BACKGROUND & AIMS Bone morphogenetic protein (BMP)4 is a mesenchymal peptide that regulates cells of the gastric epithelium. We investigated whether BMP signaling pathways affect gastric inflammation after bacterial infection of mice. METHODS We studied transgenic mice that express either the BMP inhibitor noggin or the β- galactosidase gene under the control of a BMP-responsive element and BMP4βgal/+ mice. Gastric inflammation was induced by infection of mice with either Helicobacter pylori or Helicobacter felis. Eight to 12 weeks after inoculation, gastric tissue samples were collected and immunohistochemical, quantitative, reverse-transcription polymerase chain reaction and immunoblot analyses were performed. We used enzyme-linked immunosorbent assays to measure cytokine levels in supernatants from cultures of mouse splenocytes and dendritic cells, as well as from human gastric epithelial cells (AGS cell line). We also measured the effects of BMP-2, BMP-4, BMP-7, and the BMP inhibitor LDN-193189 on the expression of interleukin (IL)8 messenger RNA by AGS cells and primary cultures of canine parietal and mucus cells. The effect of BMP-4 on NFkB activation in parietal and AGS cells was examined by immunoblot and luciferase assays. RESULTS Transgenic expression of noggin in mice increased H pylori– or H felis–induced inflammation and epithelial cell proliferation, accelerated the development of dysplasia, and increased expression of the signal transducer and activator of transcription 3 and activation-induced cytidine deaminase. BMP-4 was expressed in mesenchymal cells that expressed α-smooth muscle actin and activated BMP signaling pathways in the gastric epithelium. Neither BMP-4 expression nor BMP signaling were detected in immune cells of C57BL/6, BRE–β-galactosidase, or BMP-4βgal/+ mice. Incubation of dendritic cells or splenocytes with BMP-4 did not affect lipopolysaccharide-stimulated production of cytokines. BMP-4, BMP-2, and BMP-7 inhibited basal and tumor necrosis factor α–stimulated expression of IL8 in canine gastric epithelial cells. LDN-193189 prevented BMP4-mediated inhibition of basal and tumor necrosis factor α–stimulated expression of IL8 in AGS cells. BMP-4 had no effect on TNFα-stimulated phosphorylation and degradation of IκBα, or on TNFα induction of a NFκβ reporter gene. CONCLUSIONS BMP signaling reduces inflammation and inhibits dysplastic changes in the gastric mucosa after infection of mice with H pylori or H felis.

it is known that urocortin 1 (UCN) acts on both corticotropinreleasing factor receptors (CRF 1 and CRF2), the mechanisms underlying UCN-induced anorexia remain unclear. In contrast, ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, stimulates food intake. In the present study, we examined the effects of CRF 1 and CRF2 receptor antagonists (CRF1a and CRF2a) on ghrelin secretion and synthesis, c-fos mRNA expression in the caudal brain stem, and food intake following intracerebroventricular administration of UCN. Eight-week-old, male Sprague-Dawley rats were used after 24-h food deprivation. Acylated and des-acylated ghrelin levels were measured by enzyme-linked immunosorbent assay. The mRNA expressions of preproghrelin and c-fos were measured by real-time RT-PCR. The present study provided the following important insights into the mechanisms underlying the anorectic effects of UCN: 1) UCN increased acylated and des-acylated ghrelin levels in the gastric body and decreased their levels in the plasma; 2) UCN decreased preproghrelin mRNA levels in the gastric body; 3) UCN-induced reduction of plasma ghrelin and food intake were restored by CRF 2a but not CRF1a; 4) UCN-induced increase of c-fos mRNA levels in the caudal brain stem containing the nucleus of the solitary tract (NTS) was inhibited by CRF 2a; and 5) UCN-induced reduction of food intake was restored by exogenous ghrelin and rikkunshito, an endogenous ghrelin secretion regulator. Thus, UCN increases neuronal activation in the caudal brain stem containing NTS via CRF 2 receptors, which may be related to UCN-induced inhibition of both ghrelin secretion and food intake.corticotropin-releasing factor receptors; dorsal vagal complex; rikkunshito; digestive system hormone; anorexia STRESSFUL LIFE EVENTS have been associated with the onset or symptom exacerbation of several functional gastrointestinal disorders including functional dyspepsia and irritable bowel syndrome (24). Corticotropin-releasing factor (CRF) is a key mediator in the central nervous system and is secreted as an adaptive response to stress. In rodents, central CRF administration induces stress-like behaviors, including increased depression, decreased rearing activity, and suppression of food intake (5, 50). Urocortin 1 (UCN), a member of the mammalian CRF family, bears 45% sequence identity to CRF and acts as an endogenous ligand for CRF receptors (49). Although CRF and UCN mediate their actions through the activation of CRF 1 and CRF 2 receptors, CRF and UCN display different binding affinities for these receptors. CRF preferentially binds to CRF 1 receptors, whereas UCN shows high affinity for both receptors; we therefore believe that UCN is useful for examining the actions of both CRF 1 and CRF 2 receptors. Central UCN administration suppresses feeding in rats and mice, and the suppression was shown to be at least partly CRF 2 mediated in studies that used selective antagonists (7) or antisense oligonucleotides (38). In addition, the initial effect of food intake in...

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