Interleukin-18 Gene Polymorphisms in Tunisian Patients with Inflammatory Bowel Disease

Aleya, Walid Ben; Sfar, Imen; Habibi, Imen; Mouelhi, Leïla; Aouadi, Houda; Makhlouf, M.; Ayed-Jendoubi, Salwa; Najjar, Taoufik; Abdallah, T. Ben; Ayed, K.; Gorgi, Yousr

doi:10.1159/000319755

Cited by 18 publications

(8 citation statements)

References 86 publications

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“…Similar to IL-1β, IL-18 has strong pro-inflammatory activities and is essential for the proper regulation of CD4+ T cell function and Th1 cell differentiation (53). Likewise, IL-18 levels are commonly dysregulated in human IBD patients and mutations in the IL-18 gene are associated with UC (54,55). In mice, both IL-18 overexpression and attenuation have been demonstrated to increase pathogenesis in IBD models, which suggest that this cytokine has multiple functions, both positive and negative, during disease progression (6,56–58).…”

Section: Discussionmentioning

confidence: 99%

The NLRP1 Inflammasome Attenuates Colitis and Colitis-Associated Tumorigenesis

Williams

Leeth

Rothschild

et al. 2015

The Journal of Immunology

138

162

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NLR proteins are a diverse family of pattern recognition receptors that are essential mediators of inflammation and host defense in the gastrointestinal system. Recent studies have identified a sub-group of inflammasome forming NLRs that modulate the mucosal immune response during inflammatory bowel disease (IBD) and colitis associated tumorigenesis. To better elucidate the contribution of NLR family members in IBD and cancer, we conducted a retrospective analysis of gene expression metadata from human patients. These data revealed that NLRP1, an inflammasome forming NLR, was significantly dysregulated in IBD and colon cancer. To better characterize the function of NLRP1 in disease pathogenesis, we utilized Nlrp1b−/− mice in colitis and colitis associated cancer models. Here, we report that NLRP1 attenuates gastrointestinal inflammation and tumorigenesis. Nlrp1b−/− mice demonstrated significant increases in morbidity, inflammation and tumorigenesis compared to wild type animals. Similar to data previously reported for related inflammsome forming NLRs, the increased inflammation and tumor burden was correlated with attenuated levels of IL-1β and IL-18. Further mechanistic studies utilizing bone marrow reconstitution experiments revealed that the increased disease pathogenesis in the Nlrp1b−/− mice was associated with non-hematopoietic derived cells and suggests that NLRP1 functions in the colon epithelial cell compartment to attenuate tumorigenesis. Together, these data identify NLRP1 as an essential mediator of the host immune response during IBD and cancer. These findings are consistent with a model whereby multiple NLR inflammasomes attenuate disease pathobiology through modulating IL-1β and IL-18 levels in the colon.

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Section: Discussionmentioning

confidence: 99%

The NLRP1 Inflammasome Attenuates Colitis and Colitis-Associated Tumorigenesis

Williams

Leeth

Rothschild

et al. 2015

The Journal of Immunology

138

162

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“…Three SNPs in the promoter of the IL-18 gene at positions −656 G/T, −607 C/A and −137 G/C have been identified. These promoter SNPs have been implicated as susceptibility loci for various diseases, including asthma [22], pulmonary tuberculosis [23], inflammatory bowel disease [24], Parkinson’s disease [25], polycystic ovary syndrome [26], type I diabetes [27], and allergic disorders [28]. …”

Section: Discussionmentioning

confidence: 99%

Association of interleukin-18 gene polymorphism with body mass index in women

Kim

Cho

Kim

et al. 2012

Reprod Biol Endocrinol

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BackgroundInterleukin (IL)-18 is an important regulator of innate and acquired immune responses and has multiple roles in chronic inflammation and autoimmune disorders. Obesity is characterized by low- grade chronic inflammation. IL-18 has been suggested as an adipogenic cytokine that is associated with excess adiposity. The purpose of this study is to evaluate the relationship between IL-18 gene polymorphisms (−137 G/C and −607 C/A) and obesity.MethodsAll 680 subjects were genotyped for the polymorphisms of IL-18 gene promoters (at positions −137 G/C and −607 C/A) using a polymerase chain reaction (271 cases with BMI ≥25 kg/m2 and 409 controls with BMI <25 kg/m2). A chi-square test was used to compare the genotype and allele frequencies between the cases and control populations.ResultsAnalyses of the genotype distributions revealed that IL-18 –607 C/A polymorphism was associated with an increase in body mass index in obese women in the Korean population (chi(2) = 12.301, df = 2, p = 0.015).ConclusionCarriage of the A allele at position −607 in the promoter of the IL-18 gene may have a role in the development of obesity.

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“…57 IL-18 levels are significantly upregulated in subpopulations of patients with IBD, and recent studies revealed an association between SNPs in the promoter region of the human IL-18 gene in UC. 58,59 In mouse models, IL-18 overexpression and IL-18 attenuation have both been shown to enhance IBD pathogenesis. 48,60–62 These paradoxical findings suggest that IL-18 has multiple positive and negative functions in IBD pathobiology, and that dysregulation can significantly impact disease pathogenesis and health outcomes.…”

Section: Inflammasome-forming Nlrsmentioning

confidence: 99%

Emerging Significance of NLRs in Inflammatory Bowel Disease

Davis

Philipson

Hontecillas

et al. 2014

Inflammatory Bowel Diseases

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Pattern recognition receptors are essential mediators of host defense and inflammation in the gastrointestinal system. Recent data have revealed that toll-like receptors and nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) function to maintain homeostasis between the host microbiome and mucosal immunity. The NLR proteins are a diverse class of cytoplasmic pattern recognition receptors. In humans, only about half of the identified NLRs have been adequately characterized. The majority of well-characterized NLRs participate in the formation of a multiprotein complex, termed the inflammasome, which is responsible for the maturation of interleukin-1β and interleukin-18. However, recent observations have also uncovered the presence of a novel subgroup of NLRs that function as positive or negative regulators of inflammation through modulating critical signaling pathways, including NF-κB. Dysregulation of specific NLRs from both proinflammatory and inhibitory subgroups have been associated with the development of inflammatory bowel disease (IBD) in genetically susceptible human populations. Our own preliminary retrospective data mining efforts have identified a diverse range of NLRs that are significantly altered at the messenger RNA level in colons from patients with IBD. Likewise, studies using genetically modified mouse strains have revealed that multiple NLR family members have the potential to dramatically modulate the immune response during IBD. Targeting NLR signaling represents a promising and novel therapeutic strategy. However, significant effort is necessary to translate the current understanding of NLR biology into effective therapies.

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Interleukin-18 Gene Polymorphisms in Tunisian Patients with Inflammatory Bowel Disease

Cited by 18 publications

References 86 publications

The NLRP1 Inflammasome Attenuates Colitis and Colitis-Associated Tumorigenesis

The NLRP1 Inflammasome Attenuates Colitis and Colitis-Associated Tumorigenesis

Association of interleukin-18 gene polymorphism with body mass index in women

Emerging Significance of NLRs in Inflammatory Bowel Disease

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