Anti-ribosomal phosphoprotein autoantibody triggers interleukin-10 overproduction via phosphatidylinositol 3-kinase-dependent signalling pathways in lipopolysaccharide-activated macrophages.
Anti-ribosomal phosphoprotein autoantibodies have been shown to be significantly associated with multiple manifestations of systemic lupus erythematosus (SLE). High levels of interleukin-10 (IL-10) have been demonstrated to contribute to lupus susceptibility and severity. In this study, we investigated the molecular mechanisms of anti-ribosomal phosphoprotein monoclonal antibody (anti-P mAb)-induced autoimmune responses. Anti-P mAb promoted IL-10 overproduction in a dose- and time-dependent manner in both lipopolysaccharide (LPS)-activated RAW 264.7 cells and primary human macrophages. Anti-P mAb enhanced phosphorylation of Akt (PKB; protein kinase B), extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase 1/2 (JNK1/2), while phosphorylation of p38 remained unaltered. Furthermore, anti-P mAb decreased glycogen synthase kinase 3 (GSK3) activity and reduced the phosphorylation of I kappaB alpha in LPS-activated macrophages. The Syk, phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), JNK and ERK signalling pathways involved in anti-P mAb-triggered IL-10 secretion were also confirmed using various pharmacological inhibitors. In addition, nuclear factor (NF)-kappaB had negative regulatory effects on anti-P mAb-triggered IL-10 secretion. Using reporter plasmids containing the nuclear factor binding sites of NF-kappaB, cAMP-enhanced activation protein 1 (AP-1), serum response element (SRE) or cyclic AMP response element (CRE), treatment of anti-P mAb led to activation of the corresponding factors that bind to the AP-1 site, SRE and CRE in the LPS-activated macrophages. Furthermore, by transfection with reporter plasmids bearing various lengths of the IL-10 promoter, the AP-1 binding site, SRE and CRE were shown to be required for anti-P mAb-induced effects. Collectively, our results provide a molecular model for anti-P mAb-induced IL-10 overproduction in LPS-activated macrophages, which may play a role in the pathogenesis of SLE.
Lee
Tai-Ping
TP
Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, China.
Leu
Shr-Jeng Jim
SJ
Huang
Jason C
JC
Song
Ying-Chyi
YC
Jhou
Ren-Shiang
RS
Tang
Shye-Jye
SJ
Sun
Kuang-Hui
KH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology; D012269:Ribosomal Proteins / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D016753:Interleukin-10; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D017452:Receptors, IgG; D012269:Ribosomal Proteins
J Exp Med. 2007 Aug 6;204(8):1875-89
17664287
Rheumatology (Oxford). 2002 Dec;41(12):1357-66
12468814
Immunity. 2006 May;24(5):563-74
16713974
J Neurochem. 2001 Sep;78(6):1219-32
11579131
Curr Opin Immunol. 2002 Dec;14(6):798-802
12413532
J Exp Med. 1994 Jan 1;179(1):305-10
8270873
J Autoimmun. 2005 Mar;24(2):135-43
15829406
Lupus. 2002;11(4):234-9
12043887
Arthritis Rheum. 1999 Dec;42(12):2728-9
10616026
Nat Immunol. 2005 Aug;6(8):777-84
16007092
Arthritis Rheum. 2005 Mar;52(3):847-55
15751081
Nature. 2000 Jul 6;406(6791):86-90
10894547
J Clin Immunol. 2007 Sep;27(5):461-6
17587156
Arthritis Res Ther. 2003;5(4):160-4
12823845
J Immunol. 2004 Apr 15;172(8):4851-7
15067063
J Immunol. 1998 Jan 15;160(2):920-8
9551930
Immunol Cell Biol. 2007 Apr-May;85(3):249-56
17228323
J Immunol. 2007 Jul 1;179(1):236-46
17579043
J Immunol. 1997 Aug 15;159(4):2033-41
9257871
Eur Cytokine Netw. 1993 Nov-Dec;4(6):421-7
8186374
J Exp Med. 1994 Feb 1;179(2):551-8
8294866
Biochem Biophys Res Commun. 1999 Sep 24;263(2):334-9
10491293
Arthritis Rheum. 2007 Mar;56(3):938-48
17328071
Arthritis Rheum. 2008 Jul;58(7):1892-9
18576314
Cell Signal. 2006 Sep;18(9):1492-500
16413748
Rheumatology (Oxford). 2001 Jul;40(7):750-6
11477279
Int Rev Cytol. 1991;124:103-36
2001915
J Rheumatol. 1996 Jul;23(7):1123-5
8823680
N Engl J Med. 1987 Jul 30;317(5):265-71
3496538
Ann Rheum Dis. 2003 Jan;62(1):37-42
12480667
J Biol Chem. 1994 Dec 23;269(51):32187-93
7798217
Nat Rev Immunol. 2002 Aug;2(8):580-92
12154377
Clin Exp Immunol. 1999 Jan;115(1):189-95
9933441
Blood. 1995 Mar 1;85(5):1175-80
7858249
Clin Exp Immunol. 2003 Mar;131(3):396-7
12605690
Arthritis Rheum. 1997 Aug;40(8):1429-35
9259422
Immunol Lett. 2003 Apr 3;86(2):123-9
12644313
J Immunol. 2002 Aug 15;169(4):2148-55
12165544
J Clin Invest. 1992 Apr;89(4):1236-41
1313450
Cell. 2006 Feb 24;124(4):783-801
16497588
Arthritis Rheum. 1996 Nov;39(11):1833-9
8912505
J Immunol. 1995 May 1;154(9):4341-50
7722292
Nat Immunol. 2005 Aug;6(8):751-2
16034428
Nat Rev Immunol. 2004 Jul;4(7):499-511
15229469
Clin Exp Rheumatol. 1998 May-Jun;16(3):283-8
9631750
Immunology. 1995 Jun;85(2):262-9
7642215
Autoimmun Rev. 2007 Jan;6(3):119-25
17289545
Lupus. 2006;15(9):584-9
17080913
J Biol Chem. 2004 Mar 19;279(12):10883-91
14699155
Arthritis Rheum. 2000 Aug;43(8):1790-800
10943869
Gene. 2007 Nov 15;403(1-2):151-8
17897792
Drugs. 2006;66(15):1933-48
17100405
J Immunol. 2003 Jul 15;171(2):821-8
12847250
Arthritis Rheum. 2004 Apr;50(4):1164-71
15077298