title: The pro-inflammatory cytokine, interleukin-6, enhances the polarization of alternatively activated macrophages.
abstract: Macrophages are important innate immune cells that are associated with two distinct phenotypes: a pro-inflammatory (or classically activated) subset with prototypic macrophage functions such as inflammatory cytokine production and bactericidal activity, and an anti-inflammatory (or alternatively activated (AAM)) subset linked with wound healing and tissue repair processes. In this study, we examined the effect of interlukein-6 on human and murine macrophage polarization. The results indicate that despite being commonly associated with pro-inflammatory functions and being implicated in the pathogenesis/pathophysiology of numerous inflammatory diseases, interleukin-6 can enhance the polarization of AAMs, based on increased expression of hallmark markers: arginase-1, Ym1 and CD206; this effect required the AAM differentiating cytokines, IL-4 and IL-13. Co-treatment of AAMs with IL-6 resulted in spontaneous release of IL-10, suppressed LPS-induced nitric oxide production and inhibited cytokine production by activated CD4+ T cells - immunoregulatory features not observed in the 'parent' IL-4+IL-13-induced AAM. The effect of IL-6 required signal transducer and activator of transcription (STAT)-3, was partially dependent on up-regulation of the IL4Rα chain, and was independent of autocrine IL-10. In the presence of IFNγ, IL-6 promoted the production of IL-1β and TNFα suggesting that this cytokine can enhance the phenotype to which a macrophage has committed. This finding may explain the pleiotrophic nature of IL-6, where it is associated with the perpetuation and enhancement of disease in inflammatory situations, but is also necessary for resolution of inflammation and adequate wound healing to occur in others. Thus, the potential benefit of IL-6 in promoting an AAM, with its' anti-inflammatory and wound healing ability, may need to be considered in immunotherapies aimed at in vivo modulation or inhibition of IL-6.
authors.affiliation: Gastrointestinal Research Group, Inflammation Research Network, Department of Physiology and Pharmacology, The Calvin Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Maria Ruweka
authors.initials: MR
authors.lastname: Fernando
authors.affiliation: Gastrointestinal Research Group, Inflammation Research Network, Department of Physiology and Pharmacology, The Calvin Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Reyes
authors.affiliation: Gastrointestinal Research Group, Inflammation Research Network, Department of Physiology and Pharmacology, The Calvin Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Iannuzzi
authors.affiliation: Gastrointestinal Research Group, Inflammation Research Network, Department of Physiology and Pharmacology, The Calvin Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Leung
authors.affiliation: Gastrointestinal Research Group, Inflammation Research Network, Department of Physiology and Pharmacology, The Calvin Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Derek Mark
authors.initials: DM
authors.lastname: McKay
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D018925:Chemokines; D018793:Interleukin-13; D015847:Interleukin-4; D015850:Interleukin-6; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
references.citation: Sci Signal. 2010 Aug 17;3(135):ra62
references.pmid: 20716764
references.citation: Hum Immunol. 2005 Mar;66(3):222-30
references.pmid: 15784460
references.citation: Nat Immunol. 2000 Dec;1(6):510-4
references.pmid: 11101873
references.citation: Immunobiology. 2010 Sep-Oct;215(9-10):704-8
references.pmid: 20594611
references.citation: J Immunol. 2009 Nov 15;183(10):6469-77
references.pmid: 19841166
references.citation: J Immunol. 2010 Jun 15;184(12):7219-28
references.pmid: 20483735
references.citation: Arthritis Res Ther. 2006;8 Suppl 2:S5
references.pmid: 16899109
references.citation: J Clin Invest. 2006 Jul;116(7):2044-55
references.pmid: 16778988
references.citation: Nat Med. 2007 Feb;13(2):139-45
references.pmid: 17290272
references.citation: PLoS One. 2011;6(7):e21893
references.pmid: 21755007
references.citation: Immunity. 2010 May 28;32(5):593-604
references.pmid: 20510870
references.citation: Drugs Today (Barc). 2009 Mar;45(3):189-97
references.pmid: 19436841
references.citation: Eur J Immunol. 2010 Jul;40(7):1830-5
references.pmid: 20583029
references.citation: J Neuroinflammation. 2012 Feb 27;9:40
references.pmid: 22369693
references.citation: Blood. 2010 Jan 14;115(2):353-62
references.pmid: 19880493
references.citation: J Leukoc Biol. 2011 Nov;90(5):845-54
references.pmid: 21628332
references.citation: Eur J Immunol. 2001 Sep;31(9):2751-61
references.pmid: 11536174
references.citation: J Clin Invest. 1998 Jan 15;101(2):311-20
references.pmid: 9435302
references.citation: Nat Immunol. 2001 Oct;2(10):907-16
references.pmid: 11577346
references.citation: World J Gastroenterol. 2012 Nov 7;18(41):5848-61
references.pmid: 23139600
references.citation: Int J Biol Sci. 2012;8(9):1237-47
references.pmid: 23136552
references.citation: Am J Physiol Gastrointest Liver Physiol. 2011 Sep;301(3):G487-97
references.pmid: 21659618
references.citation: J Leukoc Biol. 2009 Nov;86(5):1105-9
references.pmid: 19605698
references.citation: J Leukoc Biol. 2002 Apr;71(4):597-602
references.pmid: 11927645
references.citation: Nat Rev Immunol. 2008 Dec;8(12):958-69
references.pmid: 19029990
references.citation: Nat Rev Immunol. 2003 Jan;3(1):23-35
references.pmid: 12511873
references.citation: Blood. 2010 Oct 28;116(17):3311-20
references.pmid: 20625006
references.citation: Trends Immunol. 2004 Dec;25(12):677-86
references.pmid: 15530839
references.citation: Nat Protoc. 2008;3(6):1101-8
references.pmid: 18546601
references.citation: Methods Mol Biol. 2009;531:29-43
references.pmid: 19347309
references.citation: Am J Respir Crit Care Med. 2006 Apr 1;173(7):781-92
references.pmid: 16415274
references.citation: Immunobiology. 2013 Nov;218(11):1336-44
references.pmid: 23870825
references.citation: Sci Transl Med. 2013 Jan 30;5(170):170ra15
references.pmid: 23363979
references.citation: BMC Musculoskelet Disord. 2012 Jun 20;13:106
references.pmid: 22716658
references.citation: PLoS One. 2012;7(6):e38441
references.pmid: 22715382
references.citation: J Immunol. 2005 Jul 1;175(1):342-9
references.pmid: 15972667
references.citation: Nat Immunol. 2010 Oct;11(10):889-96
references.pmid: 20856220
references.citation: J Leukoc Biol. 2004 Sep;76(3):509-13
references.pmid: 15218057