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Immunity. 2014 Jan 16;40(1):25-39. doi: 10.1016/j.immuni.2013.10.021. Epub 2014 Jan 9.

Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection.

Author information

1
Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
2
Department of Pathology and Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
3
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
4
Department of Pathology and Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: l-zhou@northwestern.edu.
5
Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: yfu@uchicago.edu.

Abstract

Inhibitors of the transcription factor STAT3 target STAT3-dependent tumorigenesis but patients often develop diarrhea from unknown mechanisms. Here we showed that STAT3 deficiency increased morbidity and mortality after Citrobacter rodentium infection with decreased secretion of cytokines including IL-17 and IL-22 associated with the transcription factor RORγt. Administration of the cytokine IL-22 was sufficient to rescue STAT3-deficient mice from lethal infection. Although STAT3 was required for IL-22 production in both innate and adaptive arms, by using conditional gene-deficient mice, we observed that STAT3 expression in RORγt(+) innate lymphoid cells (ILC3s), but not T cells, was essential for the protection. However, STAT3 was required for RORγt expression in T helper cells, but not in ILC3s. Activated STAT3 could directly bind to the Il22 locus. Thus, cancer therapies that utilize STAT3 inhibitors increase the risk for pathogen-mediated diarrhea through direct suppression of IL-22 from gut ILCs.

PMID:
24412612
PMCID:
PMC3919552
DOI:
10.1016/j.immuni.2013.10.021
[Indexed for MEDLINE]
Free PMC Article

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