{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T11:31:26Z","timestamp":1782991886416,"version":"3.54.5"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2016,3,15]],"date-time":"2016-03-15T00:00:00Z","timestamp":1458000000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,3,15]],"date-time":"2016-03-15T00:00:00Z","timestamp":1458000000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Transl Psychiatry"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic opioid abusers are more susceptible to bacterial and viral infections, but the molecular mechanism underlying opioid-induced immunosuppression is unknown. MicroRNAs (miRNAs) are emerging as key players in the control of biological processes, and may participate in immune regulation. In this study, we investigated the molecular mechanisms in opioid-induced and miRNA-mediated immunosuppression, in the context of miRNA dysregulation in opioid abusers. Blood samples of heroin abusers were collected and analyzed using miRNA microarray analysis and quantitative PCR validation. The purified primary human monocytes were cultured <jats:italic>in vitro<\/jats:italic> to explore the underlying mechanism. We found that morphine and its derivative heroin significantly decreased the expression levels of miR-582-5p and miR-590-5p in monocytes. cAMP response element-binding protein 1 (CREB1) and CREB5 were detected as direct target genes of miR-582-5p and miR-590-5p, respectively, by using dual-luciferase assay and western bolt. Functional studies showed that knockdown of CREB1\/CREB5 increased tumor necrosis factor alpha (TNF-\u03b1) level and enhanced expression of phospho\u2013NF-\u03baB p65 and NF-\u03baB p65. Our results demonstrated that miR-582-5p and miR-590-5p play important roles in opioid-induced immunosuppression in monocytes by targeting CREB1\/CREB5\u2013NF-\u03baB signaling pathway.<\/jats:p>","DOI":"10.1038\/tp.2016.4","type":"journal-article","created":{"date-parts":[[2016,3,15]],"date-time":"2016-03-15T14:46:46Z","timestamp":1458053206000},"page":"e757-e757","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["MiR-582-5p\/miR-590-5p targeted CREB1\/CREB5\u2013NF-\u03baB signaling and caused opioid-induced immunosuppression in human monocytes"],"prefix":"10.1038","volume":"6","author":[{"given":"X","family":"Long","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,3,15]]},"reference":[{"key":"BFtp20164_CR1","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1016\/j.bbi.2013.08.006","volume":"34","author":"LA Campbell","year":"2013","unstructured":"Campbell LA, Avdoshina V, Rozzi S, Mocchetti I . CCL5 and cytokine expression in the rat brain: differential modulation by chronic morphine and morphine withdrawal. Brain Behav Immun 2013; 34: 130\u2013140.","journal-title":"Brain Behav Immun"},{"key":"BFtp20164_CR2","doi-asserted-by":"publisher","first-page":"426","DOI":"10.4049\/jimmunol.174.1.426","volume":"174","author":"J Wang","year":"2005","unstructured":"Wang J, Barke RA, Charboneau R, Roy S . Morphine impairs host innate immune response and increases susceptibility to Streptococcus pneumoniae lung infection. J Immunol 2005; 174: 426\u2013434.","journal-title":"J Immunol"},{"key":"BFtp20164_CR3","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1046\/j.1365-2249.2003.02103.x","volume":"132","author":"V Holan","year":"2003","unstructured":"Holan V, Zajicova A, Krulova M, Blahoutova V, Wilczek H . Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice. Clin Exp Immunol 2003; 132: 40\u201345.","journal-title":"Clin Exp Immunol"},{"key":"BFtp20164_CR4","doi-asserted-by":"publisher","first-page":"3916","DOI":"10.4049\/jimmunol.173.6.3916","volume":"173","author":"JK Olson","year":"2004","unstructured":"Olson JK, Miller SD . Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 2004; 173: 3916\u20133924.","journal-title":"J Immunol"},{"key":"BFtp20164_CR5","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1016\/j.neuropharm.2008.08.027","volume":"55","author":"S Desjardins","year":"2008","unstructured":"Desjardins S, Belkai E, Crete D, Cordonnier L, Scherrmann JM, Noble F et al. Effects of chronic morphine and morphine withdrawal on gene expression in rat peripheral blood mononuclear cells. Neuropharmacology 2008; 55: 1347\u20131354.","journal-title":"Neuropharmacology"},{"key":"BFtp20164_CR6","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.1111\/j.1471-4159.2009.06086.x","volume":"109","author":"SX Li","year":"2009","unstructured":"Li SX, Liu LJ, Jiang WG, Lu L . Morphine withdrawal produces circadian rhythm alterations of clock genes in mesolimbic brain areas and peripheral blood mononuclear cells in rats. J Neurochem 2009; 109: 1668\u20131679.","journal-title":"J Neurochem"},{"key":"BFtp20164_CR7","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1038\/nri2708","volume":"10","author":"RM O'Connell","year":"2010","unstructured":"O'Connell RM, Rao DS, Chaudhuri AA, Baltimore D . Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 2010; 10: 111\u2013122.","journal-title":"Nat Rev Immunol"},{"key":"BFtp20164_CR8","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/nrg2936","volume":"12","author":"E Huntzinger","year":"2011","unstructured":"Huntzinger E, Izaurralde E . Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 2011; 12: 99\u2013110.","journal-title":"Nat Rev Genet"},{"key":"BFtp20164_CR9","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.cell.2008.12.027","volume":"136","author":"C Xiao","year":"2009","unstructured":"Xiao C, Rajewsky K . MicroRNA control in the immune system: basic principles. Cell 2009; 136: 26\u201336.","journal-title":"Cell"},{"key":"BFtp20164_CR10","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.4049\/jimmunol.1400106","volume":"194","author":"S Qiu","year":"2015","unstructured":"Qiu S, Feng Y, LeSage G, Zhang Y, Stuart C, He L et al. Chronic morphine-induced microRNA-124 promotes microglial immunosuppression by modulating P65 and TRAF6. J Immunol 2015; 194: 1021\u20131030.","journal-title":"J Immunol"},{"key":"BFtp20164_CR11","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1111\/pme.12784","volume":"16","author":"MC Li","year":"2015","unstructured":"Li MC, Yu JH, Yu SS, Chi YY, Xiang YB . MicroRNA-873 inhibits morphine-induced macrophage apoptosis by elevating A20 expression. Pain Med 2015; 16: 1993\u20131999.","journal-title":"Pain Med"},{"key":"BFtp20164_CR12","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/bjc.2013.751","volume":"110","author":"J Lu","year":"2014","unstructured":"Lu J, Xu X, Liu X, Peng Y, Zhang B, Wang L et al. Predictive value of miR-9 as a potential biomarker for nasopharyngeal carcinoma metastasis. Br J Cancer 2014; 110: 392\u2013398.","journal-title":"Br J Cancer"},{"key":"BFtp20164_CR13","doi-asserted-by":"publisher","first-page":"pii: pyv030","DOI":"10.1093\/ijnp\/pyv030","volume":"18","author":"XF Lv","year":"2015","unstructured":"Lv XF, Sun LL, Cui CL, Han JS . NAc shell Arc\/Arg3.1 protein mediates reconsolidation of morphine CPP by increased GluR1 cell surface expression: activation of ERK-coupled CREB is required. Int J Neuropsychopharmacol 2015; 18: pii: pyv030.","journal-title":"Int J Neuropsychopharmacol"},{"key":"BFtp20164_CR14","doi-asserted-by":"publisher","first-page":"5597","DOI":"10.1074\/jbc.M207448200","volume":"278","author":"S Brenner","year":"2003","unstructured":"Brenner S, Prosch S, Schenke-Layland K, Riese U, Gausmann U, Platzer C . cAMP-induced Interleukin-10 promoter activation depends on CCAAT\/enhancer-binding protein expression and monocytic differentiation. J Biol Chem 2003; 278: 5597\u20135604.","journal-title":"J Biol Chem"},{"key":"BFtp20164_CR15","doi-asserted-by":"publisher","first-page":"6413","DOI":"10.4049\/jimmunol.1001829","volume":"185","author":"AY Wen","year":"2010","unstructured":"Wen AY, Sakamoto KM, Miller LS . The role of the transcription factor CREB in immune function. J Immunol 2010; 185: 6413\u20136419.","journal-title":"J Immunol"},{"key":"BFtp20164_CR16","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1007\/s00213-005-2239-x","volume":"179","author":"S Neri","year":"2005","unstructured":"Neri S, Bruno CM, Pulvirenti D, Malaguarnera M, Italiano C, Mauceri B et al. Randomized clinical trial to compare the effects of methadone and buprenorphine on the immune system in drug abusers. Psychopharmacology (Berl) 2005; 179: 700\u2013704.","journal-title":"Psychopharmacology (Berl)"},{"key":"BFtp20164_CR17","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1016\/j.bbi.2007.12.013","volume":"22","author":"P Sacerdote","year":"2008","unstructured":"Sacerdote P, Franchi S, Gerra G, Leccese V, Panerai AE, Somaini L . Buprenorphine and methadone maintenance treatment of heroin addicts preserves immune function. Brain Behav Immun 2008; 22: 606\u2013613.","journal-title":"Brain Behav Immun"},{"key":"BFtp20164_CR18","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1007\/s11481-008-9137-z","volume":"4","author":"BE Sawaya","year":"2009","unstructured":"Sawaya BE, Deshmane SL, Mukerjee R, Fan S, Khalili K . TNF alpha production in morphine-treated human neural cells is NF-kappaB-dependent. J Neuroimmune Pharmacol 2009; 4: 140\u2013149.","journal-title":"J Neuroimmune Pharmacol"},{"key":"BFtp20164_CR19","doi-asserted-by":"crossref","first-page":"920","DOI":"10.4049\/jimmunol.160.2.920","volume":"160","author":"AD Foey","year":"1998","unstructured":"Foey AD, Parry SL, Williams LM, Feldmann M, Foxwell BM, Brennan FM . Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-alpha: role of the p38 and p42\/44 mitogen-activated protein kinases. J Immunol 1998; 160: 920\u2013928.","journal-title":"J Immunol"},{"key":"BFtp20164_CR20","doi-asserted-by":"publisher","first-page":"E3101","DOI":"10.1073\/pnas.1209100109","volume":"109","author":"M Rossato","year":"2012","unstructured":"Rossato M, Curtale G, Tamassia N, Castellucci M, Mori L, Gasperini S et al. IL-10-induced microRNA-187 negatively regulates TNF-alpha, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci USA 2012; 109: E3101\u2013E3110.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFtp20164_CR21","first-page":"157","volume":"380","author":"L Gabrysova","year":"2014","unstructured":"Gabrysova L, Howes A, Saraiva M, O'Garra A . The regulation of IL-10 expression. Curr Top Microbiol Immunol 2014; 380: 157\u2013190.","journal-title":"Curr Top Microbiol Immunol"},{"key":"BFtp20164_CR22","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/ni.1863","volume":"11","author":"T Kawai","year":"2010","unstructured":"Kawai T, Akira S . The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11: 373\u2013384.","journal-title":"Nat Immunol"},{"key":"BFtp20164_CR23","doi-asserted-by":"publisher","first-page":"12481","DOI":"10.1073\/pnas.0605298103","volume":"103","author":"KD Taganov","year":"2006","unstructured":"Taganov KD, Boldin MP, Chang KJ, Baltimore D . NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 2006; 103: 12481\u201312486.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFtp20164_CR24","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1073\/pnas.0610731104","volume":"104","author":"RM O'Connell","year":"2007","unstructured":"O'Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D . MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA 2007; 104: 1604\u20131609.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFtp20164_CR25","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.biochi.2014.08.003","volume":"106","author":"PP He","year":"2014","unstructured":"He PP, Ouyang XP, Tang YY, Liao L, Wang ZB, Lv YC et al. MicroRNA-590 attenuates lipid accumulation and pro-inflammatory cytokine secretion by targeting lipoprotein lipase gene in human THP-1 macrophages. Biochimie 2014; 106: 81\u201390.","journal-title":"Biochimie"},{"key":"BFtp20164_CR26","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/S0192-0561(00)00023-0","volume":"22","author":"R Pacifici","year":"2000","unstructured":"Pacifici R, di Carlo S, Bacosi A, Pichini S, Zuccaro P . Pharmacokinetics and cytokine production in heroin and morphine-treated mice. Int J Immunopharmacol 2000; 22: 603\u2013614.","journal-title":"Int J Immunopharmacol"}],"container-title":["Translational Psychiatry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/tp20164.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/tp20164","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/tp20164.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T08:43:53Z","timestamp":1672821833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/tp20164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,15]]},"references-count":26,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2016,3]]}},"alternative-id":["BFtp20164"],"URL":"https:\/\/doi.org\/10.1038\/tp.2016.4","relation":{},"ISSN":["2158-3188"],"issn-type":[{"value":"2158-3188","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,15]]},"assertion":[{"value":"31 August 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 December 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2016","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 March 2016","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}