STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing.
Signal transducer and activator of transcription (STAT) 3 is a pleiotropic transcription factor with important functions in cytokine signaling in a variety of tissues. However, the role of STAT3 in the intestinal epithelium is not well understood. We demonstrate that development of colonic inflammation is associated with the induction of STAT3 activity in intestinal epithelial cells (IECs). Studies in genetically engineered mice showed that epithelial STAT3 activation in dextran sodium sulfate colitis is dependent on interleukin (IL)-22 rather than IL-6. IL-22 was secreted by colonic CD11c(+) cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3(IEC-KO) mice, upon induction of colitis, showed a striking defect of epithelial restitution. Gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and pathways associated with wound healing in IECs. Consistently, both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. In summary, our data suggest that intestinal epithelial STAT3 activation regulates immune homeostasis in the gut by promoting IL-22-dependent mucosal wound healing.
Pickert
Geethanjali
G
Institute of Molecular Medicine, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany.
Neufert
Clemens
C
Leppkes
Moritz
M
Zheng
Yan
Y
Wittkopf
Nadine
N
Warntjen
Moritz
M
Lehr
Hans-Anton
HA
Hirth
Sebastian
S
Weigmann
Benno
B
Wirtz
Stefan
S
Ouyang
Wenjun
W
Neurath
Markus F
MF
Becker
Christoph
C
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D020869:Gene Expression Profiling; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014945:Wound Healing; D000097043:Interleukin-22
D016264:Dextran Sulfate; D015850:Interleukin-6; D007378:Interleukins; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22