TY - JOUR
T1 - Antibodies to proteinase 3 prime human monocytic cells via protease-activated receptor-2 and NF-κB for Toll-like receptor- and NOD-dependent activation
AU - Uehara, Akiko
AU - Iwashiro, Atsushi
AU - Sato, Tadasu
AU - Yokota, Sou
AU - Takada, Haruhiko
N1 - Funding Information:
We thank Dr. Y. Hirabayashi (Tohoku University) for discussions. We also thank D. Mrozek (Medical English Service, Kyoto, Japan) for reviewing the paper. This study was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (16390551 and 18390484 to H.T.), from the Ministry of Education, Sports, Science and Culture, Japan (18689901 to A.U.), by Naito Memorial Foundation (to A.U.) and by the Exploratory Research Program for Young Scientists from the President of Tohoku University (to A.U.).
PY - 2007/7
Y1 - 2007/7
N2 - Anti-neutrophil cytoplasmic Abs against proteinase 3 (PR3) have been detected in relation to a wide range of inflammatory conditions, and the interaction of anti-PR3 Abs with leukocytes provokes cell activation, although how is not clear. Flow cytometric analysis revealed an increase in cell-surface CD14, Toll-like receptor (TLR)2, TLR4 and intracellular TLR3, TLR7, TLR8, TLR9, NOD1 and NOD2 expression during anti-PR3 priming in human monocytic THP-1 cells. Anti-RP3 Abs markedly promoted the release of IL-8 induced by chemically synthesized TLR and NOD ligands mimicking bacterial components: TLR2-agonistic lipopeptide (FSL-1), TLR3-agonistic poly I:C, TLR4-agonistic lipid A (LA-15-PP), TLR7/8-agonistic single stranded RNA (ssPolyU), TLR9-agonistic bacterial CpG DNA, NOD1-agonistic FK156/565 and NOD2-agonistic muramyldipeptide (MDP) in THP-1 cells and human peripheral blood mononuclear cells, although sole incubation with anti-PR3 Abs induced only a low level of IL-8. The priming response was evident after 2 h of preincubation with anti-PR3 Abs and peaked after 6 h. Priming was also observed for the production of TNF-α and monocyte chemoattractant protein-1. An RNA interference assay revealed that anti-PR3 Abs activated THP-1 cells in a PR3- and protease-activated receptor-2-dependent manner. Furthermore, the anti-PR3 Ab-mediated cell activation was significantly abolished by RNA interference targeted at PR3 mRNA and by inhibition of phospholipase C and NF-κB. These results suggest that anti-PR3 Abs prime human monocytic cells to produce cytokines upon stimulation with various bacterial components by up-regulating the TLR and NOD signaling pathway, and that these mechanisms may actively participate in the inflammatory process.
AB - Anti-neutrophil cytoplasmic Abs against proteinase 3 (PR3) have been detected in relation to a wide range of inflammatory conditions, and the interaction of anti-PR3 Abs with leukocytes provokes cell activation, although how is not clear. Flow cytometric analysis revealed an increase in cell-surface CD14, Toll-like receptor (TLR)2, TLR4 and intracellular TLR3, TLR7, TLR8, TLR9, NOD1 and NOD2 expression during anti-PR3 priming in human monocytic THP-1 cells. Anti-RP3 Abs markedly promoted the release of IL-8 induced by chemically synthesized TLR and NOD ligands mimicking bacterial components: TLR2-agonistic lipopeptide (FSL-1), TLR3-agonistic poly I:C, TLR4-agonistic lipid A (LA-15-PP), TLR7/8-agonistic single stranded RNA (ssPolyU), TLR9-agonistic bacterial CpG DNA, NOD1-agonistic FK156/565 and NOD2-agonistic muramyldipeptide (MDP) in THP-1 cells and human peripheral blood mononuclear cells, although sole incubation with anti-PR3 Abs induced only a low level of IL-8. The priming response was evident after 2 h of preincubation with anti-PR3 Abs and peaked after 6 h. Priming was also observed for the production of TNF-α and monocyte chemoattractant protein-1. An RNA interference assay revealed that anti-PR3 Abs activated THP-1 cells in a PR3- and protease-activated receptor-2-dependent manner. Furthermore, the anti-PR3 Ab-mediated cell activation was significantly abolished by RNA interference targeted at PR3 mRNA and by inhibition of phospholipase C and NF-κB. These results suggest that anti-PR3 Abs prime human monocytic cells to produce cytokines upon stimulation with various bacterial components by up-regulating the TLR and NOD signaling pathway, and that these mechanisms may actively participate in the inflammatory process.
KW - Human monocytic cells
KW - NODs
KW - Protease-activated receptor-2
KW - Proteinase 3
KW - Toll-like receptors
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U2 - 10.1016/j.molimm.2007.03.010
DO - 10.1016/j.molimm.2007.03.010
M3 - Article
C2 - 17452051
AN - SCOPUS:34248584522
VL - 44
SP - 3552
EP - 3562
JO - Immunochemistry
JF - Immunochemistry
SN - 0161-5890
IS - 14
ER -