title: Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection.
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.
authors.affiliation: Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Pathology and Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Tu
authors.affiliation: Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xuanming
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Liufu
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Pathology and Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: l-zhou@northwestern.edu.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: yfu@uchicago.edu.
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D044082:Citrobacter rodentium / Q000276:immunology*; D003967:Diarrhea / Q000378:metabolism / Q000517:prevention & control; D004756:Enterobacteriaceae Infections / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007211:Indoles / Q000008:administration & dosage; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009092:Mucous Membrane; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077210:Sunitinib; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000097043:Interleukin-22
chemical_list: D007211:Indoles; D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011758:Pyrroles; D050796:STAT3 Transcription Factor; D000077210:Sunitinib; D000097043:Interleukin-22