From the Cover: Interplay Between IFN-γ and IL-6 Impacts the Inflammatory Response and Expression of Interferon-Regulated Genes in Environmental-Induced Autoimmunity

Abstract

IFN-γ has been found to be robustly important to disease pathogenesis in both idiopathic and induced models of murine lupus. In transgenic mice, over production of IFN-γ in the skin results in an inflammatory response and autoimmunity. This suggests that localized exposure to environmental factors that induce autoimmunity may be associated with expression of an IFN-γ-dependent inflammatory response. Using murine mercury-induced autoimmunity (mHgIA), the severity of inflammation and proinflammatory cytokine expression, including the cellular source of IFN-γ, were assessed at the site of subcutaneous exposure and in secondary lymphoid organs. Exposure induced a localized chronic inflammation comprising both innate and adaptive immune cells but only CD8+ T and NK cells were reduced in the absence of IFN-γ. IFN-γ+ cells began to appear as early as day 1 and comprised both resident (γδ T) and infiltrating cells (CD8+ T, NKT, CD11c+). The requirements for inflammation were examined in mice deficient in genes required (Ifng, Il6) or not required (Casp1) for mHgIA. None of these genes were essential for induction of inflammation, however IFN-γ and IL-6 were required for exacerbation of other proinflammatory cytokines. Additionally, lack of IFN-γ or IL-6 impacted expression of genes regulated by either IFN-γ or type I IFN. Significantly, both IFN-γ and IL-6 were required for increased expression of IRF-1 which regulates IFN stimulated genes and is required for mHgIA. Thus IRF-1 may be at the nexus of the interplay between IFN-γ and IL-6 in exacerbating a xenobiotic-induced inflammatory response, regulation of interferon responsive genes and autoimmunity.

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

“…Mercury exposure of human neutrophil granulocytes also induces the formation of neutrophil extracellular traps providing another source of TLR agonists (84). These studies are consistent with our observation that mercury exposure induces a localized inflammatory response (85) regulated in part by cathepsin B (61) which is known to be involved in TLR responses (86, 87). Furthermore, the reported finding that exposure of T cells to mercury induces MHC class II-dependent cytokine production and proliferation in vitro only in the presence of antigen-presenting cells (88) is consistent with mercury generating TLR ligands that activate cells to present self-antigens.…”

Quantitative Proteomic Analysis Reveals That Arctigenin Alleviates Concanavalin A-Induced Hepatitis Through Suppressing Immune System and Regulating Autophagy

“…A recent study showed that IL-6 mediated the IFN-α-induced cell apoptosis via the activation of Stat1 ( 111 ). Both IL-6 and IFN-γ were required for murine mercury-induced autoimmunity ( 112 ). They both interplayed with interferon regulatory factor 1 to exacerbate the inflammatory responses.…”

IFN‐γ/IL‐6 and related cytokines in chronic spontaneous urticaria: evaluation of their pathogenetic role and changes during omalizumab therapy

“…Interferon (IFN) plays a pivotal role in the pathogenesis of autoimmune diseases and, in particular, type 1 IFNs—A and B classes of IFNs—contribute to shaping the innate and adaptive immune responses in autoimmune processes . The role of type 2 IFN‐γ in the pathogenesis and maintenance of autoimmune diseases, including systemic lupus erythematosus (SLE), is less understood, although nowadays IFN‐γ is recognized as a central factor in autoimmune disorders …”