{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:19:57Z","timestamp":1792793997845,"version":"4.5.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>\n                    Common carotid intima-media thickness (IMT) represents a functional and structural marker of early, precocious, and subclinical atherosclerosis, independently from the carotid plaque. Macrophage cells, which have been detected in adipose tissue and atherosclerotic plaques, are regulated by interleukin-15 (IL-15). At the light of the conflicting results concerning the role of IL-15 in atherosclerosis, the aim of the study was to retrospectively evaluate in a population of 80 obese patients, with median age of 46 years (IQR 34\u201353 years), with a low rate of comorbidities but with non-alcoholic fatty liver disease (NAFLD) or hepatic steatosis (HS), the relationship between IMT and serum concentrations of IL-15. Anthropometric measures, metabolic profile, and serum inflammatory markers, as well as the levels of IL-15, MCP-1, b FGF, and GM-CSF, were analyzed by a bead-based assay. IMT, HS, subcutaneous, and visceral adipose tissues were detected by ultrasonography. The IL-15 levels of the obese patients were increased with respect to those of 44 young healthy subjects, i.e., 2.77 (1.21\u20134.8) vs. 1.55 (1\u20132.4) pg\/mL (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.002). In the univariate analysis, IL-15 levels were associated to IMT and to those of MCP-1, b FGF, and GM-CSF, without any relation to other inflammatory markers such as CRP and ferritin, except fibrinogen. In the multivariate analysis, after adjusting the HS severity for the extent of visceral adiposity, a dramatic change in prediction of IMT by HS was shown (\u03b2 from 0.29 to 0.10,\n                    <jats:italic>P<\/jats:italic>\n                    from 0.008 to 0.37). When the visceral adipose tissue was combined with IL-15, on the one hand, and the well-known coronary artery disease (CAD) risk factors\u2014i.e., age, gender, smoking status, HDL-cholesterol concentrations, triglycerides levels, and HOMA\u2014on the other, only age and IL-15 remained the predictors of IMT (\u03b2 = 0.60,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.0001 and \u03b2 = 0.25,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.024, respectively). There was no association of IL-15 with various anthropometric parameters nor with body fat distribution and severity of HS, also after adjusting for age. Age is resulted to be the main factor in the prediction of IMT and thus of early atherosclerosis. The prediction of IMT by IL-15 coupled with the lack of prediction by the well-known CAD risks is in agreement with recent data, which emphasizes the main role of the immune system in the onset\/worsening of atherosclerosis, even though the role of visceral adiposity should be further deepened. Age and IL-15 levels were both predictors of early atherosclerosis in this population of obese patients with NAFLD, suggesting a possible role of this cytokine in the atherosclerosis process.\n                  <\/jats:p>","DOI":"10.3389\/fmed.2021.634962","type":"journal-article","created":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T02:15:41Z","timestamp":1621563341000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Age and Interleukin-15 Levels Are Independently Associated With Intima-Media Thickness in Obesity-Related NAFLD Patients"],"prefix":"10.3389","volume":"8","author":[{"given":"Giovanni","family":"Tarantino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Citro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Balsano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Capone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1161\/CIRCRESAHA.111.261388","article-title":"Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence","volume":"111","author":"Wang","year":"2012","journal-title":"Circ Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1067\/mhj.2001.114972","article-title":"Noninvasive tests of vascular function and structure: why and how to perform them","volume":"141","author":"Fathi","year":"2001","journal-title":"Am Heart J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/S1074-7613(00)80564-6","article-title":"Potent and selective stimulation of memory-phenotype CD8-T cells in vivo by IL-15","volume":"8","author":"Zhang","year":"1998","journal-title":"Immunity."},{"key":"B4","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/S0002-9440(10)61712-9","article-title":"Expression of interleukin-15 in mouse and human atherosclerotic lesions","volume":"159","author":"Wuttge","year":"2001","journal-title":"Am J Pathol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1161\/hq0701.092162","article-title":"Interleukin-15 expression in atherosclerotic plaques: an alternative pathway for T-cell activation in atherosclerosis?","volume":"21","author":"Houtkamp","year":"2001","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1016\/j.amjhyper.2005.02.014","article-title":"Serum interleukin-15 concentration in patients with essential hypertension","volume":"18","author":"Kaibe","year":"2005","journal-title":"Am J Hypertens."},{"key":"B7","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.cyto.2009.09.004","article-title":"Influences of genetic variants in interleukin-15 gene and serum interleukin-15 levels on coronary heart disease","volume":"49","author":"Gokkusu","year":"2010","journal-title":"Cytokine."},{"key":"B8","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.cyto.2008.04.008","article-title":"Interleukin-15 and interleukin-15R alpha SNPs and associations with muscle, bone, and predictors of the metabolic syndrome","volume":"43","author":"Pistilli","year":"2008","journal-title":"Cytokine."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e90960","DOI":"10.1371\/journal.pone.0090960","article-title":"Interleukin-15 and soluble interleukin-15 receptor \u03b1 in coronary artery disease patients: association with epicardial fat and indices of adipose tissue distribution","volume":"9","author":"Dozio","year":"2014","journal-title":"PLoS ONE."},{"key":"B10","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.bbrc.2005.11.050","article-title":"Autocrine role of vascular IL-15 in intimal thickening","volume":"339","author":"Cercek","year":"2006","journal-title":"Biochem Biophys Res Commun."},{"key":"B11","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1042\/bj20030207","article-title":"Fractalkine (CX3CL1) stimulated by nuclear factor kappaB (NF-kappaB)-dependent inflammatory signals induces aortic smooth muscle cell proliferation through an autocrine pathway","volume":"373","author":"Chandrasekar","year":"2003","journal-title":"Biochem J."},{"key":"B12","first-page":"287","article-title":"Smooth muscle homeostasis in human atherosclerotic plaques through interleukin 15 signalling","volume":"4","author":"van der Meer","year":"2011","journal-title":"Int J Clin Exp Pathol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/S1097-2765(00)80139-2","article-title":"Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipo-protein receptor-deficient mice","volume":"2","author":"Gu","year":"1998","journal-title":"Mol Cell."},{"key":"B14","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.cell.2011.04.005","article-title":"Macrophages in the pathogenesis of atherosclerosis","volume":"145","author":"Moore","year":"2011","journal-title":"Cell."},{"key":"B15","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.mce.2011.10.018","article-title":"Adipocyte-secreted factors increase osteoblast proliferation and the OPG\/RANKL ratio to influence osteoclast formation","volume":"349","author":"K\u00fchn","year":"2012","journal-title":"Mol Cell Endocrinol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3140","DOI":"10.1161\/01.CIR.0000105723.91637.1C","article-title":"Cardiac-specific overexpression of fibroblast growth factor-2 protects against myocardial dysfunction and infarction in a murine model of low-flow ischemia","volume":"108","author":"House","year":"2003","journal-title":"Circulation."},{"key":"B17","doi-asserted-by":"publisher","first-page":"183","DOI":"10.3389\/fendo.2013.00183","article-title":"Basic fibroblast growth factor predicts cardiovascular disease occurrence in participants from the veterans affairs diabetes trial","volume":"4","author":"Zimering","year":"2013","journal-title":"Front Endocrinol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"05610","DOI":"10.1371\/journal.pone.0105610","article-title":"Carotid intima-media thickness is predicted by combined eotaxin levels and severity of hepatic steatosis at ultrasonography in obese patients with nonalcoholic fatty liver disease","volume":"9","author":"Tarantino","year":"2014","journal-title":"PLoS ONE."},{"key":"B19","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1476-9255-6-6","article-title":"Young adult obese subjects with and without insulin resistance: what is the role of chronic inflammation and how to weigh it non-invasively?","volume":"6","author":"Tarantino","year":"2009","journal-title":"J Inflamm."},{"key":"B20","doi-asserted-by":"publisher","first-page":"909","DOI":"10.2214\/AJR.07.4016","article-title":"Diagnostic value of a computerized hepatorenal index for sonographic quantification of liver steatosis","volume":"192","author":"Webb","year":"2009","journal-title":"Am J Roentgenol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/1479-5876-10-50","article-title":"Are hepatic steatosis and carotid intima media thickness associated in obese patients with normal or slightly elevated gamma-glutamyl-transferase?","volume":"10","author":"Tarantino","year":"2012","journal-title":"J Transl Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.echo.2007.11.011","article-title":"American Society of Echocardiography Carotid Intima-Media Thickness Task Force Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine","volume":"21","author":"Stein","year":"2008","journal-title":"J Am Soc Echocardiogr."},{"key":"B23","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: insulin resistance and beta-cell function from fast-ing plasma glucose and insulin concentrations in man","volume":"28","author":"Matthews","year":"1985","journal-title":"Diabetologia."},{"key":"B24","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1111\/j.1601-0825.2008.01488.x","article-title":"Multiplexed immunobead-based assay for detection of oral cancer protein biomarkers in saliva","volume":"14","author":"Arellano-Garcia","year":"2008","journal-title":"Oral Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.jri.2010.05.003","article-title":"Performance evaluation of microbead and ELISA assays for follicular G-CSF: a non-invasive biomarker of oocyte developmental competence for embryo implantation","volume":"86","author":"L\u00e9d\u00e9e","year":"2010","journal-title":"J Reprod Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1161\/HYPERTENSIONAHA.112.194456","article-title":"Arterial stiffness as surrogate end point: needed clinical trials","volume":"60","author":"Laurent","year":"2012","journal-title":"Hypertension."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1e7","DOI":"10.1016\/j.atherosclerosis.2008.04.045","article-title":"Markers of inflammation and coronary artery calcification: a systematic review","volume":"201","author":"Hamirani","year":"2008","journal-title":"Atherosclerosis."},{"key":"B28","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1161\/CIRCULATIONAHA.109.864801","article-title":"Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis","volume":"120","author":"Yeboah","year":"2009","journal-title":"Circulation."},{"key":"B29","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1476-7120-12-39","article-title":"Carotid artery intima-media thickness is closely related to impaired left ventricular function in patients with coronary artery disease: a single centre, blinded, non-randomized study","volume":"12","author":"Evensen","year":"2014","journal-title":"Cardiovasc Ultrasound."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2181","DOI":"10.1097\/HJH.0b013e32834b0eba","article-title":"METEOR Study Group. Algorithms to measure carotid intima-media thickness in trials: a comparison of reproducibility, rate of progression and treatment effect","volume":"29","author":"Dogan","year":"2011","journal-title":"J Hypertens."},{"key":"B31","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/S1052-5149(02)00015-1","article-title":"B-mode ultrasound and spiral CT for the assessment of carotid atherosclerosis","volume":"12","author":"Gr\u00f8nholdt","year":"2002","journal-title":"Neuroimaging Clin N Am."},{"key":"B32","first-page":"1979","article-title":"Effects of G-CSF on serum cholesterol and development of atherosclerotic plaque in apolipoprotein E-deficient mice","volume":"7","author":"Sinha","year":"2014","journal-title":"Int J Clin Exp Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.cardiores.2003.10.003","article-title":"Conduction performance of collateral vessels induced by vascular endothelial growth factor or basic fibroblast growth factor","volume":"61","author":"Kondoh","year":"2004","journal-title":"Cardiovasc Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"319","DOI":"10.17219\/acem\/37123","article-title":"The role of chemokines in hypertension","volume":"23","author":"Martynowicz","year":"2014","journal-title":"Adv Clin Exp Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3998","DOI":"10.1093\/eurheartj\/ehaa648","article-title":"Improved cardiovascular risk prediction using targeted plasma proteomics in primary prevention","volume":"41","author":"Hoogeveen","year":"2020","journal-title":"Eur Heart J."},{"key":"B36","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1177\/2047487314560664","article-title":"Inflammatory markers and extent and progression of early atherosclerosis: meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration","volume":"23","author":"Willeit","year":"2016","journal-title":"Eur J Prev Cardiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1016\/j.vaccine.2010.11.037","article-title":"IL-15 aggravates atherosclerotic lesion development in LDL receptor deficient mice","volume":"29","author":"van","year":"2011","journal-title":"Vaccine."},{"key":"B38","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.atherosclerosis.2013.07.052","article-title":"A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care?","volume":"230","author":"Oni","year":"2013","journal-title":"Atherosclerosis."},{"key":"B39","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.atherosclerosis.2014.05.962","article-title":"Associations between nonalcoholic fatty liver disease and subclinical atherosclerosis in middle-aged adults: the Coronary Artery Risk Development in Young Adults Study","volume":"235","author":"VanWagner","year":"2014","journal-title":"Atherosclerosis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"l5367","DOI":"10.1136\/bmj.l5367","article-title":"Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults","volume":"367","author":"Alexander","year":"2019","journal-title":"BMJ."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1172\/JCI26498","article-title":"MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity","volume":"116","author":"Kanda","year":"2006","journal-title":"J Clin Invest."},{"key":"B42","doi-asserted-by":"publisher","first-page":"7265","DOI":"10.1073\/pnas.1133870100","article-title":"Monocyte chemoattractant protein 1 in obesity and insulin resistance","volume":"100","author":"Sartipy","year":"2003","journal-title":"Proc Natl Acad Sci USA."},{"key":"B43","doi-asserted-by":"publisher","first-page":"001","DOI":"10.29328\/journal.acem.1001017","article-title":"Association between obesity profile and non-alcoholic fatty liver by race\/ethnicity","volume":"5","author":"Galindo","year":"2021","journal-title":"Ann Clin Endocrinol Metabol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1161\/STROKEAHA.111.646596","article-title":"Risk factors for progression of carotid intima-media thickness and total plaque area: a 13-year follow-up study: the Troms\u00f8 Study","volume":"43","author":"Herder","year":"2012","journal-title":"Stroke."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e0166537","DOI":"10.1371\/journal.pone.0166537","article-title":"Correction: deficiency of interleukin-15 confers resistance to obesity by diminishing inflammation and enhancing the thermogenic function of adipose tissues","volume":"11","author":"Lacraz","year":"2016","journal-title":"PLoS ONE."},{"key":"B46","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1136\/hrt.76.1.24","article-title":"Increased serum concentrations of interleukin-1 beta in patients with coronary artery disease","volume":"76","author":"Leibovitz","year":"1996","journal-title":"Heart."},{"key":"B47","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3389\/fncel.2015.00018","article-title":"Interleukin-1 and acute brain injury","volume":"9","author":"Murray","year":"2015","journal-title":"Front Cell Neurosci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"e41","DOI":"10.15190\/d.2015.33","article-title":"Interleukin-1 in cardiac injury, repair, and remodeling: pathophysiologic and translational concepts","volume":"3","author":"Frangogiannis","year":"2015","journal-title":"Discoveries."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2482","DOI":"10.1093\/eurheartj\/ehz008","article-title":"Stage-dependent differential effects of interleukin-1 isoforms on experimental atherosclerosis","volume":"40","author":"Vromman","year":"2019","journal-title":"Eur Heart J."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1016\/S0735-1097(01)01591-1","article-title":"Neutralization of interleukin-1beta in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling","volume":"38","author":"Hwang","year":"2001","journal-title":"J Am Coll Cardiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1161\/01.ATV.16.8.1000","article-title":"Interleukin-1 beta in coronary arteries of patients with ischemic heart disease","volume":"16","author":"Galea","year":"1996","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1161\/01.STR.17.2.270","article-title":"Evaluation of a scoring system for extracranial carotid atherosclerosis extent with B-mode ultrasound","volume":"17","author":"Crouse","year":"1986","journal-title":"Stroke."},{"key":"B53","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/0741-5214(87)90312-0","article-title":"Multicenter validation study of real-time (B-mode) ultrasound, arteriography, and pathologic examination","volume":"6","author":"Ricotta","year":"1987","journal-title":"J Vasc Surg."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1002\/hep.24452","article-title":"Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis","volume":"54","author":"Hernaez","year":"2011","journal-title":"Hepatology."},{"key":"B55","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/1741-7015-12-47","article-title":"Is atherosclerosis an autoimmune disease?","volume":"12","author":"Matsuura","year":"2014","journal-title":"BMC Med."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.634962\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T02:15:44Z","timestamp":1621563344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.634962\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,21]]},"references-count":55,"alternative-id":["10.3389\/fmed.2021.634962"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.634962","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,21]]},"article-number":"634962"}}