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Paradoxical effects of constitutive human IL-32{gamma} in transgenic mice during experimental colitis.

ABSTRACT: Inflammatory cytokines mediate inflammatory bowel diseases (IBDs) and cytokine blocking therapies often ameliorate the disease severity. IL-32 affects inflammation by increasing the production of IL-1, TNF?, and several chemokines. Here, we investigated the role of IL-32 in intestinal inflammation by generating a transgenic (TG) mouse expressing human IL-32? (IL-32? TG). Although IL-32? TG mice are healthy, constitutive serum and colonic tissue levels of TNF? are elevated. Compared with wild-type (WT) mice, IL-32? TG mice exhibited a modestly exacerbated acute inflammation early following the initiation of dextran sodium sulfate (DSS)-induced colitis. However, after 6 d, there was less colonic inflammation, reduced tissue loss, and improved survival rate compared with WT mice. Associated with attenuated tissue damage, colonic levels of TNF? and IL-6 were significantly reduced in the IL-32? TG mice whereas IL-10 was elevated. Cultured colon explants from IL-32? TG mice secreted higher levels of IL-10 compared with WT mice and lower levels of TNF? and IL-6. Constitutive levels of IL-32? itself in colonic tissues were significantly lower following DSS colitis. Although the highest level of serum IL-32? occurred on day 3 of colitis, IL-32 was below constitutive levels on day 9. The ability of IL-32? to increase constitutive IL-10 likely reduces TNF?, IL-6, and IL-32 itself accounting for less inflammation. In humans with ulcerative colitis (UC), serum IL-32 is elevated and colonic biopsies contain IL-32 in inflamed tissues but not in uninvolved tissues. Thus IL-32? emerges as an example of how innate inflammation worsens as well as protects intestinal integrity.

SUBMITTER: Choi J

PROVIDER: S-EPMC3000248 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Paradoxical effects of constitutive human IL-32{gamma} in transgenic mice during experimental colitis.

Choi Jida J Bae Suyoung S Hong Jaewoo J Ryoo Soyoon S Jhun Hyunjhung H Hong Kwangwon K Yoon Doyoung D Lee Siyoung S Her Erk E Choi Wonhyuk W Kim Jeonghwan J Azam Tania T Dinarello Charles A CA Kim Soohyun S

Proceedings of the National Academy of Sciences of the United States of America 20101115 49

Inflammatory cytokines mediate inflammatory bowel diseases (IBDs) and cytokine blocking therapies often ameliorate the disease severity. IL-32 affects inflammation by increasing the production of IL-1, TNFα, and several chemokines. Here, we investigated the role of IL-32 in intestinal inflammation by generating a transgenic (TG) mouse expressing human IL-32γ (IL-32γ TG). Although IL-32γ TG mice are healthy, constitutive serum and colonic tissue levels of TNFα are elevated. Compared with wild-typ ...[more]

PMID: 21078994

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Project description:BackgroundInterleukin-32 (IL-32) has long been proposed as a biomarker for coronary artery disease (CAD). We aimed to evaluate the association between IL-32 levels and coronary stenosis severity, IL-32 polymorphisms rs28372698 and rs4786370, and CAD susceptibility.MethodsA total of 362 patients with definite or suspected CAD that underwent angiography were recruited (CAD group, n = 175; nonobstructive CAD group, n = 56; control group, n = 131). The severity of coronary stenosis was assessed using the Gensini score and the number of diseased vessels. IL-32 levels were determined using enzyme-linked immunosorbent assay. Gene polymorphisms were genotyped using PCR and sequencing techniques.ResultsIL-32 levels were significantly different at different levels of coronary artery stenosis (p < 0.05), and logIL-32 was positively correlated with the Gensini score (r = 0.357, p < 0.01). Multivariate logistic regression analysis revealed that IL-32 was independently associated with CAD (OR = 6.526, 95% CI: 3.344-12.739, p < 0.01). The receiver operating characteristic analysis revealed the area under the curve for discriminating the CAD and Gensini score were 0.605 and 0.613, respectively. Furthermore, IL-32 levels were significantly higher before percutaneous coronary intervention (PCI) than at 7 days post-PCI (p = 0.012). The homozygous TT genotype and T allele of rs28372698 were found to be associated with increased risk of CAD, while TT homozygosity and the T allele of rs4786370 with reduced risk of CAD (p < 0.05). However, both SNPs had no obvious effect on IL-32 levels or coronary stenosis severity in patients with CAD.ConclusionTo the best of our knowledge, our study is the first to show that rs28372698 and rs4786370 are associated with CAD susceptibility in Chinese Han population. We also suggest that plasma IL-32 levels may be indicative of coronary artery stenosis and the efficacy of PCI and provide guidance for risk stratification and disease management.

Project description:Inflammatory bowel disease (IBD) is a type of chronic inflammatory disturbance that affects a number of individuals worldwide; the precise mechanism is unclear and treatment is frequently insufficient to maintain patients in remission. Saccharomyces boulardii is a thermophilic, non?pathogenic yeast that may be administered for prophylaxis and treatment of a variety of diarrheal diseases. Recent clinical studies have demonstrated that it may have a role in IBD; however, the mechanism of action is unclear. The hypoxia?inducible factors (HIFs) are ubiquitously expressed regulators of cellular adaptation to hypoxia and are central to the adaptive and inflammatory responses of cells of the intestinal mucosa in patients with IBD. The present study aimed to investigate the effects of S. boulardii on dextran sulfate sodium (DSS)?induced colitis in mice and the effects of S. boulardii on HIFs. Mice were divided into five groups (n=10 mice/group): i) Control; ii) DSS; iii) S. boulardii (Sb) + DSS; iv) normal saline (NS) + DSS; and v) Sb. For 14 consecutive days, mice from the Sb+DSS and Sb groups were given S. boulardii suspension in saline (150 mg/kg/day; final volume 0.2 ml) by oral gavage. The NS+DSS group received the same volume of NS by gavage. The Control mice received water only. From day 8 to day 14, 3.5% DSS was added to the drinking water of the DSS, Sb+DSS and NS+DSS groups to induce acute colitis. Body weight decreased and disease activity index and histological score increased in mice with DSS?induced colitis. Oral administration of S. boulardii reduced DSS?induced weight loss, ameliorated the histological damage and protected the colon barrier in mice with DSS?induced colitis. The expression of HIF?1? and HIF?2? in colon tissues was measured by reverse transcription?quantitative polymerase chain reaction, immunoblotting and immunohistochemistry. The increase in HIFs in the colon induced by DSS was significantly inhibited by S. boulardii treatment. The expression levels of several epithelial?mesenchymal transition (EMT) markers and of vascular endothelial growth factor (VEGF) that are regulated by HIFs were measured. S. boulardii reduced EMT and decreased expression of VEGF that was induced by DSS treatment. These results indicated that treatment with S. boulardii ameliorated DSS?induced colitis, partly through downregulation of HIF?1? and HIF?2?.

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Paradoxical effects of constitutive human IL-32{gamma} in transgenic mice during experimental colitis.

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Paradoxical effects of constitutive human IL-32{gamma} in transgenic mice during experimental colitis.

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