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Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice

Abstract

The intracellular signaling mechanisms that specify tissue-specific responses to the interleukin-6 (IL-6) family of cytokines are not well understood. Here, we evaluated the functions of the two major signaling pathways, the signal transducers and activators of transcription 1 and 3 (STAT1/3) and the Src-homology tyrosine phosphatase 2 (SHP2)-Ras-ERK, emanating from the common signal transducer, gp130, in the gastrointestinal tract. Gp130757F mice, with a 'knock-in' mutation abrogating SHP2-Ras-ERK signaling, developed gastric adenomas by three months of age. In contrast, mice harboring the reciprocal mutation ablating STAT1/3 signaling (gp130ΔSTAT), or deficient in IL-6-mediated gp130 signaling (IL-6−/− mice), showed impaired colonic mucosal wound healing. These gastrointestinal phenotypes are highly similar to the phenotypes exhibited by mice deficient in trefoil factor 1 (pS2/TFF1) and intestinal trefoil factor (ITF)/TFF3, respectively, and corresponded closely with the capacity of the two pathways to stimulate transcription of the genes encoding pS2/TFF1 and ITF/TFF3. We propose a model whereby mucosal wound healing depends solely on activation of STAT1/3, whereas gastric hyperplasia ensues when the coordinated activation of the STAT1/3 and SHP2-Ras-ERK pathways is disrupted.

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Figure 1: Altered intracellular signaling in mice with targeted gp130 mutations.
Figure 2: Histological analysis of gp130757F mice.
Figure 3: Increased susceptibility to DSS-mediated intestinal injury in 12–16-wk-old mice.
Figure 4: Tissue-specific regulation of trefoil peptide level in gp130 mutant mice.
Figure 5: Reciprocal responsiveness of genes encoding pS2/TFF1 and ITF/TFF3 to the SHP2-Ras-ERK and STAT pathways activated by gp130-signaling domain mutants.
Figure 6: Schematic of the consequences of impairing the reciprocal negative regulation between the SHP2-Ras-ERK and STAT1/3 pathways.

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Acknowledgements

Acknowledgments We thank T. Terada for the tff-luciferase promoter constructs pGV2192, pGV496 and pGV243; D. Podolsky for pRITF-luc; S. Nicholson for the expression construct encoding EpoR/gp130757F; L. Thim for recombinant human TFF2; Amgen (Thousand Oaks, California) for recombinant human GCSF and IL-6; R. Simpson for sIL-6R; L. Robb and A. Ramsay for IL-11Rα1−/− and IL-6−/− mice; V. Feakes, J. Moverley and M. Howlett for histology; and J.Stickland for photography.

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Correspondence to Matthias Ernst.

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Tebbutt, N., Giraud, A., Inglese, M. et al. Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med 8, 1089–1097 (2002). https://doi.org/10.1038/nm763

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