title: Inflammatory responses associated with acute coronary syndrome up-regulate IRAK-M and induce endotoxin tolerance in circulating monocytes.
abstract: Acute coronary syndrome (ACS) groups different cardiac diseases whose development is associated with inflammation. Here we have analyzed the levels of inflammatory cytokines and of members of the TLR/IRAK pathway including IRAK-M in monocytes from ACS patients classified as either UA (unstable angina), STEMI (ST-elevation myocardial infarction) or NSTEMI (non-ST-elevation myocardial infarction). Circulating monocytes from all patients, but not from healthy individuals, showed high levels of pro-inflammatory cytokines, TNF-alpha and IL-6, as well as of IRAK-M and IL-10. TLR4 was also up-regulated, but IRAK-1, IRAK-4 and MyD88 levels were similar in patients and controls. Further, we investigated the consequences of cytokines/IRAK-M expression on the innate immune response to endotoxin. Ex vivo responses to LPS were markedly attenuated in patient monocytes compared to controls. Control monocytes cultured for 6 h in supplemented medium (10% serum from ACS patients) expressed IRAK-M, and LPS stimulation failed to induce TNF-alpha and IL-6 in these cultures. Pre-incubation of the serum with a blocking anti-TNF-alpha antibody reduced this endotoxin tolerance effect, suggesting that TNF-alpha controls this phenomenon, at least partially. We show for the first time that inflammatory responses associated with ACS induce an unresponsiveness state to endotoxin challenge in circulating monocytes, which correlates with expression of IRAK-M, TLR4 and IL-10. The magnitude of this response varies according to the clinical condition (UA, STEMI or NSTEMI), and is regulated by TNF-alpha.
authors.affiliation: Research Unit, La Paz' Hospital, Madrid, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: del Fresno
authors.forename: Llanos
authors.initials: L
authors.lastname: Soler-Rangel
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soares-Schanoski
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gómez-Piña
authors.forename: María Carmen
authors.initials: MC
authors.lastname: González-León
authors.forename: Lourdes
authors.initials: L
authors.lastname: Gómez-García
authors.forename: Elena
authors.initials: E
authors.lastname: Mendoza-Barberá
authors.forename: Alexandro
authors.initials: A
authors.lastname: Rodríguez-Rojas
authors.forename: Felipe
authors.initials: F
authors.lastname: García
authors.forename: Pablo
authors.initials: P
authors.lastname: Fuentes-Prior
authors.forename: Francisco
authors.initials: F
authors.lastname: Arnalich
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
mesh_terms: D000789:Angina, Unstable / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019138:Antibodies, Blocking / Q000494:pharmacology; D004361:Drug Tolerance / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009203:Myocardial Infarction / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases