Enhanced plasma ghrelin levels in Helicobacter py/ori-colonized, interleukin-1-receptortype 1-homozygous knockout (IL-1R1-/-) mice

AIM: Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor, and it plays a role in stimulating the growth hormone secretion, food intake, body weight gain and gastric motility. Eradication of Helicobacterpylori (H pylori) was shown to be associated with increase of the body weight. On the other hand, H pylori infection evokes the release of gastric IL-lp. The present study was designed to investigate the involvement of the gastric IL-1 signal in the ghrelin dynamics in Hpylori-colonized mice. METHODS: Twelve-week-old female IL-1-receptor type 1-homozygous-knockout mice (IL-1R1-/-') and their wild-type littermates (WT) were orally inoculated with H pylori (Hp group), while other cohorts received oral inoculation of culture medium (Cont group). Thirteen weeks after the inoculation, the mice were examined. The plasma and stomach ghrelin levels and the gastric preproghrelin mRNA were measured. RESULTS: Although the WT mice with H pylori infection showed a significantly decreased body weight as compared with that of the animals without H pylori infection, H pylori infection did not influence the body weight of the IL-1R1-knockout (IL-1R1-/-) mice. In the H pylori-infected IL-1R1-/-mice, the total and active ghrelin levels in the plasma were significantly increased, and the gastric ghrelin level was decreased. No significant differences were noted in the gastric preproghrelin mRNA expression. CONCLUSION: Ghrelin secretion triggered by H pylori infection might be suppressed by IL-1β, the release of which is also induced by the infection, resulting in the body weight loss of mice with H pylori infection.     

胰腺内分泌肿瘤ghrelin和受体GHS-R1A的表达及患者血浆ghrelin、瘦素水平

目的 检测胰腺内分泌肿瘤患者血浆及肿瘤组织ghrelin水平、血浆瘦素水平,探讨它们之间的关系及临床意义.方法 采用ELISA法检测11例胰腺内分泌肿瘤患者的术前血浆ghrelin及瘦素水平,以28例正常志愿者作为对照.免疫组织化学染色法检测11个肿瘤和27个对照组织ghrelin及其受体GHS-R1A的表达.并与临床病理资料进行相关分析.结果 胰腺内分泌肿瘤患者血浆ghrelin水平为(16.0±5.0)pg/ml,显著低于对照组的(21.0±2.0)pg/ml(P=0.047);瘦素水平为(0.34±0.03)ng/ml,与对照组的(0.38±0.04)ng/ml无显著差异.肿瘤患者的血浆ghrelin与瘦素水平呈正相关(P=0.015),但与各项临床病理指标均不相关;对照组的血浆瘦素水平与体重指数呈正相关(P=0.002),而肿瘤患者两者不相关.肿瘤组织ghrelin的表达率明显低于对照组织(64%对100%,P=0.004),而GHS-R1A的表达率与对照组无显著差异.肿瘤组织ghrelin和GHS-R 1A的表达与各项临床病理指标均不相关.结论 胰腺内分泌肿瘤表达ghrelin及GHS-R1A,患者血浆ghrelin及瘦素水平发生变化.     

Circulating levels of tumor necrosis factor and interleukin-1 in cystic fibrosis

To assess the role of tumor necrosis factor (TNF) and interleukin-1 (IL-1) in the pathophysiology of cystic fibrosis (CF)-associated growth failure/cachexia and lung disease we measured height, weight, triceps skin fold, forced vital capacity, forced expiratory volume in 1 second, and plasma levels of TNF, interleukin-1-alpha (IL-1 alpha), interleukin-1-beta (IL-1 beta), and alpha-1-antitrypsin (A1AT) in 12 patients with CF, and in 12 age- and gender-matched healthy controls. The patients as a group had significantly lower values for the anthropomorphic measurements and lung function parameters as compared to controls. They also had higher circulating levels of A1AT than controls. TNF, however, was detected less frequently in patients than in controls. Neither group had detectable levels of circulating IL-1 alpha or IL-1 beta, which is consistent with the observation that CF patients infrequently present with fever. Potential explanations for these findings include compartmentalization of secreted TNF/IL-1, altered regulation of TNF/IL-1 secretion as a result of the chronic inflammatory state seen in CF, or increased degradation of TNF/IL-1, also a result of chronic inflammation. The role of these cytokines in the pathophysiology of CF remains unclear, but should be explored further; however it seems unlikely that circulating TNF plays a role in the growth failure/cachexia associated with CF.     

Enhanced levels of C-X-C chemokine,human GROα, in Helicobacter pylori-associated gastric disease*

C-X-C Chemokines play an important role for neutrophil extravasation through microvessels. Although the level of interleukin (IL)-8 is known to increase in the Helicobacter pylori-infected gastric mucosa, another C-X-C chemokine, GROα, has not been evaluated in the H. pylori-associated gastric mucosal injury. The present study was designed to investigate gastric contents of GROα in relation to those of IL-8 in the gastric mucosa of H. pylori-infected peptic ulcer patients. Thirty-eight patients with gastric ulcer and 41 with gastritis underwent endoscopy with informed consent and 49 were found to be H. pylori positive and 30 H. pylori negative. Biopsies from the gastric corpus were performed in each patient to examine the H. pylori colonization by bacterial culture, the rapid urease test and histological specimens as well as measurement of the contents of human GROα and IL-8. Helicobacter pylori infection was eradicated in 21 patients by triple therapy (lansoprazole 30mg, amoxycillin 2.0g, clarithromycin 600 mg; 2 weeks). The samples for GROα and IL-8 assay were homogenized in 0.02% aprotinin containing phosphate-buffered solution and the mucosal contents of GROα and IL-8 in the supernatants were quantified by sandwich enzyme immunoassay methods. The levels of GROα and IL-8 in H. pylori-positive gastric mucosa were significantly higher than those in the H. pylori-negative mucosa. There was a significant linear correlation between the levels of GROα and IL-8 (r= 0.798, P < 0.01). After the eradication of H. pylori by the triple therapy, the levels of GROα and IL-8 were significantly decreased. The GROα showed an increase in the H. pylori-positive gastric mucosa in a similar fashion as IL-8 contents, suggesting a pathogenetic role for GROα in H. pylori-associated gastric mucosal injury.     

Associations between interleukin-1 (IL-1) gene variations or IL-1 receptor antagonist levels and the development of type 2 diabetes

Abstract. Luotola K, Pietilä A, Zeller T, Moilanen L, Kähönen M, Nieminen MS, Kesäniemi YA, Blankenberg S, Jula A, Perola M, Salomaa V (Helsinki University Hospital, Helsinki; National Institute for Health and Welfare, Helsinki, Finland; University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany; University Hospital of Kuopio, Kuopio; Tampere University Hospital and Medical School, University of Tampere, Tampere; University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu; National Institute for Health and Welfare, Turku; and Institute for Molecular Medicine Finland, Helsinki, Finland). Associations between interleukin‐1 (IL‐1) gene variations or IL‐1 receptor antagonist levels and the development of type 2 diabetes. J Intern Med 2010; 269 : 322–332. Objectives. To examine whether interleukin‐1 receptor antagonist (IL‐1Ra) is a predictor for clinically incident diabetes in subjects with metabolic syndrome (MetS) and whether its predictive power is independent of C‐reactive protein (CRP), an established marker of inflammation. We further examined whether genetic variants at the interleukin‐1 (IL‐1) locus would predict clinically incident diabetes. Design. Two observational prospective cohort studies. Setting. Two separate cohorts, Health 2000 and FINRISK 1997, followed up for an average of 7.1 and 10.8 years, respectively. Subjects. Random population samples consisting of 5511 subjects aged 30–74 years in Health 2000 and 7374 subjects aged 25–74 years in FINRISK 1997. Results. During follow‐up, 141 cases of clinically incident diabetes were observed amongst subjects with MetS at baseline in Health 2000 and 248 cases in FINRISK 97. After adjustment for multiple traditional risk factors of diabetes, including age and body mass index, IL‐1Ra was a significant (P < 0.01) predictor of incident diabetes amongst men in both cohorts and amongst women in FINRISK 1997. Further adjustment for CRP reduced the hazard ratios only slightly. Genetic analyses produced nominally significant associations for three single‐nucleotide polymorphisms: rs3213448 in IL‐1 receptor antagonist (IL1RN), rs1143634 in IL‐1 beta (IL1B) and rs1800587 in IL‐1 alpha (IL1A). The two latter variants had an interaction with gender (P = 0.023 and 0.002, respectively) suggesting the presence of gender‐specific associations with the risk of clinically incident diabetes. Conclusions. IL‐1Ra predicted the progression of MetS to clinically incident diabetes independently of CRP and other risk factors. Genetic variation in the IL‐1 locus may have gender‐specific associations with the risk of type 2 diabetes.     

Normal pharmacologically-induced, but decreased regenerative liver growth in interleukin-6-deficient (IL-6(-/-)) mice

BACKGROUND/AIMS: In the absence of liver damage, rapid liver growth can be induced pharmacologically by so-called primary liver growth promoters. The importance of the acute-phase cytokines interleukin-6 and tumor necrosis factor-alpha for the actions of these compounds is not clear. This study aimed to investigate the importance of IL-6 and TNF-receptor-1 in pharmacologically-induced liver growth. METHODS: IL-6 knockout (IL-6(-/-)), TNF-receptor-1 knockout (TNFR1(-/-)) and wild-type mice were treated with the peroxisome proliferator nafenopin and the anti-androgen cyproterone acetate (CPA) in one single injection or for 6 days with daily injections, and examined at 24 or 48 h after treatment. In a control experiment, IL-6(-/-) mice were subjected to two-thirds partial hepatectomy. RESULTS: Nafenopin treatment increased relative liver weight and DNA synthesis similarly in IL-6(-/-), TNFR1(-/-) and wild-type mice. CPA increased liver weight similarly in all groups, but did not increase DNA synthesis. Expression of peroxisome proliferator activated receptor-alpha mRNA was increased in both IL-6(-/-) and wild-type mice by nafenopin treatment, but not by CPA treatment. After hepatectomy DNA synthesis was suppressed in IL-6(-/-) mice compared to wild-type mice. CONCLUSIONS: Liver growth induced by nafenopin and CPA was not dependent on the presence of IL-6 or TNF receptor-1, whereas liver regeneration was decreased in IL-6(-/-) mice.     

Hepatic stress in hereditary tyrosinemia type 1 (HT1) activates the AKT survival pathway in the fah-/- knockout mice model

BACKGROUND/AIMS: The AKT survival pathway is involved in a wide variety of human cancers. We investigated the implication of this pathway in hereditary tyrosinemia type 1 (HT1), a metabolic disease exhibiting hepatocellular carcinoma (HCC), despite treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexadione (NTBC) which prevents liver damage. HT1 is an autosomal recessive disorder caused by accumulation of toxic metabolites due to a deficiency in fumarylacetoacetate hydrolase (FAH), the last enzyme in the catabolism of tyrosine. METHODS: NTBC withdrawal in the murine fah(-/-) knockout model was used to analyze in vivo the correlation between pathophysiological, biochemical and histological features consistent with hepatocarcinogenesis and activation of the AKT survival pathway. RESULTS: The HT1 stress initiated by NTBC discontinuation causes a progressive increase of liver and kidney pathophysiology. A stable activation of the AKT survival pathway is observed in the liver but not in kidneys of fah(-/-) mice. Hepatic survival is reinforced by inhibition of mitochondrial-mediated apoptosis through inactivation of Bad and induction of BCl-X(L) and BCl-2. CONCLUSIONS: The chronic stress induced by liver disease in HT1 activates the AKT survival signal and inhibits intrinsic apoptosis to confer cell death resistance in vivo and favor hepatocarcinogenesis.     

幽门螺杆菌感染患者血清可溶性黏附分子1(sICAM-1)检测研究

目的研究慢性胃病患者幽门螺杆菌(Helicobacter pylori,Hp)感染与血清可溶性黏附分子1(Soluble Intercellular Adhesion molecule-1,sICAM-1)水平关系。方法对205例慢性胃病患者进行了血清sICAM-1水平检测,并同时进行RUT、组织MB染色、Hp抗体和~(14)C-UBT四项方法检测Hp感染。结果胃粘膜Hp阳性组患者血清sICAM-1为889.43±22.52ng/m1,明显高于Hp阴性组患者747.07±30.45ng/ml(P<0.05);胃粘膜Hp感染菌量+、++、+++三组患者sICM-1水平分别为841.68±72.36ng/ml、905.43±37.59ng/ml和1012.54±49.34ng/ml,三组间差异显著(P<0.05);慢性胃炎、消化性溃疡患者血清sICAM-1水平明显高于正常对照组(P<0.05).结论胃粘膜Hp感染患者血清sICAM-1水平明显升高,血清sICAM-1水平可作为判断Hp感染新的感染免疫活动指标。