M1633 Regulation of Gastric Inflammation By Bone Morphogenetic Protein Signaling
2009
BACKGROUND/AIMS: The bonemorphogenetic proteins (BMP)s are regulators of gastrointestinal physiology. The BMPs can inhibit inflammation in the gut. BMP-2 and BMP-4 are expressed in epithelial and mesenchymal cells of the stomach, respectively. We tested the hypothesis that 1) inhibition of BMP signaling In Vivo, by means of the BMP-signaling inhibitor noggin, activates inflammatory mechanisms and that 2) inflammatory stimuli regulate BMP expression. METHODS: The parietal cell-specific H+/K+-ATPase beta-subunit gene promoter was used to drive expression of noggin in the gastric epithelium. Morphology of the fundus was analyzed in sections stained with H&E. Expression of the MIP-2, TNF-alfa, INF-gamma, BMP-4 and BMP-2 genes was measured by QRT-PCR. Western blots were used to assess the phosphorylation and activation of Smad1-5-8, JNK and ERK and to measure the expression of BMP-4. Canine mesenchymal cells isolated from the gastric mucosa, were characterized by staining with antibodies against vimentin and cytokeratin 18, mesenchymal and epithelial cell markers, respectively. Mesenchymal cell proliferation was assessed by BrdU incorporation. RESULTS: The mucosa of the TG-mice exhibited decreased phosphorylation of Smad1-58, confirming inhibition of BMP signaling, and it displayed increased height, dilated glands and a modest increase in inflammatory cells. The TG-mice also exhibited enhanced ERK and JNK activation and a 2to 3-fold increase in MIP-2, INF-gamma and TNF-alfa gene expression. Infection of TG-mice for 4 months with Helicobacter pylori (HP), led to a greater then 100-fold increase in the expression of these cytokines, to a robust influx of inflammatory cells, and to the development of numerous lymphoid follicles and severe dysplasia. Infection of non-TG mice with HP led to inflammatory changes that were less severe then those seen in HP-infected TG-mice. In the non-TG mice, HP also caused a 5-fold increase in cytokine gene expression and it stimulated more then 5-fold the expression of BMP-4 but not that of BMP-2. INF-gamma induced BMP-4 gene and protein expression and it induced cell proliferation in cultures of gastric mesenchymal cells. CONCLUSIONS: The BMPs inhibit gastric inflammation since inhibition of BMP signaling activates pro-inflammatory mechanisms and it leads to an enhanced response to inflammatory stimuli. Moreover, cytokines stimulate BMP-4 expression, an event that might represent a self-safe mechanism that limits the intensity of the inflammatory response. These findings might contribute to a better understanding of the mechanisms that lead to the development of both dysplastic and neoplastic lesions in the stomach.
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