Induction of Innate Lymphoid Cell-Derived Interleukin-22 by the Transcription Factor STAT3 Mediates Protection against Intestinal Infection.
Guo, Xiaohuan 1; Qiu, Ju 2; Tu, Tony 1; Yang, Xuanming 1; Deng, Liufu 1; Anders, Robert A. 3; Zhou, Liang 2,*; Fu, Yang-Xin 1,*
[Article] Immunity. 40(1):25-39, January 16, 2014.

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SUMMARY: 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 ROR[gamma]t. 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 ROR[gamma]t innate lymphoid cells (ILC3s), but not T cells, was essential for the protection. However, STAT3 was required for ROR[gamma]t 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.

Highlights:

* STAT3 and IL-22 from innate but not adaptive ROR[gamma]t cells are crucial for protection

* STAT3 controls the development of ROR[gamma]t T helper cells but not ILC3s

* STAT3 can directly control IL-22 production in both ILC3s and T cells

* Inhibition of IL-22 production could cause pathogen-induced diarrhea

(C) 2014Elsevier, Inc.