Glucocorticoids (GCs) are potent anti-inflammatory agents that are widely agents that are widely used in the treatment of rheumatic diseases, including rheumatoid arthritis (RA) and systematic lupus erythematosis (SLE). GCs represent a highly effective therapy, but use is limited by side effects. Thus, there are extensive efforts underway to understand the mechanisms underlying the anti-inflammatory effects of GCS, with a view towards designing novel therapeutic compounds that avoid the limiting toxicities associated with long term GC treatment. A large body of evidence suggests that one major mechanism underlying anti- inflammatory actions of GCs is the expression of cytokines and chemokines, including IL-1, IL-2, IL-6, IFNgamma, and IL-8. This suppression is accomplished by antagonizing the AP-1 and NF-kappaB transcription factors. Although blockade of AP-1 and NF-kappaB action would partially block signaling by IL-1 and TNFalpha, this mechanism does not affect signaling by cytokines, such as IL-2, IL-4, IL-6, and IFNgamma, which utilize the Jak-STAT (signal transducer and activator of transcription) pathway for signal transduction. Limited information exists concerning the effects of GCs on Jak-STAT signaling, but the recent description of physical and functional interactions between glucocorticoid receptors (GCRs) and Stat5 led up to explore the interactions of GC and Jak-STAT signaling. Preliminary results demonstrate that pretreatment of cells with GCs leads to suppression of STAT activation by IL-2, IL-4, and IFNgamma, but not IL-6. Inhibition of IL-2 triggered Stat5 activation correlated with suppression of gene activation and proliferation. We hypothesize that GCS suppress cytokine signaling by inhibiting the Jak-STAT pathway, and that suppression of cytokine signaling is an important component of the anti-inflammatory effects of GCS. Two independent levels of action of inhibiting both the production and activity of certain cytokines may explain the anti- inflammatory potency of these agents. These hypotheses will be tested in the following specific aims: (1) To delineate the mechanisms by which GCS inhibit signaling by cytokines that utilize the Jak-STAT signal transduction pathway. (2) To characterize the functional consequences of GC inhibition of cytokine signaling in the context of the pathogenesis of SLE and RA, and determine whether the suppressive effects of GCS are mediated through inhibition of STAT proteins. (3) To determine the mechanisms by which GC treatment of SLE and RA patients lead to suppression of cytokine signaling by the Jak-STAT pathway in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046712-02
Application #
6362438
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Ridge, John P
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
2
Fiscal Year
2001
Total Cost
$231,531
Indirect Cost
Name
Hospital for Special Surgery
Department
Type
DUNS #
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
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
Kang, Kyuho; Park, Sung Ho; Chen, Janice et al. (2017) Interferon-? Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF. Immunity 47:235-250.e4
Ivashkiv, Lionel B; Park, Sung Ho (2016) Epigenetic Regulation of Myeloid Cells. Microbiol Spectr 4:
Qiao, Yu; Kang, Kyuho; Giannopoulou, Eugenia et al. (2016) IFN-? Induces Histone 3 Lysine 27 Trimethylation in a Small Subset of Promoters to Stably Silence Gene Expression in Human Macrophages. Cell Rep 16:3121-3129
Lee, Min Joon; Lim, Elisha; Mun, Sehwan et al. (2016) Intravenous Immunoglobulin (IVIG) Attenuates TNF-Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression. J Cell Physiol 231:449-458
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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