Peptidoglycan-induced IL-6 production in RAW 264.7 macrophages is mediated by cyclooxygenase-2, PGE2/PGE4 receptors, protein kinase A, IκB kinase, and NF-κB

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摘要

In this study, we investigated the signaling pathway involved in IL-6 production caused by peptidoglycan (PGN), a cell wall component of the Gram-positive bacterium, Staphylococcus aureus, in RAW 264.7 macrophages. PGN caused concentration- and time-dependent increases in IL-6, PGE2, and cAMP production. PGN-mediated IL-6 production was inhibited by a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), a PGE2 (EP2) antagonist (AH6809), a PGE4 (EP4) antagonist (AH23848), and a protein kinase A (PKA) inhibitor (KT5720), but not by a nonselective NO synthase inhibitor (NG-nitro-L-arginine methyl ester). Furthermore, PGE2, an EP2 agonist (butaprost), an EP2/PGE3 (EP3)/EP4 agonist (misoprostol), and misoprostol in the presence of AH6809 all induced IL-6 production, whereas an EP1/EP3 agonist (sulprostone) did not. PGN caused time-dependent activations of IκB kinase αβ (IKKdβ) and p65 phosphoryiation at Ser276, and these effects were inhibited by NS398 and KT5720. Both PGE2 and 8-bromo-cAMP also caused IKKdβ kinase αβ phosphorylation. PGN resulted in two waves of the formation of NF-κB-specific DNA-protein complexes. The first wave of NF-κB activation occurred at 10-60 min of treatment, whereas the later wave occurred at 2-12 h of treatment. The PGN-induced increase in κB luciferase activity was inhibited by NS398, AH6809, AH23848, KT5720, a protein kinase C inhibitor (Ro31-8220), and a p38 MAPK inhibitor (SB203580). These results suggest that PGN-induced IL-6 production involves COX-2-generated PGE2, activation of the EP2 and EP4 receptors, cAMP formation, and the activation of PKA, protein kinase C, p38 MAPK, IKKdβ, kinase αβ, p65 phosphorylation, and NF-κB. However, PGN-induced NO release is not involved in the signaling pathway of PGN-induced DL-6 production.
原文英語
頁(從 - 到)681-693
頁數13
期刊Journal of Immunology
177
發行號1
出版狀態已發佈 - 七月 1 2006

指紋

Prostaglandin E Receptors
Peptidoglycan
Cyclooxygenase 2
Cyclic AMP-Dependent Protein Kinases
Interleukin-6
Phosphotransferases
Macrophages
Dinoprostone
Misoprostol
p38 Mitogen-Activated Protein Kinases
Protein Kinase Inhibitors
Protein Kinase C
Phosphorylation
Cyclic AMP Receptors
eIF-2 Kinase
8-Bromo Cyclic Adenosine Monophosphate
Cyclooxygenase Inhibitors
Protein C Inhibitor
Cyclooxygenase 2 Inhibitors
NG-Nitroarginine Methyl Ester

ASJC Scopus subject areas

  • Immunology

引用此文

@article{8a230a83fd1f44d5aa539a7cda1bcea3,
title = "Peptidoglycan-induced IL-6 production in RAW 264.7 macrophages is mediated by cyclooxygenase-2, PGE2/PGE4 receptors, protein kinase A, IκB kinase, and NF-κB",
abstract = "In this study, we investigated the signaling pathway involved in IL-6 production caused by peptidoglycan (PGN), a cell wall component of the Gram-positive bacterium, Staphylococcus aureus, in RAW 264.7 macrophages. PGN caused concentration- and time-dependent increases in IL-6, PGE2, and cAMP production. PGN-mediated IL-6 production was inhibited by a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), a PGE2 (EP2) antagonist (AH6809), a PGE4 (EP4) antagonist (AH23848), and a protein kinase A (PKA) inhibitor (KT5720), but not by a nonselective NO synthase inhibitor (NG-nitro-L-arginine methyl ester). Furthermore, PGE2, an EP2 agonist (butaprost), an EP2/PGE3 (EP3)/EP4 agonist (misoprostol), and misoprostol in the presence of AH6809 all induced IL-6 production, whereas an EP1/EP3 agonist (sulprostone) did not. PGN caused time-dependent activations of IκB kinase αβ (IKKdβ) and p65 phosphoryiation at Ser276, and these effects were inhibited by NS398 and KT5720. Both PGE2 and 8-bromo-cAMP also caused IKKdβ kinase αβ phosphorylation. PGN resulted in two waves of the formation of NF-κB-specific DNA-protein complexes. The first wave of NF-κB activation occurred at 10-60 min of treatment, whereas the later wave occurred at 2-12 h of treatment. The PGN-induced increase in κB luciferase activity was inhibited by NS398, AH6809, AH23848, KT5720, a protein kinase C inhibitor (Ro31-8220), and a p38 MAPK inhibitor (SB203580). These results suggest that PGN-induced IL-6 production involves COX-2-generated PGE2, activation of the EP2 and EP4 receptors, cAMP formation, and the activation of PKA, protein kinase C, p38 MAPK, IKKdβ, kinase αβ, p65 phosphorylation, and NF-κB. However, PGN-induced NO release is not involved in the signaling pathway of PGN-induced DL-6 production.",
author = "Chen, {Bing Chang} and Liao, {Chiao Chun} and Hsu, {Ming Jen} and Liao, {Yi Ting} and Chia-Chin Lin and Sheu, {Joen Rong} and Chien-Huang Lin",
year = "2006",
month = "7",
day = "1",
language = "English",
volume = "177",
pages = "681--693",
journal = "Journal of Immunology",
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publisher = "American Association of Immunologists",
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T1 - Peptidoglycan-induced IL-6 production in RAW 264.7 macrophages is mediated by cyclooxygenase-2, PGE2/PGE4 receptors, protein kinase A, IκB kinase, and NF-κB

AU - Chen, Bing Chang

AU - Liao, Chiao Chun

AU - Hsu, Ming Jen

AU - Liao, Yi Ting

AU - Lin, Chia-Chin

AU - Sheu, Joen Rong

AU - Lin, Chien-Huang

PY - 2006/7/1

Y1 - 2006/7/1

N2 - In this study, we investigated the signaling pathway involved in IL-6 production caused by peptidoglycan (PGN), a cell wall component of the Gram-positive bacterium, Staphylococcus aureus, in RAW 264.7 macrophages. PGN caused concentration- and time-dependent increases in IL-6, PGE2, and cAMP production. PGN-mediated IL-6 production was inhibited by a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), a PGE2 (EP2) antagonist (AH6809), a PGE4 (EP4) antagonist (AH23848), and a protein kinase A (PKA) inhibitor (KT5720), but not by a nonselective NO synthase inhibitor (NG-nitro-L-arginine methyl ester). Furthermore, PGE2, an EP2 agonist (butaprost), an EP2/PGE3 (EP3)/EP4 agonist (misoprostol), and misoprostol in the presence of AH6809 all induced IL-6 production, whereas an EP1/EP3 agonist (sulprostone) did not. PGN caused time-dependent activations of IκB kinase αβ (IKKdβ) and p65 phosphoryiation at Ser276, and these effects were inhibited by NS398 and KT5720. Both PGE2 and 8-bromo-cAMP also caused IKKdβ kinase αβ phosphorylation. PGN resulted in two waves of the formation of NF-κB-specific DNA-protein complexes. The first wave of NF-κB activation occurred at 10-60 min of treatment, whereas the later wave occurred at 2-12 h of treatment. The PGN-induced increase in κB luciferase activity was inhibited by NS398, AH6809, AH23848, KT5720, a protein kinase C inhibitor (Ro31-8220), and a p38 MAPK inhibitor (SB203580). These results suggest that PGN-induced IL-6 production involves COX-2-generated PGE2, activation of the EP2 and EP4 receptors, cAMP formation, and the activation of PKA, protein kinase C, p38 MAPK, IKKdβ, kinase αβ, p65 phosphorylation, and NF-κB. However, PGN-induced NO release is not involved in the signaling pathway of PGN-induced DL-6 production.

AB - In this study, we investigated the signaling pathway involved in IL-6 production caused by peptidoglycan (PGN), a cell wall component of the Gram-positive bacterium, Staphylococcus aureus, in RAW 264.7 macrophages. PGN caused concentration- and time-dependent increases in IL-6, PGE2, and cAMP production. PGN-mediated IL-6 production was inhibited by a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), a PGE2 (EP2) antagonist (AH6809), a PGE4 (EP4) antagonist (AH23848), and a protein kinase A (PKA) inhibitor (KT5720), but not by a nonselective NO synthase inhibitor (NG-nitro-L-arginine methyl ester). Furthermore, PGE2, an EP2 agonist (butaprost), an EP2/PGE3 (EP3)/EP4 agonist (misoprostol), and misoprostol in the presence of AH6809 all induced IL-6 production, whereas an EP1/EP3 agonist (sulprostone) did not. PGN caused time-dependent activations of IκB kinase αβ (IKKdβ) and p65 phosphoryiation at Ser276, and these effects were inhibited by NS398 and KT5720. Both PGE2 and 8-bromo-cAMP also caused IKKdβ kinase αβ phosphorylation. PGN resulted in two waves of the formation of NF-κB-specific DNA-protein complexes. The first wave of NF-κB activation occurred at 10-60 min of treatment, whereas the later wave occurred at 2-12 h of treatment. The PGN-induced increase in κB luciferase activity was inhibited by NS398, AH6809, AH23848, KT5720, a protein kinase C inhibitor (Ro31-8220), and a p38 MAPK inhibitor (SB203580). These results suggest that PGN-induced IL-6 production involves COX-2-generated PGE2, activation of the EP2 and EP4 receptors, cAMP formation, and the activation of PKA, protein kinase C, p38 MAPK, IKKdβ, kinase αβ, p65 phosphorylation, and NF-κB. However, PGN-induced NO release is not involved in the signaling pathway of PGN-induced DL-6 production.

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