Cimato Thomas R, Palka Beth A
Department of Medicine, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Clinical and Translational Research Center , Buffalo, NY , USA.
PeerJ. 2015 Feb 5;3:e764. doi: 10.7717/peerj.764. eCollection 2015.
Background. Activation of the innate immune system by cholesterol accelerates atherosclerosis. High levels or modified forms of cholesterol stimulate release of the inflammatory cytokines IL-12 and IL-18 that synergistically stimulate T lymphocytes to produce the atherogenic cytokine interferon-γ. While activation of the innate immune system by cholesterol is well-described in animal models and human subjects with high cholesterol levels or known atherosclerotic disease, the interaction of cholesterol and lipoproteins with the innate immune system in human subjects without known atherosclerosis is less well-described. The goal of our study was to assess the TH1 modulating cytokines IL-12 p40 and IL-18, and their counter regulatory cytokines IL-18 binding protein and IL-27, to determine if their levels are linked to cholesterol levels or other factors. Methods. We performed a blinded, randomized hypothesis-generating study in human subjects without known atherosclerotic disease. We measured serum lipids, lipoprotein levels, and collected plasma samples at baseline. Subjects were randomized to two weeks of therapy with atorvastatin, pravastatin, or rosuvastatin. Lipids and cytokine levels were measured after two weeks of statin treatment. Subjects were given a four-week statin-free period. At the end of the four-week statin-free period, venous blood was sampled again to determine if serum lipids returned to within 5% of their pre-statin levels. When lipid levels returned to baseline, subjects were again treated with the next statin in the randomization scheme. IL-12, IL-18, IL-18 binding protein, and IL-27 were measured at baseline and after each statin treatment to determine effects of statin treatment on their blood levels, and identify correlations with lipids and lipoproteins. Results. Therapy with statins revealed no significant change in the levels of IL-12, IL-18, IL-18 binding protein or IL-27 levels. We found that IL-18 levels positively correlate with total cholesterol levels (r (2) = 0.15, p < 0.03), but not HDL or LDL cholesterol. In contrast, IL-12 p40 levels inversely correlated with total cholesterol (r (2) = -0.17, p < 0.008), HDL cholesterol (r (2) = -0.22, p < 0.002), and apolipoprotein A1 (r (2) = -0.21, p < 0.002). Similarly, IL-18 binding protein levels inversely correlated with apolipoprotein A1 levels (r (2) = -0.13, p < 0.02). Conclusions. Our findings suggest that total cholesterol levels positively regulate IL-18, while HDL cholesterol and apolipoprotein A1 may reduce IL-12 p40 and IL-18 binding protein levels. Additional studies in a larger patient population are needed to confirm these findings, and verify mechanistically whether HDL cholesterol can directly suppress IL-12 p40 and IL-18 binding protein levels in human subjects.
背景。胆固醇激活先天性免疫系统会加速动脉粥样硬化。高水平或修饰形式的胆固醇会刺激炎性细胞因子白细胞介素-12（IL-12）和白细胞介素-18（IL-18）的释放，它们协同刺激T淋巴细胞产生促动脉粥样硬化细胞因子干扰素-γ。虽然在动物模型以及高胆固醇水平或已知动脉粥样硬化疾病的人类受试者中，胆固醇对先天性免疫系统的激活已得到充分描述，但在无已知动脉粥样硬化的人类受试者中，胆固醇和脂蛋白与先天性免疫系统的相互作用描述较少。我们研究的目的是评估TH1调节细胞因子IL-12 p40和IL-18，以及它们的反调节细胞因子IL-18结合蛋白和IL-27，以确定它们的水平是否与胆固醇水平或其他因素相关。方法。我们在无已知动脉粥样硬化疾病的人类受试者中进行了一项盲法、随机假设生成研究。我们在基线时测量血清脂质、脂蛋白水平，并采集血浆样本。受试者被随机分配接受阿托伐他汀、普伐他汀或瑞舒伐他汀治疗两周。他汀类药物治疗两周后测量脂质和细胞因子水平。受试者有四周的无他汀类药物治疗期。在四周无他汀类药物治疗期结束时，再次采集静脉血以确定血清脂质是否恢复到他汀类药物治疗前水平的5%以内。当脂质水平恢复到基线时，受试者按照随机方案再次接受下一种他汀类药物治疗。在基线和每次他汀类药物治疗后测量IL-12、IL-18、IL-18结合蛋白和IL-27，以确定他汀类药物治疗对其血液水平的影响，并确定与脂质和脂蛋白的相关性。结果。他汀类药物治疗显示IL-12、IL-18、IL-18结合蛋白或IL-27水平无显著变化。我们发现IL-18水平与总胆固醇水平呈正相关（r(2)=0.15，p<0.03），但与高密度脂蛋白（HDL）或低密度脂蛋白（LDL）胆固醇无关。相比之下，IL-12 p40水平与总胆固醇（r(2)=-0.17，p<0.008）、HDL胆固醇（r(2)=-0.22，p<0.002）和载脂蛋白A1（r(2)=-0.21，p<0.002）呈负相关。同样，IL-18结合蛋白水平与载脂蛋白A1水平呈负相关（r(2)=-0.13，p<0.02）。结论。我们的研究结果表明，总胆固醇水平正向调节IL-18，而HDL胆固醇和载脂蛋白A1可能降低IL-12 p40和IL-18结合蛋白水平。需要在更大的患者群体中进行进一步研究以证实这些发现，并从机制上验证HDL胆固醇是否能直接抑制人类受试者的IL-12 p40和IL-18结合蛋白水平。
