IL-22 produced by Th22 cells aggravates atherosclerosis development in ApoE-/- mice by enhancing DC-induced Th17 cell proliferation.

Th22 cells are a novel subset of CD4+ T cells that primarily mediate biological effects through IL-22, with both Th22 cells and IL-22 being closely associated with multiple autoimmune and chronic inflammatory diseases. In this study, we investigated whether and how Th22 cells affect atherosclerosis. ApoE-/- mice and age-matched C57BL/6J mice were fed a Western diet for 0, 4, 8 or 12 weeks. The results of dynamic analyses showed that Th22 cells, which secrete the majority of IL-22 among the known CD4+ cells, play a major role in atherosclerosis. ApoE-/- mice fed a Western diet for 12 weeks and administered recombinant mouse IL-22 (rIL-22) developed substantially larger plaques in both the aorta and aortic root and higher levels of CD3+ T cells, CD68+ macrophages, collagen, IL-6, Th17 cells, dendritic cells (DCs) and pSTAT3 but lower smooth muscle cell (SMC) α-actin expression than the control mice. Treatment with a neutralizing anti-IL-22 monoclonal antibody (IL-22 mAb) reversed the above effects. Bone marrow-derived DCs exhibited increased differentiation into mature DCs following rIL-22 and ox-LDL stimulation. IL-17 and pSTAT3 were up-regulated after stimulation with IL-22 and ox-LDL in cells cocultured with CD4+ T cells and mature DC supernatant, but this up-regulation was significantly inhibited by IL-6mAb or the cell-permeable STAT3 inhibitor S31-201. Thus, Th22 cell-derived IL-22 aggravates atherosclerosis development through a mechanism that is associated with IL-6/STAT3 activation, DC-induced Th17 cell proliferation and IL-22-stimulated SMC dedifferentiation into a synthetic phenotype.

Interleukin-18 Expression Increases in the Aorta and Plasma of Patients with Acute Aortic Dissection.

BACKGROUND: Interleukin- (IL-) 18 is a proinflammatory cytokine related to cardiovascular diseases, including hypertension and atherosclerosis. This study is aimed at determining whether IL-18 is related to aortic dissection (AD) and identifying the underlying mechanisms. METHODS: IL-18 expression in human aorta samples from AD (n = 8) and non-AD (NAD, n = 7) patients was measured. In addition, the IL-18, IL-6, interferon- (IFN-) γ, and IL-18-binding protein (IL-18BP) concentrations in plasma samples collected from the NAD and AD patients were detected. The effects of IL-18 on macrophage differentiation and smooth muscle cell (SMC) apoptosis were investigated in vitro. RESULTS: IL-18 expression was significantly increased in the aorta samples from the AD patients compared with those from the NAD patients, especially in the torn section. Aortic IL-18 was mainly derived from macrophages and also partly derived from CD4+ T lymphocytes and vascular SMCs. Plasma IL-18, IFN-γ, and IL-6 levels were significantly higher in the AD group than in the NAD group, and the IL-18 levels were positively correlated with the IFN-γ and IL-6 levels. In addition, plasma IL-18BP and free IL-18 levels were also elevated in the AD group. Linear regression analysis showed that the IL-18 level was independently associated with the presence of AD. In addition, anti-mouse IL-18-neutralizing monoclonal antibodies (anti-IL-18 nAb) inhibited angiotensin II-induced M1 macrophage differentiation and SMC apoptosis in vitro. CONCLUSION: IL-18 may participate in AD by regulating macrophage differentiation and macrophage-induced SMC apoptosis.

Association between interleukin-35 polymorphisms and coronary heart disease in the Chinese Zhuang population: a case-control study.

OBJECTIVES: Inflammatory cytokines play an important role in the pathogenesis of cardiovascular disease. Few studies have investigated the association between interleukin-35 (IL-35) genetic variants and the risk of coronary heart disease (CHD). We examined the association between IL-35 polymorphisms and CHD in the Chinese Zhuang population. PATIENTS AND METHODS: A total of 707 CHD patients and 707 age-matched and sex-matched controls were enrolled in this case-control study. Genotypes of the single nucleotide polymorphisms (SNPs) of IL-35, including rs428253, rs6613, rs9807813, rs2243115, rs568408, rs582054, rs583911, rs4740, and rs393581, were examined by MassArray. Plasma IL-35 level was measured using an enzyme-linked immunosorbent assay. The multivariate logistic regression model was used to evaluate the association between the SNPs and the risk of CHD. RESULTS: In the Chinese Zhuang population, compared with the GG genotype of EBI3 rs428253, individuals with the CC genotype had a 2.02-fold (95% confidence interval: 1.07-3.84, P=0.031) higher risk of CHD. Further adjustment for potential risk factors did not alter the positive association (CC vs. GG, odds ratio=2.30, 95% confidence interval: 1.16-4.54, P=0.042). SNPs rs4740, rs2243115, rs568408, and rs582054 were not statistically related to the risk of CHD. The plasma IL-35 levels showed a marginally significant difference between rs428253 genotypes [GG: 13.39 (7.89-19.25) vs. CC+GC: 17.53 (8.98-22.56) pg/ml, P=0.057]. CONCLUSION: The EBI3 rs428253 CC genotype was associated with an increased risk of CHD in the Chinese Zhuang population, although no significant difference in IL-35 levels was observed between genotypes in healthy controls.