Interplay between IFN-γ and IL-6 impacts the inflammatory response and expression of interferon-regulated genes in environmental-induced autoimmunity

David M. Cauvi, Gabrielle Cauvi, Christopher B. Toomey, Eric Jacquinet, Kenneth Michael Pollard

Research output: Contribution to journalArticlepeer-review

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. The Author 2017.

Original languageEnglish (US)
Article numberkfx083
Pages (from-to)227-239
Number of pages13
JournalToxicological Sciences
Volume158
Issue number1
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

Keywords

  • Environmental autoimmunity
  • Inflammation
  • Interferon
  • Interleukin 6
  • Mercury
  • Mouse

ASJC Scopus subject areas

  • Toxicology

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