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A polymorphism in the coding region of Il12b promotes IL-12p70 and IL-23 heterodimer formation.

ABSTRACT: IL-12 and IL-23 are heterodimeric cytokines involved in the induction of Th1 and Th17 immune responses. Previous work indicated that a region on chromosome 11 encoding the IL-12p40 subunit regulates strain differences in susceptibility to murine trinitrobenzene sulfonic acid-induced colitis. In addition, this region determines strain differences in LPS-induced IL-12 responses. In this study, we investigated how polymorphisms in the coding region of murine Il12b influence IL-12 and IL-23 heterodimer formation. Transfection studies using constructs containing IL-12p35 linked to IL-12p40 from the colitis-resistant C57BL/6 strain or to the polymorphic p40 variant from the colitis-susceptible SJL/J strain demonstrated that SJL/J-derived p40 constructs synthesized significantly more IL-12p70 than did constructs harboring the C57BL/6-p40 variant. This could not be attributed to differences in synthesis rate or secretion, implicating a greater affinity of SJL/J-derived IL-12p40 for its IL-12p35 subunit. This greater affinity is also associated with increased IL-23 synthesis. In addition, C57BL/6 mice transgenic for the SJL/J 40 variant synthesized significantly more IL-12p70 upon LPS challenge and were more prone to develop colonic inflammation than did C57BL/6 mice transgenic for the C57BL/6-p40 variant. The more efficient binding of the polymorphic Il12b variant to p35 and p19 is most likely due to conformational changes following differential glycosylation as a consequence of the polymorphism. The high synthesis rate of the mature cytokines resulting from this efficient binding can lead to rapid proinflammatory skewing of immune responses and distortion of the homeostatic balance underlying the greater susceptibility for colitis.

SUBMITTER: Zwiers A

PROVIDER: S-EPMC3673698 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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A polymorphism in the coding region of Il12b promotes IL-12p70 and IL-23 heterodimer formation.

Zwiers Antonie A Fuss Ivan J IJ Seegers Diana D Konijn Tanja T Garcia-Vallejo Juan J JJ Samsom Janneke N JN Strober Warren W Kraal Georg G Bouma Gerd G

Journal of immunology (Baltimore, Md. : 1950) 20110214 6

IL-12 and IL-23 are heterodimeric cytokines involved in the induction of Th1 and Th17 immune responses. Previous work indicated that a region on chromosome 11 encoding the IL-12p40 subunit regulates strain differences in susceptibility to murine trinitrobenzene sulfonic acid-induced colitis. In addition, this region determines strain differences in LPS-induced IL-12 responses. In this study, we investigated how polymorphisms in the coding region of murine Il12b influence IL-12 and IL-23 heterodi ...[more]

PMID: 21321105

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Project description:BackgroundDental implantation has been practiced since ancient times and has gone through several stages. Dentists use dental implants to support dental prostheses such as crowns, bridges, dentures, face prostheses, or as an orthodontic anchor. Thus, the purpose of this study is to detect the role of the immune-genetic variation of IL-17A and related inflammatory cytokine (IL-23) in the initiation and progress of peri implantitis.Material and methodsThis cross-sectional study included 80 subjects (15 peri-implantitis patients, 35 successful implants, and 30 healthy controls); their mean age was (43.91 ± 11.33) years. Blood samples and Peri-implant sulcus fluid (PISF) were collected from all subjects (patients with peri-implantitis, successful implants, and healthy controls) attending the Department of Oral and Maxillofacial Surgery in the Dental College Teaching Hospital, Baghdad University, Baghdad, Iraq. The blood sample detects gene polymorphisms in interleukin-17A by a polymerase chain reaction (PCR). An enzyme-linked immunosorbent assay (ELISA) was carried out to estimate the Peri-implant sulcus fluid (PISF) levels of interleukin-23.ResultThe current study revealed an obvious significant elevation in the mean level of interleukin-23 in the peri-implantitis patient's group more than its level in the successful implant and control groups (P < 0.05). In addition, the result showed that A/A genotype is associated significantly with peri-implantitis OR (95%confidence interval) =6.9 (1.7121 to 27.4638) folds increase risk of peri-implantitis) (p = 0.0065), while G/A genotype had OR 4.9 (0.9539-24.9394) folds increased risk of peri-implantitis, (p = 0.0572). But it was not statistically significant and G/G genotype had a one-fold increase risk of peri-implantitis.ConclusionThe increased level of inflammatory cytokine (interleukin-23) might add to the systemic inflammatory burden a predisposing factor, which may lead to impaired osseointegration and subsequent bone loss or implant failure. In addition, IL-17A gene polymorphism may play a role in peri-implant disease susceptibility, especially in persons carrying the rs2275913 A allele at a higher risk of developing peri-implantitits as compared with those carrying the G allele.

Dataset Information

A polymorphism in the coding region of Il12b promotes IL-12p70 and IL-23 heterodimer formation.

Publications

A polymorphism in the coding region of Il12b promotes IL-12p70 and IL-23 heterodimer formation.

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