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7?, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseases.

ABSTRACT: EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7?, 25-dihydroxyxcholesterol (7?, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7?, 25-OHC bound to EBI2, and how a gradient of 7?, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7?, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases.

SUBMITTER: Sun S

PROVIDER: S-EPMC4371701 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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7α, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseases.

Sun Siquan S Liu Changlu C

Frontiers in pharmacology 20150324

EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt's lymphoma cell line BL41 by Epstein-Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand ...[more]

PMID: 25852561

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Project description:ImportanceImmune regulation is important for carcinogenesis; however, the cancer risk profiles associated with immune-mediated diseases need further characterization.ObjectiveTo assess the prospective association of 48 immune-mediated diseases with the risk of total and individual cancers and the prospective association of organ-specific immune-mediated diseases with the risk of local and extralocal cancers.Design, setting, and participantsThis prospective cohort study used data from the UK Biobank cohort study on adults aged 37 to 73 years who were recruited at 22 assessment centers throughout the UK between January 1, 2006, and December 31, 2010, with follow-up through February 28, 2019.ExposuresImmune-mediated diseases.Main outcomes and measuresThe association of immune-mediated diseases with risk of cancer was assessed with multivariable hazard ratios (HRs) and 95% CIs after adjusting for various potential confounders using time-varying Cox proportional hazards regression. Heterogeneity in the associations of organ-specific immune-mediated diseases with local and extralocal cancers was assessed using the contrast test method.ResultsA total of 478 753 participants (mean [SD] age, 56.4 [8.1] years; 54% female) were included in the study. During 4 600 460 person-years of follow-up, a total of 2834 cases of cancer were documented in 61 496 patients with immune-mediated diseases and 26 817 cases of cancer in 417 257 patients without any immune-mediated diseases (multivariable HR, 1.08; 95% CI, 1.04-1.12). Five of the organ-specific immune-mediated diseases were significantly associated with higher risk of local but not extralocal cancers: asthma (HR, 1.34; 95% CI, 1.14-1.56), celiac disease (HR, 6.89; 95% CI, 2.18-21.75), idiopathic thrombocytopenic purpura (HR, 6.94; 95% CI, 3.94-12.25), primary biliary cholangitis (HR, 42.12; 95% CI, 20.76-85.44), and autoimmune hepatitis (HR, 21.26; 95% CI, 6.79-66.61) (P < .002 for heterogeneity). Nine immune-mediated diseases were associated with an increased risk of cancers in the involved organs (eg, asthma with lung cancer [HR, 1.34; 95% CI, 1.14-1.57; P < .001] and celiac disease with small intestine cancer [HR, 6.89; 95% CI, 2.18-21.75; P = .001]); 13 immune-mediated diseases were associated with an increased risk of cancer in the near organs (eg, Crohn disease with liver cancer: [HR, 4.01; 95% CI, 1.65-9.72; P = .002]) or distant organs (eg, autoimmune hepatitis with tongue cancer [HR, 27.75; 95% CI, 3.82-199.91; P = .001]) or in different systems (eg, idiopathic thrombocytopenic purpura with liver cancer [HR, 11.96; 95% CI, 3.82-37.42; P < .001]).Conclusions and relevanceIn this cohort study, immune-mediated diseases were associated with an increased risk of total cancer. Organ-specific immune-mediated diseases had stronger associations with risk of local cancers than extralocal cancers. The associations for individual immune-mediated diseases were largely organ specific but were also observed for some cancers in the near and distant organs or different systems. Our findings support the role of local and systemic immunoregulation in cancer development.

Dataset Information

7?, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseases.

Publications

7α, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseases.

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