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

Nial C Tebbutt, Andrew S Giraud, Melissa Inglese, Brendan John Jenkins, Paul Waring, Fiona Jane Clay, Sina Malki, Dianne Grail, Frederic Hollande, Joan K Heath, Matthias R Ernst

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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. Gp130(757F) 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 (gp130(Delta STAT)), 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.
Original languageEnglish
Pages (from-to)1089 - 1097
Number of pages9
JournalNature Medicine
Volume8
Issue number10
Publication statusPublished - 2002

Cite this

Tebbutt, N. C., Giraud, A. S., Inglese, M., Jenkins, B. J., Waring, P., Clay, F. J., Malki, S., Grail, D., Hollande, F., Heath, J. K., & Ernst, M. R. (2002). Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nature Medicine, 8(10), 1089 - 1097.