title: Anti-ribosomal phosphoprotein autoantibody triggers interleukin-10 overproduction via phosphatidylinositol 3-kinase-dependent signalling pathways in lipopolysaccharide-activated macrophages.
abstract: 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.
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, China.
authors.forename: Tai-Ping
authors.initials: TP
authors.lastname: Lee
authors.forename: Shr-Jeng Jim
authors.initials: SJ
authors.lastname: Leu
authors.forename: Jason C
authors.initials: JC
authors.lastname: Huang
authors.forename: Ying-Chyi
authors.initials: YC
authors.lastname: Song
authors.forename: Ren-Shiang
authors.initials: RS
authors.lastname: Jhou
authors.forename: Shye-Jye
authors.initials: SJ
authors.lastname: Tang
authors.forename: Kuang-Hui
authors.initials: KH
authors.lastname: Sun
mesh_terms: 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
chemical_list: 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
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