title: Secreted Thrombospondin-1 Regulates Macrophage Interleukin-1β Production and Activation through CD47.
abstract: Thrombospondin-1 regulates inflammation by engaging several cell surface receptors and by modulating activities of other secreted factors. We have uncovered a novel role of thrombospondin-1 in modulating production and activation of the proinflammatory cytokine IL-1β by human and murine macrophages. Physiological concentrations of thrombospondin-1 limit the induction by lipopolysaccharide of IL-1β mRNA and total protein production by human macrophages. This inhibition can be explained by the ability of thrombospondin-1 to disrupt the interaction between CD47 and CD14, thereby limiting activation of NFκB/AP-1 by lipopolysaccharide. Only the CD47-binding domain of thrombospondin-1 exhibits this activity. In contrast, CD47, CD36, and integrin-binding domains of thrombospondin-1 independently enhance the inflammasome-dependent maturation of IL-1β in human THP-1 monocyte-derived macrophages. Correspondingly, mouse bone marrow-derived macrophages that lack either thrombospondin-1 or CD47 exhibit diminished induction of mature IL-1β in response to lipopolysaccharide. Lack of CD47 also limits lipopolysaccharide induction of IL-1β, NLRP3, and caspase-1 mRNAs. These data demonstrate that thrombospondin-1 exerts CD47-dependent and -independent pro-and anti-inflammatory effects on the IL-1β pathway. Therefore, thrombospondin-1 and its receptor CD47 may be useful targets for limiting the pro-inflammatory effects of lipopolysaccharide and for treating endotoxemia.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.|Microbiology and Immunology Program of the Institute for Biomedical Sciences, Departments of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, 20037, USA.
authors.forename: Erica V
authors.initials: EV
authors.lastname: Stein
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Miller
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Ivins-O'Keefe
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
authors.forename: Sukhbir
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1500, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D051928:CD47 Antigen; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D019700:Thrombospondin 1; D051197:Toll-Like Receptor 4; D000255:Adenosine Triphosphate; D020170:Caspase 1
references.citation: Nat Immunol. 2012 Mar;13(3):246-54
references.pmid: 22267217
references.citation: Matrix Biol. 2012 Apr;31(3):152-4
references.pmid: 22265891
references.citation: Matrix Biol. 2012 Apr;31(3):162-9
references.pmid: 22266027
references.citation: Curr Opin Immunol. 2012 Apr;24(2):225-32
references.pmid: 22310103
references.citation: J Immunol. 2012 May 1;188(9):4249-55
references.pmid: 22461697
references.citation: Sci Rep. 2012;2:512
references.pmid: 22803005
references.citation: Cell. 2012 Aug 3;150(3):606-19
references.pmid: 22819539
references.citation: PLoS One. 2012;7(11):e48775
references.pmid: 23144964
references.citation: Autophagy. 2012 Nov;8(11):1628-42
references.pmid: 22874555
references.citation: Blood. 2013 Feb 21;121(8):1316-25
references.pmid: 23293079
references.citation: Sci Rep. 2013;3:1673
references.pmid: 23591719
references.citation: J Immunol. 2013 Jun 1;190(11):5722-30
references.pmid: 23630357
references.citation: J Immunol. 2000 Feb 15;164(4):2193-9
references.pmid: 10657674
references.citation: Science. 2000 Jun 16;288(5473):2051-4
references.pmid: 10856220
references.citation: Thromb Res. 2000 Jul 1;99(1):41-50
references.pmid: 10904102
references.citation: Br J Pharmacol. 2000 Nov;131(6):1143-53
references.pmid: 11082122
references.citation: J Immunol. 2001 Feb 15;166(4):2427-36
references.pmid: 11160302
references.citation: Surgery. 2008 Nov;144(5):752-61
references.pmid: 19081017
references.citation: J Biol Chem. 2009 Jan 9;284(2):1116-25
references.pmid: 19004835
references.citation: Nat Rev Microbiol. 2009 Feb;7(2):99-109
references.pmid: 19148178
references.citation: FASEB J. 2009 Oct;23(10):3368-76
references.pmid: 19528255
references.citation: Nat Immunol. 2013 Aug;14(8):812-20
references.pmid: 23812099
references.citation: Matrix Biol. 2013 Aug 8;32(6):316-24
references.pmid: 23499828
references.citation: Cell Mol Immunol. 2013 Nov;10(6):506-12
references.pmid: 23954950
references.citation: Mediators Inflamm. 2013;2013:824919
references.pmid: 24489448
references.citation: Mucosal Immunol. 2014 Mar;7(2):440-8
references.pmid: 24045574
references.citation: J Immunol. 2014 Mar 1;192(5):2029-33
references.pmid: 24489101
references.citation: Immunology. 2014 Sep;143(1):61-7
references.pmid: 24786312
references.citation: J Leukoc Biol. 2014 Nov;96(5):797-807
references.pmid: 25001859
references.citation: Cancer Res. 2014 Dec 1;74(23):6771-83
references.pmid: 25297630
references.citation: Mol Immunol. 2015 Feb;63(2):143-52
references.pmid: 24951397
references.citation: PLoS One. 2014;9(12):e115107
references.pmid: 25501558
references.citation: Science. 2015 Apr 3;348(6230):56-61
references.pmid: 25838373
references.citation: Cell Signal. 2001 Feb;13(2):85-94
references.pmid: 11257452
references.citation: Eur J Immunol. 2001 Nov;31(11):3153-64
references.pmid: 11745332
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Blood. 2002 May 15;99(10):3500-4
references.pmid: 11986200
references.citation: J Exp Med. 2003 Oct 20;198(8):1277-83
references.pmid: 14568985
references.citation: Circ Res. 2003 Nov 14;93(10):925-31
references.pmid: 14563713
references.citation: J Immunol. 2003 Dec 15;171(12):6329-33
references.pmid: 14662828
references.citation: Scand J Immunol. 2004 Jan;59(1):40-9
references.pmid: 14723620
references.citation: Int J Biochem Cell Biol. 2004 Jun;36(6):1126-34
references.pmid: 15094127
references.citation: J Biol Chem. 2004 Oct 1;279(40):41734-43
references.pmid: 15292271
references.citation: Am J Clin Pathol. 1986 Sep;86(3):317-23
references.pmid: 3751996
references.citation: FASEB J. 1992 Nov;6(14):3290-9
references.pmid: 1426766
references.citation: Mol Cell Biol. 1993 Oct;13(10):6231-40
references.pmid: 8413223
references.citation: Science. 1996 Nov 1;274(5288):795-8
references.pmid: 8864123
references.citation: J Biol Chem. 1999 May 7;274(19):13586-93
references.pmid: 10224129
references.citation: J Exp Med. 1999 Oct 18;190(8):1175-82
references.pmid: 10523615
references.citation: Blood. 2005 Dec 1;106(12):3860-6
references.pmid: 16118322
references.citation: Cell Microbiol. 2006 Dec;8(12):1899-909
references.pmid: 16848791
references.citation: EMBO J. 2006 Nov 29;25(23):5560-8
references.pmid: 17093498
references.citation: Cell Death Differ. 2007 Jan;14(1):10-22
references.pmid: 16977329
references.citation: J Immunol. 2007 May 1;178(9):5930-9
references.pmid: 17442977
references.citation: Crit Care Med. 2007 May;35(5):1244-50
references.pmid: 17414736
references.citation: Circ Res. 2007 May 11;100(9):1308-16
references.pmid: 17413041
references.citation: Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5262-70
references.pmid: 17875754
references.citation: J Immunol. 2008 May 15;180(10):6947-53
references.pmid: 18453616
references.citation: Cytokine. 2008 May;42(2):145-51
references.pmid: 18304834
references.citation: Cancer Res. 2008 Sep 1;68(17):7090-9
references.pmid: 18757424
references.citation: J Immunol. 2008 Oct 15;181(8):5204-8
references.pmid: 18832672
references.citation: Curr Drug Targets. 2008 Oct;9(10):842-50
references.pmid: 18855618
references.citation: PLoS One. 2015;10(5):e0128220
references.pmid: 26010544
references.citation: PLoS One. 2015;10(6):e0127178
references.pmid: 26057870
references.citation: Circ Res. 2015 Jul 3;117(2):129-41
references.pmid: 25940549
references.citation: Clin Cancer Res. 2015 Aug 15;21(16):3597-601
references.pmid: 26116271
references.citation: Crit Rev Biochem Mol Biol. 2015;50(3):212-30
references.pmid: 25708195
references.citation: PLoS One. 2015;10(9):e0137345
references.pmid: 26390038
references.citation: J Biol Chem. 2015 Oct 9;290(41):24858-74
references.pmid: 26311851
references.citation: Cell. 2010 Mar 19;140(6):821-32
references.pmid: 20303873
references.citation: J Immunol. 2010 Sep 1;185(5):2998-3006
references.pmid: 20675593
references.citation: J Biol Chem. 2010 Dec 10;285(50):38923-32
references.pmid: 20923780
references.citation: PLoS One. 2011;6(5):e19654
references.pmid: 21573017
references.citation: Mediators Inflamm. 2011;2011:296069
references.pmid: 21765615
references.citation: Cell. 2011 Nov 11;147(4):868-80
references.pmid: 22078883
references.citation: J Biol Chem. 2012 Feb 3;287(6):4211-21
references.pmid: 22167178