL-1 production and activity. However, it is clear that, at least during active disease, synovial IL-10 is insufficient to suppress TNF and IL-1 to the point where synovitis diminishes or resolves. The presence of autoantibodies and immune complexes in RA synovium was discovered over 25 years ago, and a prominent role for immune complexes in RA pathogenesis has been proposed. Recently, there has been a resurgence of interest in the role of humoral immunity, immune complexes, and downstream effector pathways mediated by Fc receptors for IgG (Fc?Rs) and complement in RA pathogenesis. ? ? In this application, we propose to link the emerging ideas and evidence on the importance of autoantibodies and immune complexes in RA with the established paradigm concerning the importance of balance between pro- and antiinflammatory cytokines. Our hypothesis is that ligation of Fc?Rs by immune complexes in RA synovium shifts cytokine balance toward increased production of pro-inflammatory cytokines. This hypothesis is based upon our preliminary data that Fc?R ligation suppresses IL-10 signaling, Stat3 activation, and bioactivity, thus compromising the ability of IL-10 to suppress TNF production. We have found that IL-10 signaling is blocked in RA synovial macrophages. In addition, low levels of IFN7 (which activates Statl), such as those found in RA synovium, modulate Fc?TR expression and function to more strongly inhibit IL-10 signaling, with concomitant increases in TNF production. We propose that greater understanding of the molecular mechanisms that regulate IL-10 signaling in RA, and underlie the cross talk between Fc? Rs, IL-10, and IFN 7 will yield insight into RA pathogenesis and may serve as the basis for novel therapeutic approaches.
Our specific aims are to: 1. Delineate the molecular basis and pathophysiological significance of the suppression of IL-10 signaling in RA. 2. Identify mechanisms by which FcRs regulate cytokine balance in inflammatory arthritis using the K/BxN serum-induced arthritis murine model. 3. Characterize the effects of IFN7 and STATs on immune complex-induced, Fc?R-dependent arthritis, and explore underlying mechanisms. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050401-02
Application #
6948267
Study Section
Special Emphasis Panel (ZRG1-ACTS (01))
Program Officer
Gretz, Elizabeth
Project Start
2004-09-10
Project End
2009-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
2
Fiscal Year
2005
Total Cost
$348,076
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
Sokhi, Upneet K; Liber, Mark P; Frye, Laura et al. (2018) Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models. Nat Commun 9:658
Binder, Nikolaus; Miller, Christine; Yoshida, Masaki et al. (2017) Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption. J Immunol 198:3436-3447
Loupasakis, Konstantinos; Kuo, David; Sokhi, Upneet K et al. (2017) Tumor Necrosis Factor dynamically regulates the mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes. PLoS One 12:e0179762
Park, Sung Ho; Kang, Kyuho; Giannopoulou, Eugenia et al. (2017) Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Nat Immunol 18:1104-1116
Murata, Koichi; Fang, Celestia; Terao, Chikashi et al. (2017) Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis. Immunity 47:66-79.e5
Ivashkiv, Lionel B; Park, Sung Ho (2016) Epigenetic Regulation of Myeloid Cells. Microbiol Spectr 4:
Foldi, Julia; Shang, Yingli; Zhao, Baohong et al. (2016) RBP-J is required for M2 macrophage polarization in response to chitin and mediates expression of a subset of M2 genes. Protein Cell 7:201-9
Miller, Christine H; Smith, Sinead M; Elguindy, Mahmoud et al. (2016) RBP-J-Regulated miR-182 Promotes TNF-?-Induced Osteoclastogenesis. J Immunol 196:4977-86
Huynh, Linda; Kusnadi, Anthony; Park, Sung Ho et al. (2016) Opposing regulation of the late phase TNF response by mTORC1-IL-10 signaling and hypoxia in human macrophages. Sci Rep 6:31959
Kalliolias, George D; Ivashkiv, Lionel B (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12:49-62

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