T B Opstad1, B S Brusletto2, H Arnesen3, A Å Pettersen4, I Seljeflot3. 1. Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway; Center for Heart Failure Research, Oslo University Hospital, Norway; Faculty of Medicine, University of Oslo, Norway. Electronic address: trineoa@medisin.uio.no. 2. Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Norway. 3. Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway; Center for Heart Failure Research, Oslo University Hospital, Norway; Faculty of Medicine, University of Oslo, Norway. 4. Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevål, Norway; Center for Heart Failure Research, Oslo University Hospital, Norway.
Abstract
RATIONALE: 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). OBJECTIVES: To 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 RESULTS: The 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. CONCLUSION: Smoking 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.
RATIONALE: 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). OBJECTIVES: To 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 RESULTS: The 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. CONCLUSION: Smoking 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.
Authors: Arno R Bourgonje; Laura A Bolte; Lianne L C Vranckx; Lieke M Spekhorst; Ranko Gacesa; Shixian Hu; Hendrik M van Dullemen; Marijn C Visschedijk; Eleonora A M Festen; Janneke N Samsom; Gerard Dijkstra; Rinse K Weersma; Marjo J E Campmans-Kuijpers Journal: Nutrients Date: 2022-06-17 Impact factor: 6.706
Authors: Arno R Bourgonje; Shixian Hu; Lieke M Spekhorst; Daria V Zhernakova; Arnau Vich Vila; Yanni Li; Michiel D Voskuil; Lisette A van Berkel; Brenda Bley Folly; Mohammed Charrout; Ahmed Mahfouz; Marcel J T Reinders; Julia I P van Heck; Leo A B Joosten; Marijn C Visschedijk; Hendrik M van Dullemen; Klaas Nico Faber; Janneke N Samsom; Eleonora A M Festen; Gerard Dijkstra; Rinse K Weersma Journal: J Crohns Colitis Date: 2022-03-14 Impact factor: 9.071