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.
MeSH terms
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Adenoma / metabolism
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Adenoma / pathology
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Animals
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Cell Line
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Colon / metabolism
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Colon / pathology
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Cytokine Receptor gp130
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DNA-Binding Proteins / metabolism*
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Digestive System Physiological Phenomena*
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Gastric Mucosa / metabolism
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Gene Expression Regulation
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Growth Substances / genetics*
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Growth Substances / metabolism
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Homeostasis*
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Interleukin-11 / metabolism
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Interleukin-6 / metabolism
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Transgenic
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Mitogen-Activated Protein Kinases / metabolism
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Mucins*
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Muscle Proteins*
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Neuropeptides*
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Peptides / genetics*
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Peptides / metabolism
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Protein Phosphatase 2
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases / metabolism*
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Proteins / genetics
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Proteins / metabolism
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STAT1 Transcription Factor
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Signal Transduction / physiology
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Spleen / cytology
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Spleen / metabolism
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Stomach / cytology
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Stomach / pathology
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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Trans-Activators / metabolism*
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Transcriptional Activation
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Trefoil Factor-2
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Trefoil Factor-3
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Wound Healing
Substances
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Antigens, CD
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DNA-Binding Proteins
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Growth Substances
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Il6st protein, mouse
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Interleukin-11
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Mucins
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Muscle Proteins
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Neuropeptides
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Peptides
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Proteins
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STAT1 Transcription Factor
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Stat1 protein, mouse
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TFF3 protein, human
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TFF3 protein, rat
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Trans-Activators
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Trefoil Factor-2
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Trefoil Factor-3
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Cytokine Receptor gp130
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Mitogen-Activated Protein Kinases
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Protein Phosphatase 2
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PTPN11 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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Ptpn11 protein, rat