Tumor necrosis factor α decreases glucagon-like peptide-2 expression by up-regulating G-protein-coupled receptor 120 in Crohn disease.

Abstract

Glucagon-like peptide (GLP)-2, secreted by L cells in the small intestine, has anti-inflammatory effects in the gastrointestinal tract. A GLP-2 analogue has been an effective treatment for Crohn disease (CD). G-protein-coupled receptor (GPR) 40 and GPR120 are probably involved in GLP-2 production, the mechanisms of which remain unclear. In our experiments, normal ileal mucosa expressed GPR40, but rarely expressed GPR120. However, both GPRs were overexpressed in the L cells of the inflamed ileal mucosa of CD patients. Mucosal inflammation induced the overexpression of GPR40, GPR120, and several inflammatory cytokines, with correlations between ileal concentrations of tumor necrosis factor (TNF)-α and GPR expression levels; however, inflammation did not induce the expression of proglucagon, a precursor of GLP-2 in CD patients. In rat L cells and GLUTag cells, TNF-α treatment increased GPR120 mRNA expression without affecting GPR40 mRNA expression. Dual agonists of GPR40 and GPR120, GW9508 and linoleic acid, respectively, increased GLP-2 production from L cells, but these agonists decreased it in the presence of TNF-α. The GPR40 antagonist, GW1100, inhibited the GW9508-induced increase in GLP-2 production, and silencing GPR120 resulted in further elevation of GLP-2 production. Thus, GPR120-dependent signaling inhibited the stimulatory effects of GPR40 on GLP-2 expression, and TNF-α treatment decreased GLP-2 expression by up-regulating GPR120 expression in L cells.

• Authors: Takuya Tsukahara, Kenji Watanabe, Toshio Watanabe, Hirokazu Yamagami, Mitsue Sogawa, Tetsuya Tanigawa, Masatsugu Shiba, Kazunari Tominaga, Yasuhiro Fujiwara, Kiyoshi Maeda, Kosei Hirakawa, Tetsuo Arakawa
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 1 Pg. 185-96 (Jan 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25447053 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Benzoates
• Cytokines
• FFAR1 protein, human
• FFAR4 protein, human
• GW1100
• GW9508
• Glucagon-Like Peptide 2
• Methylamines
• Propionates
• Pyrimidines
• Receptors, G-Protein-Coupled
• Tumor Necrosis Factor-alpha

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Benzoates (chemistry)
• Case-Control Studies
• Cohort Studies
• Crohn Disease (metabolism)
• Cytokines (metabolism)
• Female
• Gene Expression Regulation
• Glucagon-Like Peptide 2 (metabolism)
• Humans
• Immunoenzyme Techniques
• Inflammation
• Intestinal Mucosa (pathology)
• Male
• Methylamines (chemistry)
• Middle Aged
• Propionates (chemistry)
• Pyrimidines (chemistry)
• Rats
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (metabolism)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)
• Up-Regulation
• Young Adult