title: Interleukin-6 protects human macrophages from cellular cholesterol accumulation and attenuates the proinflammatory response.
abstract: Cholesterol-laden monocyte-derived macrophages are phagocytic cells characteristic of early and advanced atherosclerotic lesions. Interleukin-6 (IL-6) is a macrophage secretory product that is abundantly expressed in atherosclerotic plaques but whose precise role in atherogenesis is unclear. The capacity of macrophages to clear apoptotic cells, through the efferocytosis mechanism, as well as to reduce cellular cholesterol accumulation contributes to prevent plaque progression and instability. By virtue of its capacity to promote cellular cholesterol efflux from phagocyte-macrophages, ABCA1 was reported to reduce atherosclerosis. We demonstrated that lipid loading in human macrophages was accompanied by a strong increase of IL-6 secretion. Interestingly, IL-6 markedly induced ABCA1 expression and enhanced ABCA1-mediated cholesterol efflux from human macrophages to apoAI. Stimulation of ABCA1-mediated cholesterol efflux by IL-6 was, however, abolished by selective inhibition of the Jak-2/Stat3 signaling pathway. In addition, we observed that the expression of molecules described to promote efferocytosis, i.e. c-mer proto-oncogene-tyrosine kinase, thrombospondin-1, and transglutaminase 2, was significantly induced in human macrophages upon treatment with IL-6. Consistent with these findings, IL-6 enhanced the capacity of human macrophages to phagocytose apoptotic cells; moreover, we observed that IL-6 stimulates the ABCA1-mediated efflux of cholesterol derived from the ingestion of free cholesterol-loaded apoptotic macrophages. Finally, the treatment of human macrophages with IL-6 led to the establishment of an anti-inflammatory cytokine profile, characterized by an increased secretion of IL-4 and IL-10 together with a decrease of that of IL-1β. Taken together, our results indicate that IL-6 favors the elimination of excess cholesterol in human macrophages and phagocytes by stimulation of ABCA1-mediated cellular free cholesterol efflux and attenuates the macrophage proinflammatory phenotype. Thus, high amounts of IL-6 secreted by lipid laden human macrophages may constitute a protective response from macrophages to prevent accumulation of cytotoxic-free cholesterol. Such a cellular recycling of free cholesterol may contribute to reduce both foam cell formation and the accumulation of apoptotic bodies as well as intraplaque inflammation in atherosclerotic lesions.
authors.affiliation: INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Frisdal
authors.affiliation: INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lesnik
authors.affiliation: INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Olivier
authors.affiliation: INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Robillard
authors.affiliation: INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Huby
authors.affiliation: INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France.
authors.forename: Maryse
authors.initials: M
authors.lastname: Guerin
authors.affiliation: INSERM, UMR_S939, Dyslipidemia, Inflammation, and Atherosclerosis in Metabolic Diseases, and the ICAN Institute of CardioMetabolism and Nutrition F-75013 and the Université Pierre et Marie Curie Paris 06, UMR_S939, F-75005, Paris, France. Electronic address: wilfried.le_goff@upmc.fr.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism*; D019169:Jurkat Cells; D008074:Lipoproteins / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D010587:Phagocytosis; D010641:Phenotype; D000090063:Proto-Oncogene Mas; D034622:RNA Interference
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines; D015850:Interleukin-6; D008074:Lipoproteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D002784:Cholesterol