title: Thrombospondin 1 activates the macrophage Toll-like receptor 4 pathway.
abstract: Previously, we demonstrated that macrophages from thrombospondin 1 (TSP1)-deficient mice have a reduced inflammatory phenotype, suggesting that TSP1 plays a role in macrophage activation. In this study, we determined how TSP1 regulates macrophage function. We found that recombinant or purified platelet human TSP1 treatment stimulated tumor-necrosis factor (TNF)-α expression in bone marrow-derived macrophages in a time- and dose-dependent manner. Toll-like receptor 4 (TLR4) expression (at the mRNA and protein levels) and nuclear factor-kappaB (NF-κB) activity were also stimulated by TSP1 treatment. The TSP1-mediated increase in TNF-α production was abolished in TLR4-deficient macrophages, suggesting that TSP1 activates macrophages through a TLR4-dependent pathway. TSP1 also stimulated TLR4 activation in macrophages in vivo. Furthermore, TSP1-mediated macrophage activation was attenuated by using a peptide or an antibody to block the association between TSP1 and CD36. Taken together, these data suggest that the stimulation of the macrophage TLR4 pathway by TSP1 is partially mediated by the interaction of TSP1 with its receptor, CD36.
authors: 1] Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA [2] Current address: College of Medicine, Henan University, Kaifeng 475004, China.
authors: Yanzhang
authors: Y
authors: Li
authors: Xinyu
authors: X
authors: Qi
authors: Xiaopeng
authors: X
authors: Tong
authors: Shuxia
authors: S
authors: Wang
mesh_terms: D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens / Q000378:metabolism; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018955:CD36 Antigens; D016328:NF-kappa B; D019700:Thrombospondin 1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha
references: Nat Immunol. 2010 Feb;11(2):155-61
references: 20037584
references: J Immunol. 2006 Jul 1;177(1):322-32
references: 16785528
references: J Clin Invest. 2001 Apr;107(8):929-34
references: 11306593
references: Invest Ophthalmol Vis Sci. 2006 Oct;47(10):4356-64
references: 17003426
references: Kidney Int. 1995 Dec;48(6):1846-56
references: 8587244
references: J Biol Chem. 1978 Dec 10;253(23):8609-16
references: 101549
references: Cardiovasc Res. 2010 Dec 1;88(3):471-81
references: 20610415
references: J Lab Clin Med. 1998 Dec;132(6):519-29
references: 9851743
references: J Biol Chem. 1999 Mar 26;274(13):8554-60
references: 10085089
references: Nat Med. 2000 Jan;6(1):41-8
references: 10613822
references: J Cell Biol. 1987 Oct;105(4):1603-11
references: 2444599
references: Proc Natl Acad Sci U S A. 1971 Jan;68(1):240-3
references: 5276296
references: Circ Res. 2010 Nov 26;107(11):1313-25
references: 20884877
references: Diabetes. 2008 Feb;57(2):432-9
references: 18057090
references: J Cell Biol. 1988 Dec;107(6 Pt 1):2351-61
references: 2848850
references: J Cell Biol. 1993 Aug;122(4):923-32
references: 8349738
references: J Biol Chem. 2000 Nov 17;275(46):36358-68
references: 10964924
references: Environ Health. 2012 Mar 28;11:17
references: 22452745
references: J Cell Biochem. 2004 Mar 1;91(4):766-76
references: 14991768
references: Gastroenterology. 2006 Jan;130(1):34-43
references: 16401466
references: J Biol Chem. 2009 Sep 25;284(39):26695-707
references: 19640849
references: PLoS One. 2011;6(10):e26656
references: 22039525
references: Cell. 1998 Jun 26;93(7):1159-70
references: 9657149
references: Cell Mol Life Sci. 2002 Nov;59(11):1960-71
references: 12530526
references: Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770-4
references: 8421714
references: J Biol Chem. 2007 Nov 30;282(48):35279-92
references: 17916553
references: J Biol Chem. 1997 Mar 7;272(10):6784-91
references: 9045712
references: J Cell Physiol. 1990 Oct;145(1):16-23
references: 2211838
references: J Biol Chem. 1996 Jan 5;271(1):21-4
references: 8550562
references: J Cell Biol. 1987 Nov;105(5):2409-15
references: 3680388
references: J Biol Chem. 1992 Sep 5;267(25):18244-50
references: 1381367
references: J Biol Chem. 1995 Feb 17;270(7):2981-6
references: 7531696
references: J Biol Chem. 2004 Sep 3;279(36):38032-9
references: 15208302
references: J Clin Invest. 1998 Mar 1;101(5):982-92
references: 9486968
references: J Clin Invest. 2001 Sep;108(6):785-91
references: 11560944
references: Korean Circ J. 2012 Feb;42(2):100-6
references: 22396697
references: J Neuroimmunol. 2007 Jul;187(1-2):166-74
references: 17572512
references: Mol Biol Cell. 2000 Sep;11(9):2885-900
references: 10982388
references: Endocrinology. 2005 Oct;146(10):4545-54
references: 16020476