{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:57:15Z","timestamp":1791928635166,"version":"4.3.4"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,12]],"date-time":"2023-11-12T00:00:00Z","timestamp":1699747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Peripheral artery disease (PAD) involves atherosclerosis of the lower extremity arteries and is a major contributor to limb loss and death worldwide. Several studies have demonstrated that interleukins (ILs) play an important role in the development and progression of PAD; however, a comprehensive literature review has not been performed. Methods: A systematic review was conducted and reported according to PRISMA guidelines. MEDLINE was searched from inception to 5 December 2022, and all studies assessing the association between ILs and PAD were included. Results: We included 17 studies from a pool of 771 unique articles. Five pro-inflammatory ILs (IL-1\u03b2, IL-2, IL-5, IL-6, and IL-8) and one pro-atherogenic IL (IL-12) were positively correlated with PAD diagnosis and progression. In contrast, two anti-inflammatory ILs (IL-4 and IL-10) were protective against PAD diagnosis and adverse limb events. Specifically, IL-6 and IL-8 were the most strongly associated with PAD and can act as potential disease biomarkers to support the identification and treatment of PAD. Conclusions: Ongoing work to identify and validate diagnostic\/prognostic inflammatory biomarkers for PAD has the potential to assist clinicians in identifying high-risk patients for further evaluation and management which could reduce the risk of adverse cardiovascular and limb events.<\/jats:p>","DOI":"10.3390\/biom13111640","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T02:10:43Z","timestamp":1699841443000},"page":"1640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A Systematic Review of Interleukins as Diagnostic and Prognostic Biomarkers for Peripheral Artery Disease"],"prefix":"10.3390","volume":"13","author":[{"given":"Niousha","family":"Djahanpour","sequence":"first","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naiyara","family":"Ahsan","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamzah","family":"Khan","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Connelly","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"},{"name":"Division of Cardiology, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Leong-Poi","sequence":"additional","affiliation":[{"name":"Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"},{"name":"Division of Cardiology, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Qadura","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"},{"name":"Keenan Research Center for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael\u2019s Hospital, Unity Health Toronto, University of Toronto, Toronto, ON M5B 1W8, Canada"},{"name":"Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e026945","DOI":"10.1161\/JAHA.122.026945","article-title":"NLRP3 Inflammasome Activation in Peripheral Arterial Disease","volume":"12","author":"Zimmer","year":"2023","journal-title":"J. Am. Heart Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.cjca.2022.02.029","article-title":"Canadian Cardiovascular Society 2022 Guidelines for Peripheral Arterial Disease","volume":"38","author":"Abramson","year":"2022","journal-title":"Can. J. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1161\/01.ATV.0000168911.78624.b7","article-title":"Sensitivity and Specificity of the Ankle\u2013Brachial Index to Predict Future Cardiovascular Outcomes: A Systematic Review","volume":"25","author":"Doobay","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e022232","DOI":"10.1161\/JAHA.121.022232","article-title":"Association of Disease-Specific Health Status with Long-Term Survival in Peripheral Artery Disease","volume":"11","author":"Tran","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/j.jvs.2019.05.050","article-title":"Critical Analysis and Limitations of Resting Ankle-Brachial Index in the Diagnosis of Symptomatic Peripheral Arterial Disease Patients and the Role of Diabetes Mellitus and Chronic Kidney Disease","volume":"71","author":"AbuRahma","year":"2020","journal-title":"J. Vasc. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1161\/hc0902.104353","article-title":"Inflammation and Atherosclerosis","volume":"105","author":"Libby","year":"2002","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1126\/science.aaa8064","article-title":"Neutrophil Extracellular Traps License Macrophages for Cytokine Production in Atherosclerosis","volume":"349","author":"Warnatsch","year":"2015","journal-title":"Science"},{"key":"ref_8","unstructured":"(2023, November 08). EndNote Version 20.1 [Computer Software]. Available online: http:\/\/endnote.com."},{"key":"ref_9","unstructured":"(2023, November 08). Covidence Systematic Review Software, [Computer Software]. Available online: https:\/\/www.covidence.org."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1177\/0003319713501376","article-title":"Impaired Vascular Endothelial Growth Factor A and Inflammation in Patients with Peripheral Artery Disease","volume":"65","author":"Gardner","year":"2014","journal-title":"Angiology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1016\/j.jvs.2009.12.068","article-title":"Ferritin Levels, Inflammatory Biomarkers, and Mortality in Peripheral Arterial Disease: A Substudy of the Iron (Fe) and Atherosclerosis Study (FeAST) Trial","volume":"51","author":"DePalma","year":"2010","journal-title":"J. Vasc. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.4062\/biomolther.2010.18.2.135","article-title":"Interleukin-4, Oxidative Stress, Vascular Inflammation and Atherosclerosis","volume":"18","author":"Lee","year":"2010","journal-title":"Biomol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.avsg.2011.02.013","article-title":"Effects of Lower Extremity Revascularization on the Endothelial Functions Measured with Noninvasive Brachial Artery Flow-Mediated Dilatation","volume":"25","author":"Unal","year":"2011","journal-title":"Ann. Vasc. Surg."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1016\/j.amjcard.2011.01.007","article-title":"Relation of Interleukin-6 and Vascular Cellular Adhesion Molecule-1 Levels to Functional Decline in Patients with Lower Extremity Peripheral Arterial Disease","volume":"107","author":"McDermott","year":"2011","journal-title":"Am. J. Cardiol."},{"key":"ref_15","first-page":"w13623","article-title":"Impact of Exercise Trainting on Inflammation and Platelet Activation in Patients with Intermittent Claudication","volume":"142","author":"Schlager","year":"2012","journal-title":"Swiss. Med. Wkly."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.cyto.2012.04.038","article-title":"Patients with Unrecognized Peripheral Arterial Disease (PAD) Assessed by Ankle-Brachial Index (ABI) Present a Defined Profile of Proinflammatory Markers Compared to Healthy Subjects","volume":"59","author":"Signorelli","year":"2012","journal-title":"Cytokine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1093\/ajh\/hps073","article-title":"Associations of Candidate Biomarkers of Vascular Disease with the Ankle-Brachial Index and Peripheral Arterial Disease","volume":"26","author":"Ye","year":"2013","journal-title":"Am. J. Hypertens."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.avsg.2014.12.006","article-title":"Interleukins and Inflammatory Markers in In-Stent Restenosis after Femoral Percutaneous Transluminal Angioplasty","volume":"29","author":"Ribeiro","year":"2015","journal-title":"Ann. Vasc. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1177\/0003319716633339","article-title":"Plasma Levels of Inflammatory Biomarkers in Peripheral Arterial Disease: Results of a Cohort Study","volume":"67","author":"Signorelli","year":"2016","journal-title":"Angiology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.atherosclerosis.2017.06.029","article-title":"Circulating Malondialdehyde-Modified Low-Density Lipoprotein (MDA-LDL) as a Novel Predictor of Clinical Outcome after Endovascular Therapy in Patients with Peripheral Artery Disease (PAD)","volume":"263","author":"Takamura","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.avsg.2017.11.064","article-title":"The Role of Interleukins and Inflammatory Markers in the Early Restenosis of Covered Stents in the Femoropopliteal Arterial Segment","volume":"50","author":"Guimaraes","year":"2018","journal-title":"Ann. Vasc. Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10740","DOI":"10.1038\/s41598-019-47217-1","article-title":"A Pro-Inflammatory Biomarker-Profile Predicts Amputation-Free Survival in Patients with Severe Limb Ischemia","volume":"9","author":"Gremmels","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1177\/1708538120921005","article-title":"Six-Month Results of Stenting of the Femoropopliteal Artery and Predictive Value of Interleukin-6: Comparison with High-Sensitivity C-Reactive Protein","volume":"28","author":"Guo","year":"2020","journal-title":"Vascular"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"mfab030","DOI":"10.1093\/mtomcs\/mfab030","article-title":"Optimal Serum Ferritin Level Range: Iron Status Measure and Inflammatory Biomarker","volume":"13","author":"DePalma","year":"2021","journal-title":"Metallomics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"18388","DOI":"10.1038\/s41598-022-23260-3","article-title":"Discovery of Four Plasmatic Biomarkers Potentially Predicting Cardiovascular Outcome in Peripheral Artery Disease","volume":"12","author":"Kremers","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8422","DOI":"10.1038\/s41598-022-12548-z","article-title":"Klotho Expression in Peripheral Blood Circulating Cells Is Associated with Vascular and Systemic Inflammation in Atherosclerotic Vascular Disease","volume":"12","author":"Tagua","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1134\/S0006297916110134","article-title":"The Role of Cytokines in the Development of Atherosclerosis","volume":"81","author":"Fatkhullina","year":"2016","journal-title":"Biochem. Mosc."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gremmel, T., Perkmann, T., Kopp, C.W., Seidinger, D., Eichelberger, B., Koppensteiner, R., Steiner, S., and Panzer, S. (2015). Interleukin-6 and Asymmetric Dimethylarginine Are Associated with Platelet Activation after Percutaneous Angioplasty with Stent Implantation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0122586"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.3389\/fimmu.2018.02712","article-title":"Role of Platelets in Leukocyte Recruitment and Resolution of Inflammation","volume":"9","author":"Rossaint","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1161\/CIRCULATIONAHA.104.513085","article-title":"C-Reactive Protein, Interleukin-6, and Soluble Adhesion Molecules as Predictors of Progressive Peripheral Atherosclerosis in the General Population: Edinburgh Artery Study","volume":"112","author":"Tzoulaki","year":"2005","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1093\/cvr\/cvp241","article-title":"Interleukin 8 and Cardiovascular Disease","volume":"84","author":"Apostolakis","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1053\/ejvs.1999.0927","article-title":"Interleukin-8 (IL-8) May Contribute to the Activation of Neutrophilsin Patients with Peripheral Arterial Occlusive Disease (PAOD)","volume":"18","author":"Kirk","year":"1999","journal-title":"Eur. J. Vasc. Endovasc. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1016\/j.jacc.2017.09.028","article-title":"Interleukin-1 Beta as a Target for Atherosclerosis Therapy","volume":"70","author":"Libby","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1177\/1358863X19859072","article-title":"A Randomized, Placebo-Controlled Trial of Canakinumab in Patients with Peripheral Artery Disease","volume":"24","author":"Russell","year":"2019","journal-title":"Vasc. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1038\/sj.embor.7401099","article-title":"Interleukin 2: From Immunostimulation to Immunoregulation and Back Again","volume":"8","author":"Bachmann","year":"2007","journal-title":"EMBO Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.avsg.2008.06.005","article-title":"Inflammatory Profiling of Peripheral Arterial Disease","volume":"23","author":"Chaparala","year":"2009","journal-title":"Ann. Vasc. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e17","DOI":"10.1161\/01.RES.85.8.e17","article-title":"Protective Role of Interleukin-10 in Atherosclerosis","volume":"85","author":"Mallat","year":"1999","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1378\/chest.117.4.1162","article-title":"Anti-Inflammatory Cytokines","volume":"117","author":"Opal","year":"2000","journal-title":"Chest"},{"key":"ref_39","first-page":"331","article-title":"High MAPK P38 Activity and Low Level of IL-10 in Intermittent Claudication as Opposed to Stable Angina","volume":"29","author":"Abuabaid","year":"2010","journal-title":"Int. Angiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1177\/1358863X07083387","article-title":"An Overview of Cytokine Interactions in Atherosclerosis and Implications for Peripheral Arterial Disease","volume":"12","author":"Girn","year":"2007","journal-title":"Vasc. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1007\/s00380-015-0753-2","article-title":"Increased IL18 MRNA Levels in Peripheral Artery Disease and Its Association with Triglyceride and LDL Cholesterol Levels: A Pilot Study","volume":"31","author":"Deser","year":"2016","journal-title":"Heart Vessel."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1172\/JCI118650","article-title":"Cross-Regulatory Roles of Interleukin (IL)-12 and IL-10 in Atherosclerosis","volume":"97","author":"Uyemura","year":"1996","journal-title":"J. Clin. Investig."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/11\/1640\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:21:46Z","timestamp":1760131306000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/11\/1640"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,12]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["biom13111640"],"URL":"https:\/\/doi.org\/10.3390\/biom13111640","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,12]]}}}