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Anti‐ribosomal phosphoprotein autoantibody triggers interleukin‐10 overproduction via phosphatidylinositol 3‐kinase‐dependent signalling pathways in lipopolysaccharide‐activated macrophages
Author(s) -
Lee TaiPing,
Leu ShrJeng Jim,
Huang Jason C.,
Song YingChyi,
Jhou RenShiang,
Tang ShyeJye,
Sun KuangHui
Publication year - 2009
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2008.02925.x
Subject(s) - microbiology and biotechnology , kinase , protein kinase a , ribosomal s6 kinase , protein kinase b , biology , mitogen activated protein kinase kinase , phosphorylation , chemistry , p70 s6 kinase 1
Summary 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 IκBα 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)‐κB had negative regulatory effects on anti‐P mAb‐triggered IL‐10 secretion. Using reporter plasmids containing the nuclear factor binding sites of NF‐κB, 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.