Tyrosine kinase 2 promotes sepsis-associated lethality by facilitating production of interleukin-27

Abstract

The aim of this study was to test the hypothesis that gene expression and release of IL-27 may be modulated by Tyk2. Macrophages derived from the peritoneum or bone marrow of C57BL/10SnJ (WT) mice produced abundant amounts of IL-27(p28) following TLR4 activation by LPS. In contrast, production of IL-27(p28), but not EBI3, was reduced by ∼50% in TLR4-activated macrophages derived from mice with genetic deficiency of Tyk2 compared with WT macrophages. Frequencies of IL-27(p28)+F4/80+CD11b+ cells were lower in TLR4-activated macrophages derived from Tyk2-/- mice. Mechanistically, Tyk2-/- resulted in disruption of a type I IFN-dependent mechanism for production of IL-27(p28), which was induced by type I IFNs, and release of IL-27 was defective in macrophages from IFN-β-/- and IFNAR1-/- mice. In contrast, Tyk2 was not required to mediate the effects of IL-27 on target gene expression in CD4(+) T cells. In vivo, we observed that Tyk2-/- mice have improved survival following endotoxic shock or polymicrobial sepsis induced by CLP. Plasma levels of IL-27(p28) during endotoxic shock or polymicrobial sepsis were markedly reduced in Tyk2-/- mice compared with WT mice. Disruption of IL-27 signaling using IL-27RA-/- mice was protective against sepsis-associated mortality. These data suggest that Tyk2 may mediate adverse outcomes of SIRS by promoting the production of IL-27. In conclusion, this report identifies Tyk2 as a prerequisite factor in the molecular networks that are involved in generation of IL-27.

Interruption of Macrophage-Derived IL-27(p28) Production by IL-10 during Sepsis Requires STAT3 but Not SOCS3

“…We have recently shown that IL-27RA -/- mice have improved survival rates during endotoxic shock (46). IL-27(p28) production during endotoxic shock and polymicrobial sepsis induced by CLP is partly dependent on tyrosine kinase 2 via an autocrine type I interferon loop (46).…”

“…We have recently shown that IL-27RA -/- mice have improved survival rates during endotoxic shock (46). IL-27(p28) production during endotoxic shock and polymicrobial sepsis induced by CLP is partly dependent on tyrosine kinase 2 via an autocrine type I interferon loop (46). Our finding that F4/80 + CD11b + macrophages derived from IL-27RA -/- mice displayed increased ROS production after stimulation with opsonized E. coli is consistent with similar findings in LPS-stimulated phagocytes derived from EBI3 -/- mice (12).…”

Neuroendocrine Modulation of IL-27 in Macrophages

“…Both Toll/IL-1R domain-containing adaptor inducing IFN-b and MyD88 adaptor proteins are required for IL-27p28 production in LPS-activated macrophages (9,18,19). Tyrosine kinase 2 specifically promotes the gene expression of IL-27p28 rather than EBI3 following TLR4 activation (20). The downstream signaling pathways involve recruitment of IFN regulatory factors 1, 3, and 9 and NF-kB (c-Rel) transcription factors to the promoter region of the IL-27p28 gene (18,19,21).…”

“…The downstream signaling pathways involve recruitment of IFN regulatory factors 1, 3, and 9 and NF-kB (c-Rel) transcription factors to the promoter region of the IL-27p28 gene (18,19,21). Additionally, IL-27 production is greatly amplified by type I and type II IFNs based on autocrine/ paracrine-positive feedback loops (20,21). Alternatively, PI3K/ Akt and STAT3 represent inhibitory signaling pathways for antagonizing IL-27p28 gene expression in LPS/TLR4-activated macrophages (9,16).…”

“…To investigate whether the neuroendocrine regulatory circuits defined in macrophage cultures are also present in vivo, we employed a model of endotoxic shock in C57BL/6J mice during which splenic macrophages are the major cellular source of IL-27p28 (9,20).…”