Interferon gamma in autoimmunity: A complicated player on a complex stage

Lees, Jason R.

doi:10.1016/j.cyto.2014.10.014

Cited by 72 publications

(70 citation statements)

References 172 publications

(175 reference statements)

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“…This reasoning is supported by the observation that the Th1, Th2, and Th17 cells can modulate each other’s development/activity in part via specific cytokines secreted by them [24, 58]. IFN-γ may play a role in the induction and maintenance of autoimmune inflammation under certain set of conditions [1, 59, 60], yet be protective against arthritis and other autoimmune diseases under another set of conditions [61–63]. In this context, we proposed a model in which a particular threshold of IFN-γ was required for the initiation of inflammation, whereas secretion of a critical, higher level of IFN-γ instead triggered regulatory mechanisms to suppress the ongoing disease [6, 37].…”

Section: Ifn-γ-induced Immune Regulationmentioning

confidence: 99%

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

2017

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Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed a paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.

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Section: Ifn-γ-induced Immune Regulationmentioning

confidence: 99%

Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines

2017

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“…For example, the formation of the heterotrimeric transcription factor complex known as ISGF3 between Stat1 and IFN-regulatory factor 9 (Irf9) required type I IFN priming and prolonged IFN␥ activation (Fig. 1A) (62,63). Those complexes elicited Stat1 regulation over gene promoters with GAS and/or interferonstimulated response elements (ISRE) (64) allowing regulation of genes with either one or both elements such as the IFN␥-regulated cytokine CXCL10/Cxcl10 (IP-10) (65).…”

Section: Chronic Exposure To Ifn␥ Leads To Adsmentioning

confidence: 99%

Current prospects of type II interferon γ signaling and autoimmunity

Green

Young

Valencia

2017

Journal of Biological Chemistry

138

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Edited by Charles E. SamuelInterferon ␥ (IFN␥) is a pleiotropic protein secreted by immune cells. IFN␥ signals through the IFN␥ receptor, a protein complex that mediates downstream signaling events. Studies into IFN␥ signaling have provided insight into the general concepts of receptor signaling, receptor internalization, regulation of distinct signaling pathways, and transcriptional regulation. Although IFN␥ is the central mediator of the adaptive immune response to pathogens, it has been shown to be involved in several non-infectious physiological processes. This review will provide an introduction into IFN␥ signaling biology and the functional roles of IFN␥ in the autoimmune response.According to the National Institutes of Health, autoimmune diseases (ADs) 3 are one of the top 10 leading causes of death in female children and women in all age groups up to 64 years of age (1). Excess secretion of IFNs has been associated with development of human ADs (2). Interferons (IFNs) comprise a family of proteins classified as type I (IFN-␣, -␤, -⑀, -, and -), type II (IFN-␥, herein IFN␥), and type III (IFN-1-4) that have pleiotropic roles in immunity, cancer biology, and autoimmunity (2). Here, we aim to provide a basic understanding of the functions of the type II IFN␥ and the IFN␥-signaling pathway (hereafter referred to as IFN signaling) in a contextual and timing perspective related to the autoimmune environment and the development of ADs.

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“…29,30 We and others have reported inhibition of hematopoiesis by IFN-g in assays of human progenitor cells in vitro, [20][21][22]31 overexpression of its gene in bone marrow (BM) cells and T cells, 32,33 upregulation of genes downstream of IFN-g signaling, and alterations of the T-bet regulator of IFN-g in BM failure. 12,34 In our murine models of immune-mediated marrow destruction, infusion of H2 or minor histocompatibility antigen mismatched lymph node (LN) cells rapidly induces AA with elevated circulating IFN-g. 35 Development of marrow failure can be ameliorated by both broadly acting immunosuppressive agents and monoclonal antibody specific to IFN-g. 36,37 Inhibitory effects of IFN-g on human hematopoietic cells have been localized molecularly to an essential role for Mnk kinases and sprouty proteins. 38,39 IFN-g appears to suppress HSC self-renewal and multilineage differentiation, thus impairing normal hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%

“…8,9 However, the precise roll of IFN-g in animal models, and particularly in human diseases, has not always been easy to define because of conflicting data among experiments and sometimes strikingly poor correlation between murine experiments and the clinic. [10][11][12] Effects of IFN-g on hematopoiesis, mainly assessed by progenitor assays in vitro, have been reported as both stimulatory [13][14][15][16][17] and suppressive [18][19][20][21][22][23] under various circumstances. IFN-g has been reported to stimulate myelopoiesis under specific infectious conditions.…”

Section: Introductionmentioning

confidence: 99%