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

Markus Bosmann1, Birgit Strobl2, Nadia Kichler2

  • 1Center for Thrombosis and Hemostasis and Department of Hematology, Oncology and Pneumology, University Medical Center, Mainz, Germany; markus.bosmann@unimedizin-mainz.de.

Journal of Leukocyte Biology
|March 8, 2014
PubMed

Insights

The tyrosine kinase 2 (Tyk2) enzyme promotes the production of Interleukin-27 (IL-27), a cytokine implicated in severe systemic inflammation. Inhibiting Tyk2 may offer a therapeutic strategy for sepsis and endotoxic shock by reducing IL-27 levels.

Area of Science:

  • Immunology
  • Molecular Biology
  • Inflammation Research

Background:

  • Interleukin-27 (IL-27) is a key cytokine in immune responses.
  • Tyk2 (tyrosine kinase 2) is an enzyme involved in cytokine signaling.
  • The precise role of Tyk2 in IL-27 production and its impact on systemic inflammation is not fully understood.

Purpose of the Study:

  • To investigate the role of Tyk2 in the gene expression and release of IL-27.
  • To determine if Tyk2 modulates IL-27 production in macrophages.
  • To assess the in vivo relevance of Tyk2-mediated IL-27 production in models of sepsis and endotoxic shock.

Main Methods:

  • Utilized wild-type (WT) and Tyk2-deficient (Tyk2-/-) mouse macrophages (peritoneal and bone marrow-derived).
  • Stimulated macrophages with lipopolysaccharide (LPS) to activate Toll-like receptor 4 (TLR4).
  • Measured IL-27(p28) and EBI3 production via quantitative assays and flow cytometry.
  • Investigated the role of type I interferons (IFN) and IL-27 receptor alpha (IL-27RA) in vivo.
  • Assessed survival rates in Tyk2-/- and IL-27RA-/- mice subjected to endotoxic shock and cecal ligation and puncture (CLP) sepsis models.

Main Results:

  • Tyk2 deficiency significantly reduced IL-27(p28) production (by ~50%) in TLR4-activated macrophages, while EBI3 production remained unaffected.
  • Tyk2 deficiency impaired a type I IFN-dependent mechanism for IL-27(p28) production.
  • Tyk2 was not required for IL-27's effects on CD4+ T cells.
  • Tyk2-/- mice exhibited improved survival rates in models of endotoxic shock and polymicrobial sepsis.
  • Plasma IL-27(p28) levels were markedly reduced in Tyk2-/- mice during sepsis.
  • Disruption of IL-27 signaling via IL-27RA deficiency was protective against sepsis-associated mortality.

Conclusions:

  • Tyk2 is a critical prerequisite factor for IL-27(p28) generation, particularly in response to TLR4 activation.
  • Tyk2-mediated IL-27 production contributes to adverse outcomes in systemic inflammatory responses such as sepsis.
  • Targeting Tyk2 may represent a potential therapeutic strategy to mitigate inflammatory conditions driven by excessive IL-27 production.
Keywords:
inflammationinterferonlipopolysaccharidemacrophagesshock

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