Regulation of gene expression of epithelial calcium channels in intestine and kidney of mice by 1alpha,25-dihydroxyvitamin D3

In wild-type (VDR(+/+)) mice, ECaC2 expression was confirmed in the intestine and kidney, while ECaC1 expression was exclusively confined to the kidney. Both mRNAs expression of ECaC1 and ECaC2 in the kidney and ECaC2 mRNA expression in the intestine increased time- and dose-dependently in response to 1alpha,25(OH)(2)D(3) injection in VDR(+/+) mice, but not in VDR(-/-) mice. The mRNA levels of ECaC2 in the intestine of VDR(-/-) mice were remarkably reduced when compared to VDR(+/+) mice, while no significant differences were observed in both mRNA levels of ECaC1 and ECaC2 in the kidney between VDR(+/+) mice and VDR(-/-) mice. In the primary renal tubular cells (PRTC) isolated from VDR(+/+) mice, both ECaCs mRNA expression increased in response to 1alpha,25(OH)(2)D(3) treatment, but not in the PRTC of VDR(-/-) mice. PTH increased both ECaCs mRNA expression in the PRTC of VDR(+/+) mice. These results suggest that 1alpha,25(OH)(2)D(3) directly modulates the gene expression of ECaC1 and ECaC2 together with PTH in the kidney of mice. 1alpha,25(OH)(2)D(3) also modulates the gene expression of ECaC2 in the intestine of mice, however, further studies are needed to elucidate the direct action of 1alpha,25(OH)(2)D(3) on the expression of ECaC2 in the intestine.     

The diacylated lipopeptide FSL-1 induces TLR2-mediated Th2 responses

The diacylated lipopeptide FSL-1 enhanced the generation of IgG antibodies in TLR2(+/+) mice, but not in TLR2(-/-) mice, when administered together with hen egg lysozyme as an antigen. Escherichia coli lipopolysaccharide enhanced the generation of antigen-specific antibodies in both TLR2(-/-) and TLR2(+/+) mice. In TLR2(+/+) mice, the level of enhancement due to FSL-1 was similar to that caused by lipopolysaccharide. Analysis of the IgG antibodies subclass demonstrated that the level of Th2-type IgG1 antibodies was higher than that of Th1-type IgG2a antibodies. Both FSL-1 and lipopolysaccharide induced production of IL-10 and IL-6 by splenocytes from TLR2(+/+) mice. Lipopolysaccharide also induced production of these cytokines by splenocytes from TLR2(-/-) mice, but FSL-1 did not. Neither FSL-1 nor lipopolysaccharide induced IL-12p70 production by splenocytes from either type of mice. FSL-1 upregulated B7.2 expression in B220(+) cells from TLR2(+/+) mice but not those from TLR2(-/-) mice, whereas lipopolysaccharide upregulated B7.2 expression in B220(+) cells from both types of mice. FSL-1 and, to a lesser extent, lipopolysaccharide activated mitogen-activated protein kinases in splenocytes. FSL-1 and, to a lesser extent, lipopolysaccharide induced the expression of c-Fos, which is known to be involved in Th2-type responses, in splenocytes. Thus, this study demonstrated that FSL-1 possessed TLR2-mediated Th2-type responses in vivo.     

细胞粘附分子CHL1缺失对炎症性肠病的影响

目的：探讨细胞粘附分子CHL1缺失对炎症性肠病（IBD）的影响。方法：采用葡聚糖硫酸钠（DSS）建立CHL1（-/-）炎症性肠病小鼠模型,将10只C57/BL6为遗传背景的CHL1（+/+）型小鼠分为对照组、DSS模型组（n=5）;将10只C57/BL6为背景的CHL （-/-）型小鼠分为CHL1缺失组、CHL1缺失DSS模型组（n=5）。DSS模型组和CHL1缺失DSS模型组自主饮用7 d含1.5% DSS蒸馏水,随后改用蒸馏水饲喂2 d;对照组和CHL1缺失组连续饮用蒸馏水9 d,观察小鼠体重、血便、生存率及结肠组织长度的变化。结果：CHL1缺失DSS模型组小鼠在炎症性肠病的发生中便血明显,从应激的第7天开始,体重明显减轻,在第9天,CHL1缺失DSS模型组型小鼠死亡率明显增加;结肠长度明显缩短,损伤加重。结论：细胞粘附分子CHL1缺失加重炎症性肠病的发生。     

Angiotensin II type 1 receptor signaling regulates feeding behavior through anorexigenic corticotropin-releasing hormone in hypothalamus

The activation of renin-angiotensin system contributes to the development of metabolic syndrome and diabetes as well as hypertension. However, it remains undetermined how renin-angiotensin system is implicated in feeding behavior. Here, we show that angiotensin II type 1 (AT(1)) receptor signaling regulates the hypothalamic neurocircuit that is involved in the control of food intake. Compared with wild-type Agtr1a(+/+) mice, AT(1) receptor knock-out (Agtr1a(-/-)) mice were hyperphagic and obese with increased adiposity on an ad libitum diet, whereas Agtr1a(-/-) mice were lean with decreased adiposity on a pair-fed diet. In the hypothalamus, mRNA levels of anorexigenic neuropeptide corticotropin-releasing hormone (Crh) were lower in Agtr1a(-/-) mice than in Agtr1a(+/+) mice both on an ad libitum and pair-fed diet. Furthermore, intracerebroventricular administration of CRH suppressed food intake both in Agtr1a(+/+) and Agtr1a(-/-) mice. In addition, the Crh gene promoter was significantly transactivated via the cAMP-responsive element by angiotensin II stimulation. These results thus demonstrate that central AT(1) receptor signaling plays a homeostatic role in the regulation of food intake by maintaining gene expression of Crh in hypothalamus and suggest a therapeutic potential of central AT(1) receptor blockade in feeding disorders.     

Targeted disruption of the murine CCK1 receptor gene reduces intestinal lipid-induced feedback inhibition of gastric function

Cholecystokinin (CCK), acting at CCK1 receptors (CCK1Rs) on intestinal vagal afferent terminals, has been implicated in the control of gastrointestinal function and food intake. Using CCK1R(-/-) mice, we tested the hypothesis that lipid-induced activation of the vagal afferent pathway and intestinal feedback of gastric function is CCK1R dependent. In anesthetized CCK1R(+/+) ("wild type") mice, meal-stimulated gastric acid secretion was inhibited by intestinal lipid infusion; this was abolished in CCK1R(-/-) mice. Gastric emptying of whole egg, measured by nuclear scintigraphy in awake mice, was significantly faster in CCK1R(-/-) than CCK1R(+/+) mice. Gastric emptying of chow was significantly slowed in response to administration of CCK-8 (22 pmol) in CCK1R(+/+) but not CCK1R(-/-) mice. Activation of the vagal afferent pathway was measured by immunohistochemical localization of Fos protein in the nucleus of the solitary tract (NTS; a region where vagal afferents terminate). CCK-8 (22 pmol ip) increased neuronal Fos expression in the NTS of fasted CCK1R(+/+) mice; CCK-induced Fos expression was reduced by 97% in CCK1R(-/-) compared with CCK1R(+/+) mice. Intralipid (0.2 ml of 20% Intralipid and 0.04 g lipid), but not saline, gavage increased Fos expression in the NTS of fasted CCK1R(+/+) mice; lipid-induced Fos expression was decreased by 47% in CCK1R(-/-) compared with CCK1R(+/+)mice. We conclude that intestinal lipid activates the vagal afferent pathway, decreases gastric acid secretion, and delays gastric emptying via a CCK1R-dependent mechanism. Thus, despite a relatively normal phenotype, intestinal feedback in response to lipid is severely impaired in these mice.