Cigarette smoking represses expression of cytokine IL-12 and its regulator miR-21—An observational study in patients with coronary artery disease

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• 作者：T.B. Opstad ; MSc ; PhD^a ; ^b ; ^c ; ^{trineoa@medisin.uio.no} ; B.S. Brusletto ; MSc^d ; H. Arnesen ; MD^a ; ^b ; ^c (Prof.) ; A.Å ; . Pettersen ; MD ; PhD^a ; ^b ; I. Seljeflot ; PhD^a ; ^b ; ^c (Prof.)
• 关键词：ath-159a ; Arabidopsis thaliana-159a ; ASCET ; Aspirin non-responsiveness and Clopidogrel Endpoint Trial ; CSE ; cigarette smoke extract ; Ct ; cycle threshold ; EDTA ; ethylenediaminetetraacetic acid ; HWE ; Hardy-Weinberg equilibrium ; let-7 ; Caenorhabditis elegans-7 ; miR ; micro-RNA ; PCR ; polymerase chain reaction ; PDCD4 ; Programmed Cell Death 4 ; snRNA ; small nuclear RNA ; RNU ; small nucleolar RNA ; RQ ; relative quantification ; Th ; T-helper cell ; UTR ; untranslated region
• 刊名：Immunobiology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：222
• 期：2
• 页码：169-175
• 全文大小：2217 K
• 卷排序：222

文摘

The heterodimer IL-12 is an inducer of Th1 responses and stimulates INFƴ production. Micro-RNA-21 (miR-21) is described as a key regulator of the pro-inflammatory response and has IL-12p35 mRNA as one of its main targets. The IL-12p40 1188A/C genetic variant located in 3’untranslated region (UTR), thus environmentally exposed, has further been reported to modify IL-12 levels. We have previously reported on the lowering effect of cigarette smoke on circulating IL-12 in patients with coronary artery disease (CAD).ObjectivesTo explore if cigarette smoking affects IL-12p35, IL-12p40, INFƴ and miR-21 gene-expression and further modulates any effect of the IL-12p40 polymorphism on circulating IL-12 levels.Methods and ResultsThe IL-12p40 1188A/C polymorphism was analyzed in 1001 stable CAD patients, of which 330 subjects were included for IL-12p35, IL-12p40 and INFƴ gene-expression analyses in circulating leukocytes and 200 were further selected for plasma miR-21 analysis.Smoking associated with lower expression of miR-21 and its target IL-12p35 mRNA (adjusted p < 0.05, both) whereas the influence on INFƴ expression tended to be high-dose reliant (p = 0.057). The IL-12p40 CC genotype associated with elevated circulating IL-12 levels, however, when stratified according to smoking, only in the non-smoking group (adjusted p < 0.05).Although the markers were mainly downregulated in current smokers, their inter-correlations were potentiated.ConclusionSmoking associated with reduced miR-21 gene-repression and the results can therefore not explain the previously observed reduction in circulating IL-12. Smoking attenuated the IL-12 pro-inflammatory axis in which the investigated IL-12p40 genetic variant may have different clinical impact in smokers vs non-smokers.