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

Nature Medicine volume 8, pages 1089–1097 (2002)Cite this article

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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Author notes

  1. Niall C. Tebbutt and Andrew S. Giraud: N.C.T. and A.S.G. contributed equally to this study.

Authors and Affiliations

  1. Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria, Australia

    Niall C. Tebbutt, Melissa Inglese, Brendan Jenkins, Fiona J. Clay, Dianne Grail, Joan K. Heath & Matthias Ernst

  2. Department of Medicine, University of Melbourne, Western Hospital, Footscray, Victoria, Australia

    Andrew S. Giraud, Sina Malki & Barbara M. Alderman

  3. Department of Pathology, Peter MacCallum Institute, East Melbourne, Victoria, Australia

    Paul Waring

  4. Laboratoire de Signalisation Cellulaire Normale et Tumorale, Faculté de Pharmacie, Montpellier, France

    Frédéric Hollande

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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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