title: Tie2 signaling cooperates with TNF to promote the pro-inflammatory activation of human macrophages independently of macrophage functional phenotype.
abstract: Angiopoietin (Ang) -1 and -2 and their receptor Tie2 play critical roles in regulating angiogenic processes during development, homeostasis, tumorigenesis, inflammation and tissue repair. Tie2 signaling is best characterized in endothelial cells, but a subset of human and murine circulating monocytes/macrophages essential to solid tumor formation express Tie2 and display immunosuppressive properties consistent with M2 macrophage polarization. However, we have recently shown that Tie2 is strongly activated in pro-inflammatory macrophages present in rheumatoid arthritis patient synovial tissue. Here we examined the relationship between Tie2 expression and function during human macrophage polarization. Tie2 expression was observed under all polarization conditions, but was highest in IFN-γ and IL-10 -differentiated macrophages. While TNF enhanced expression of a common restricted set of genes involved in angiogenesis and inflammation in GM-CSF, IFN-γ and IL-10 -differentiated macrophages, expression of multiple chemokines and cytokines, including CXCL3, CXCL5, CXCL8, IL6, and IL12B was further augmented in the presence of Ang-1 and Ang-2, via Tie2 activation of JAK/STAT signaling. Conditioned medium from macrophages stimulated with Ang-1 or Ang-2 in combination with TNF, sustained monocyte recruitment. Our findings suggest a general role for Tie2 in cooperatively promoting the inflammatory activation of macrophages, independently of polarization conditions.
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands ; Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Samuel
authors.initials: S
authors.lastname: García
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands ; Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Krausz
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands ; Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Ambarus
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands ; Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Beatriz Malvar
authors.initials: BM
authors.lastname: Fernández
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands ; Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Hartkamp
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands ; Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Inge E
authors.initials: IE
authors.lastname: van Es
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hamann
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands ; Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Dominique L
authors.initials: DL
authors.lastname: Baeten
authors.affiliation: Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.affiliation: Department of Experimental Immunology, University of Amsterdam, Amsterdam, the Netherlands ; Department of Clinical Immunology and Rheumatology, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
mesh_terms: D042683:Angiopoietin-1 / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016207:Cytokines; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D042787:Receptor, TIE-2; D053612:Janus Kinases