title: S100A12 suppresses pro-inflammatory, but not pro-thrombotic functions of serum amyloid A.
abstract: S100A12 is elevated in the circulation in patients with chronic inflammatory diseases and recent studies indicate pleiotropic functions. Serum amyloid A induces monocyte cytokines and tissue factor. S100A12 did not stimulate IL-6, IL-8, IL-1β or TNF-α production by human peripheral blood mononuclear cells but low amounts consistently reduced cytokine mRNA and protein levels induced by serum amyloid A, by ∼49% and ∼46%, respectively. However, S100A12 did not affect serum amyloid A-induced monocyte tissue factor. In marked contrast, LPS-induced cytokines or tissue factor were not suppressed by S100A12. S100A12 did not alter cytokine mRNA stability or the cytokine secretory pathway. S100A12 and serum amyloid A did not appear to form complexes and although they may have common receptors, suppression was unlikely via receptor competition. Serum amyloid A induces cytokines via activation of NF-κB and the MAPK pathways. S100A12 reduced serum amyloid A-, but not LPS-induced ERK1/2 phosphorylation to baseline. It did not affect JNK or p38 phosphorylation or the NF-κB pathway. Reduction in ERK1/2 phosphorylation by S100A12 was unlikely due to changes in intracellular reactive oxygen species, Ca(2+) flux or to recruitment of phosphatases. We suggest that S100A12 may modulate sterile inflammation by blunting pro-inflammatory properties of lipid-poor serum amyloid A deposited in chronic lesions where both proteins are elevated as a consequence of macrophage activation.
authors: Inflammation and Infection Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
authors: Yuen Ming
authors: YM
authors: Chung
authors: Jesse
authors: J
authors: Goyette
authors: Nicodemus
authors: N
authors: Tedla
authors: Kenneth
authors: K
authors: Hsu
authors: Carolyn L
authors: CL
authors: Geczy
mesh_terms: D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism* / Q000494:pharmacology; D000067616:S100A12 Protein; D000685:Serum Amyloid A Protein / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D017382:Reactive Oxygen Species; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D000685:Serum Amyloid A Protein; D013925:Thromboplastin; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium
references: Am J Physiol Heart Circ Physiol. 2008 Dec;295(6):H2399-408
references: 18931033
references: Genomics. 2004 Jul;84(1):10-22
references: 15203200
references: Atherosclerosis. 2009 Feb;202(2):596-604
references: 18571179
references: Proc Natl Acad Sci U S A. 1980 Nov;77(11):6860-4
references: 6161374
references: Cell Mol Life Sci. 2009 Jan;66(1):9-26
references: 18726069
references: Immunol Rev. 2009 Mar;228(1):342-59
references: 19290938
references: J Immunol. 2008 Jul 1;181(1):22-6
references: 18566366
references: Scand J Gastroenterol. 2007 Nov;42(11):1321-31
references: 17852869
references: Thromb Haemost. 1991 Nov 1;66(5):552-8
references: 1803619
references: FEBS Lett. 2000 Apr 28;472(2-3):259-62
references: 10788622
references: Lancet. 2003 Apr 12;361(9365):1270-2
references: 12699958
references: Arthritis Rheum. 2012 Apr;64(4):1035-45
references: 22076945
references: PLoS Biol. 2009 Apr 28;7(4):e97
references: 19402754
references: J Biol Chem. 2005 Dec 16;280(50):41521-9
references: 16216873
references: Blood. 2003 Feb 15;101(4):1572-81
references: 12393391
references: Scand J Immunol. 2000 Jul;52(1):7-12
references: 10886778
references: Biochim Biophys Acta. 2009 Jun;1793(6):1008-22
references: 19110011
references: Biochem Biophys Res Commun. 2000 Apr 13;270(2):331-5
references: 10753626
references: Arch Dis Child. 1993 Feb;68(2):210-4
references: 8481043
references: J Biol Chem. 2010 Mar 12;285(11):8492-506
references: 20075072
references: Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):935-40
references: 22215599
references: Atherosclerosis. 2009 Dec;207(2):374-83
references: 19535079
references: Int J Biochem Cell Biol. 2010 May;42(5):651-61
references: 20025991
references: J Mol Biol. 2009 Aug 21;391(3):536-51
references: 19501594
references: Cell. 1999 Jun 25;97(7):889-901
references: 10399917
references: Atherosclerosis. 2003 Dec;171(2):211-8
references: 14644389
references: J Immunol. 2011 Jul 1;187(1):64-73
references: 21622869
references: Clin Biochem. 1994 Dec;27(6):469-73
references: 7535207
references: Biochem Biophys Res Commun. 2000 Feb 16;268(2):405-8
references: 10679217
references: Nat Med. 2010 Jun;16(6):713-7
references: 20473308
references: J Leukoc Biol. 2009 Sep;86(3):557-66
references: 19451397
references: J Lab Clin Med. 1998 Nov;132(5):414-20
references: 9823935
references: Biochemistry. 2001 Jan 9;40(1):241-8
references: 11141076
references: Mol Med. 2011;17(11-12):1357-64
references: 21953420
references: J Biol Chem. 2005 Jul 22;280(29):26825-37
references: 15923644
references: Am J Pathol. 2006 Oct;169(4):1223-37
references: 17003481
references: Circ Res. 2008 May 23;102(10):1239-46
references: 18403730
references: J Immunol. 2009 Jul 1;183(1):593-603
references: 19542470
references: Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1645-50
references: 17463335
references: N Engl J Med. 1994 Aug 18;331(7):417-24
references: 7880233
references: Physiol Rev. 2007 Jan;87(1):245-313
references: 17237347
references: Arthritis Rheum. 2004 Jun;50(6):1788-99
references: 15188355
references: Biochem Biophys Res Commun. 1999 Jan 8;254(1):143-6
references: 9920747
references: Biometals. 1998 Dec;11(4):383-97
references: 10191501
references: FEBS Lett. 2005 Jan 3;579(1):236-40
references: 15620719
references: Int Rev Cytol. 1994;152:49-108
references: 8206706
references: Eur J Biochem. 1996 Oct 1;241(1):265-71
references: 8898915
references: Cardiovasc Res. 2012 Apr 1;94(1):154-62
references: 22328092
references: J Immunol. 2007 Feb 1;178(3):1852-60
references: 17237436
references: Glia. 2012 Oct;60(10):1619-28
references: 22777957
references: Eur J Biochem. 1999 Oct;265(2):501-23
references: 10504381
references: Chem Phys Lipids. 2009 Nov;162(1-2):62-8
references: 19665458
references: Arthritis Rheum. 2004 Dec;50(12):3762-71
references: 15593206
references: J Histochem Cytochem. 1998 Dec;46(12):1377-84
references: 9815279
references: J Leukoc Biol. 2008 Feb;83(2):245-53
references: 17984291
references: Arthritis Res Ther. 2006;8(3):R69
references: 16613612
references: J Cell Biochem. 2010 Jun 1;110(3):645-59
references: 20512925
references: Clin Exp Allergy. 2011 Jun;41(6):878-89
references: 21418345
references: Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3186-90
references: 8159722
references: J Allergy Clin Immunol. 2007 Jan;119(1):106-14
references: 17208591
references: Amino Acids. 2011 Oct;41(4):821-42
references: 20213444
references: Science. 1998 May 22;280(5367):1262-5
references: 9596579
references: Free Radic Res. 1997 Nov;27(5):487-500
references: 9518065
references: Nat Med. 2007 Sep;13(9):1042-9
references: 17767165
references: Mediators Inflamm. 2003 Jun;12(3):173-8
references: 12857601
references: Curr Opin Immunol. 2000 Feb;12(1):20-6
references: 10679411
references: J Leukoc Biol. 2001 Jun;69(6):986-94
references: 11404386
references: FASEB J. 2000 Jan;14(1):6-16
references: 10627275
references: J Immunol. 2005 Feb 15;174(4):2318-26
references: 15699168
references: J Leukoc Biol. 2008 May;83(5):1174-80
references: 18252871
references: J Immunol. 2006 Aug 1;177(3):1636-45
references: 16849472
references: J Immunol. 2008 Sep 15;181(6):4332-9
references: 18768891
references: Cell. 2005 Mar 11;120(5):649-61
references: 15766528
references: J Biol Chem. 2008 May 9;283(19):13035-43
references: 18292089
references: Anal Chem. 1996 Mar 1;68(5):850-8
references: 8779443
references: Anal Biochem. 2003 Jul 1;318(1):132-41
references: 12782041
references: Blood. 2009 Jan 8;113(2):429-37
references: 18952897
references: J Exp Med. 1994 Jul 1;180(1):203-9
references: 7516407
references: J Biol Chem. 2005 Mar 4;280(9):8031-40
references: 15576377
references: J Rheumatol. 2008 May;35(5):752-6
references: 18322992
references: Curr Opin Hematol. 2000 Jan;7(1):64-9
references: 10608507
references: FEMS Immunol Med Microbiol. 2003 Aug 18;38(1):81-4
references: 12900059
references: J Biol Chem. 1996 Feb 23;271(8):4138-42
references: 8626753
references: Gut. 2003 Jun;52(6):847-53
references: 12740341
references: Arthritis Rheum. 2010 Nov;62(11):3353-64
references: 20662072
references: Biochemistry. 2007 May 8;46(18):5562-9
references: 17425332
references: Mol Pharmacol. 2006 Jul;70(1):241-8
references: 16569709
references: Amyloid. 2000 Jun;7(2):105-10
references: 10842712
references: Free Radic Biol Med. 2011 Oct 1;51(7):1390-8
references: 21784147
references: FEBS Lett. 2003 Jul 17;547(1-3):92-6
references: 12860392
references: J Cell Physiol. 2008 Jul;216(1):276-85
references: 18270969
references: Nat Cell Biol. 2008 Nov;10(11):1349-55
references: 18820689
references: N Engl J Med. 2000 Mar 23;342(12):836-43
references: 10733371
references: EMBO J. 1998 Dec 15;17(24):7337-50
references: 9857190
references: Clin Chim Acta. 2004 Jun;344(1-2):37-51
references: 15149869
references: J Rheumatol. 2000 Jan;27(1):58-63
references: 10648018
references: J Clin Invest. 2001 Jan;107(1):7-11
references: 11134171
references: J Leukoc Biol. 2008 Jun;83(6):1484-92
references: 18339893
references: J Biol Chem. 2005 Jan 28;280(4):2954-61
references: 15561721
references: Arterioscler Thromb Vasc Biol. 2011 Feb;31(2):337-44
references: 20966394
references: J Biol Chem. 1982 Sep 10;257(17):10518-22
references: 6809750