http://repub.eur.nl/res/aut/23752/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/30808/ 2012-01-11T00:00:00Z Cytokine-signaling plays an important role in IBD. Proinflammatory cytokines like IL-6 contribute to the protection against pathogens, whereas they are also involved in chronic inflammation and are able to drive the survival and proliferation of cancer cells. Anti-inflammatory cytokines like IL-10 could help-out with the resolution of inflammation or prevent autoimmunity. On the other hand these anti-inflammatory cytokines can contribute to cancer development by inhibiting proper immune surveillance. All these effect warrant proper regulation of cytokine-signaling especially in a complex environment like the intestinal mucosa. In this thesis we focus on the role of SOCS3 the inhibitor of STAT3-signaling and its role in UC and UC-related CRC. http://repub.eur.nl/res/pub/33052/ 2010-10-01T00:00:00Z OBJECTIVE - Early developmental adaptations in response to undernutrition may play an essential role in susceptibility to type 2 diabetes, particularly for those experiencing a "mismatched rich nutritional environment" in later life. We examined the associations of exposure to the Chinese famine (1959-1961) during fetal life and childhood with the risk of hyperglycemia and type 2 diabetes in adulthood. RESEARCH DESIGN AND METHODS - We used the data for 7,874 rural adults born between 1954 and 1964 in selected communities from the cross-sectional 2002 China National Nutrition and Health Survey. Hyperglycemia was defined as fasting plasma glucose ≥6.1 mmol/l and/or 2-h plasma glucose ≥7.8 mmol/l and/or a previous clinical diagnosis of type 2 diabetes. RESULTS - Prevalences of hyperglycemia among adults in nonexposed, fetal exposed, early-childhood, mid-childhood, and late-childhood exposed cohorts were 2.4%, 5.7%, 3.9%, 3.4%, and 5.9%, respectively. In severely affected famine areas, fetal-exposed subjects had an increased risk of hyperglycemia compared with nonexposed subjects (odds ratio = 3.92; 95% CI: 1.64 -9.39; P = 0.002); this difference was not observed in less severely affected famine areas (odds ratio = 0.57; 95% CI: 0.25-1.31; P = 0.185). The odds ratios were significantly different between groups from the severe and less severe famine areas (P for interaction = 0.001). In severely affected famine areas, fetalexposed subjects who followed an affluent/Western dietary pattern (odds ratios = 7.63; 95% CI: 2.41-24.1; P = 0.0005) or who had a higher economic status in later life experienced a substantially elevated risk of hyperglycemia (odds ratios = 6.20; 95% CI: 2.08 -18.5; P = 0.001). CONCLUSIONS - Fetal exposure to the severe Chinese famine increases the risk of hyperglycemia in adulthood. This association appears to be exacerbated by a nutritionally rich environment in later life. http://repub.eur.nl/res/pub/19266/ 2010-02-01T00:00:00Z Background: Mouse models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of signal transducers and activators of transcription 3 (STAT3). Objective To investigate the expression of IL6/ phosphorylated STAT3 (p-STAT3)/suppressor of cytokine signalling 3 (SOCS3) in biopsy specimens from patients with ulcerative colitis (UC) and UC-related colorectal cancer (CRC) progression. Methods: Biopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with low-grade dysplasia (LGD) (n=9), UC with high-grade dysplasia (HGD) (n=7), UC-CRC (n=11) and sporadic CRC (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of IL6, p-STAT3 and SOCS3 was determined immunohistochemically. Results Patients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls (strong positive IL6: 53.6%, 11.1% and 0%, respectively; p-STAT3: 64.3%, 22.2% and 11.1%, respectively; all p≤0.012). SOCS3-positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In dysplasia and cancer, significantly more epithelial cells expressed IL6 and p-STAT3 compared with controls (strong positive IL6: 72.7% and 0% respectively; p-STAT3: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of SOCS3-positive cells in this progression reduced (LGD 33.3%; HGD 14.3%; UC-CRC 9.1%). In addition, methylation of the SOCS3 gene was detected in epithelial cells from UC-CRC biopsy specimens. Conclusion The importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression. http://repub.eur.nl/res/pub/25587/ 2010-02-01T00:00:00Z Background: The highly polymorphic nonclassical MHC class I chain-related genes A and B (MICA and MICB) encode stress-inducible glycoproteins expressed on various epithelial cells including intestinal epithelial cells. MICA and MICB gene polymorphisms and expressions are associated with autoimmune diseases but not known in ulcerative colitis (UC). Aims: To investigate the association of MICB exon 2-4 polymorphisms and soluble MICA (sMICA) expression with the susceptibility of UC in central China. Materials and methods: Genomic DNA was isolated from peripheral blood. The allele frequencies of MICB exon 2-4 were genotyped in 105 UC patients and 213 healthy controls by PCR single-stranded conformation polymorphism method. Thirty-two patients and 32 controls were selected for determining serum sMICA expression by ELISA. Results: Allele frequency of MICB0106 was significantly higher in UC patients than in healthy controls (19.0% vs. 8.9%, corrected P (Pc)=0.0006), especially in patients with extensive colitis (24.4% vs. 8.9%, Pc=0.0006), moderate and severe disease (24.1% vs. 8.9%, Pc=0.0006), extraintestinal manifestations (20.5% vs. 8.9%, Pc=0.012), male patients (22.1% vs. 8.0%, Pc=0.006), and patients over the age of 40 years (28.8% vs. 8.3%, Pc=0.0006). The sMICA level was significantly higher in UC than in healthy controls (604.41±480.43 pg/ml vs. 175.37±28.31 pg/ml, P=0.0001) but not associated with the MICB0106 genotypes. Conclusions: Overall, MICB0106 allele was positively associated with UC in the Han Chinese in central China. sMICA was highly expressed in UC but not associated with the MICB0106 genotype.