Cytosolic phospholipase A2 induction and prostaglandin E 2 release by interleukin-1β via the myeloid differentiation factor 88-dependent pathway and cooperation of p300, Akt, and NF-κB activity in human rheumatoid arthritis synovial fibroblasts

Pei Ling Chi, Shue Fen Luo, Hsi Lung Hsieh, I-Ta Lee, Li Der Hsiao, Yuh Lien Chen, Chuen Mao Yang

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Objective Cytosolic phospholipase A2 (cPLA2) is a rate-limiting enzyme that plays a critical role in the biosynthesis of eicosanoids. The aim of this study was to investigate the mechanisms underlying interleukin-1β (IL-1β)-induced cPLA2 expression in human rheumatoid arthritis synovial fibroblasts (RASFs). Methods Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. In a mouse model of IL-1β-mediated inflammatory arthritis, neutrophil infiltration, bone erosion, and cPLA2 expression in ankle synovium were analyzed by immunohistochemistry. IL-1β-induced cPLA2 expression was determined by Western blotting, real-time polymerase chain reaction, and gene promoter assay using pharmacologic inhibitors and transfection with short hairpin RNAs or small interfering RNAs. The recruitment of NF-κB and p300 to the cPLA2 promoter was determined by chromatin immunoprecipitation assay. Prostaglandin E2 (PGE 2) biosynthesis was evaluated by enzyme-linked immunosorbent assay. Results IL-1β-induced cPLA2 expression and PGE2 release were mediated through a myeloid differentiation factor 88 (MyD88)/c-Src-dependent matrix metalloproteinase (MMP)/heparin-binding epidermal growth factor (HB-EGF) cascade linking to transactivation of the EGF receptor (EGFR)/phosphatidylinositol 3-kinase (PI 3-kinase)/Akt, p300, and NF-κB p65 pathways. IL-1β also stimulated Akt phosphorylation and nuclear translocation. Activation of Akt eventually led to the acetylation of histone residues by phosphorylation and recruitment of p300 and enhanced its histone acetyltransferase activity on the NF-κB elements of the cPLA2 promoter. IL-1β-induced NF-κB transcriptional activity was mediated through a PI 3-kinase/Akt-dependent cascade. Up-regulation of cPLA2 by IL-1β increased PGE2 biosynthesis in RASFs. Conclusion IL-1β-induced cPLA2 expression is mediated through activation of the MyD88/c-Src, MMP/HB-EGF, EGFR/PI 3-kinase/Akt, p300, and NF-κB pathways. These results provide insights into the mechanisms underlying IL-1β-enhanced joint inflammatory responses in RA and may inspire new targeted therapeutic approaches.

Original languageEnglish
Pages (from-to)2905-2917
Number of pages13
JournalArthritis and Rheumatism
Volume63
Issue number10
DOIs
Publication statusPublished - Oct 1 2011
Externally publishedYes

Fingerprint

Myeloid Differentiation Factor 88
Cytosolic Phospholipases A2
Prostaglandins E
Interleukin-1
Human Activities
Rheumatoid Arthritis
Fibroblasts
Phosphatidylinositol 3-Kinase
Dinoprostone
Matrix Metalloproteinases
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Small Interfering RNA
Heparin
Replacement Arthroplasties
Phosphorylation
Histone Acetyltransferases
Eicosanoids
Neutrophil Infiltration
Synovial Membrane

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

Cite this

Cytosolic phospholipase A2 induction and prostaglandin E 2 release by interleukin-1β via the myeloid differentiation factor 88-dependent pathway and cooperation of p300, Akt, and NF-κB activity in human rheumatoid arthritis synovial fibroblasts. / Chi, Pei Ling; Luo, Shue Fen; Hsieh, Hsi Lung; Lee, I-Ta; Hsiao, Li Der; Chen, Yuh Lien; Yang, Chuen Mao.

In: Arthritis and Rheumatism, Vol. 63, No. 10, 01.10.2011, p. 2905-2917.

Research output: Contribution to journalArticle

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title = "Cytosolic phospholipase A2 induction and prostaglandin E 2 release by interleukin-1β via the myeloid differentiation factor 88-dependent pathway and cooperation of p300, Akt, and NF-κB activity in human rheumatoid arthritis synovial fibroblasts",
abstract = "Objective Cytosolic phospholipase A2 (cPLA2) is a rate-limiting enzyme that plays a critical role in the biosynthesis of eicosanoids. The aim of this study was to investigate the mechanisms underlying interleukin-1β (IL-1β)-induced cPLA2 expression in human rheumatoid arthritis synovial fibroblasts (RASFs). Methods Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. In a mouse model of IL-1β-mediated inflammatory arthritis, neutrophil infiltration, bone erosion, and cPLA2 expression in ankle synovium were analyzed by immunohistochemistry. IL-1β-induced cPLA2 expression was determined by Western blotting, real-time polymerase chain reaction, and gene promoter assay using pharmacologic inhibitors and transfection with short hairpin RNAs or small interfering RNAs. The recruitment of NF-κB and p300 to the cPLA2 promoter was determined by chromatin immunoprecipitation assay. Prostaglandin E2 (PGE 2) biosynthesis was evaluated by enzyme-linked immunosorbent assay. Results IL-1β-induced cPLA2 expression and PGE2 release were mediated through a myeloid differentiation factor 88 (MyD88)/c-Src-dependent matrix metalloproteinase (MMP)/heparin-binding epidermal growth factor (HB-EGF) cascade linking to transactivation of the EGF receptor (EGFR)/phosphatidylinositol 3-kinase (PI 3-kinase)/Akt, p300, and NF-κB p65 pathways. IL-1β also stimulated Akt phosphorylation and nuclear translocation. Activation of Akt eventually led to the acetylation of histone residues by phosphorylation and recruitment of p300 and enhanced its histone acetyltransferase activity on the NF-κB elements of the cPLA2 promoter. IL-1β-induced NF-κB transcriptional activity was mediated through a PI 3-kinase/Akt-dependent cascade. Up-regulation of cPLA2 by IL-1β increased PGE2 biosynthesis in RASFs. Conclusion IL-1β-induced cPLA2 expression is mediated through activation of the MyD88/c-Src, MMP/HB-EGF, EGFR/PI 3-kinase/Akt, p300, and NF-κB pathways. These results provide insights into the mechanisms underlying IL-1β-enhanced joint inflammatory responses in RA and may inspire new targeted therapeutic approaches.",
author = "Chi, {Pei Ling} and Luo, {Shue Fen} and Hsieh, {Hsi Lung} and I-Ta Lee and Hsiao, {Li Der} and Chen, {Yuh Lien} and Yang, {Chuen Mao}",
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T1 - Cytosolic phospholipase A2 induction and prostaglandin E 2 release by interleukin-1β via the myeloid differentiation factor 88-dependent pathway and cooperation of p300, Akt, and NF-κB activity in human rheumatoid arthritis synovial fibroblasts

AU - Chi, Pei Ling

AU - Luo, Shue Fen

AU - Hsieh, Hsi Lung

AU - Lee, I-Ta

AU - Hsiao, Li Der

AU - Chen, Yuh Lien

AU - Yang, Chuen Mao

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Objective Cytosolic phospholipase A2 (cPLA2) is a rate-limiting enzyme that plays a critical role in the biosynthesis of eicosanoids. The aim of this study was to investigate the mechanisms underlying interleukin-1β (IL-1β)-induced cPLA2 expression in human rheumatoid arthritis synovial fibroblasts (RASFs). Methods Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. In a mouse model of IL-1β-mediated inflammatory arthritis, neutrophil infiltration, bone erosion, and cPLA2 expression in ankle synovium were analyzed by immunohistochemistry. IL-1β-induced cPLA2 expression was determined by Western blotting, real-time polymerase chain reaction, and gene promoter assay using pharmacologic inhibitors and transfection with short hairpin RNAs or small interfering RNAs. The recruitment of NF-κB and p300 to the cPLA2 promoter was determined by chromatin immunoprecipitation assay. Prostaglandin E2 (PGE 2) biosynthesis was evaluated by enzyme-linked immunosorbent assay. Results IL-1β-induced cPLA2 expression and PGE2 release were mediated through a myeloid differentiation factor 88 (MyD88)/c-Src-dependent matrix metalloproteinase (MMP)/heparin-binding epidermal growth factor (HB-EGF) cascade linking to transactivation of the EGF receptor (EGFR)/phosphatidylinositol 3-kinase (PI 3-kinase)/Akt, p300, and NF-κB p65 pathways. IL-1β also stimulated Akt phosphorylation and nuclear translocation. Activation of Akt eventually led to the acetylation of histone residues by phosphorylation and recruitment of p300 and enhanced its histone acetyltransferase activity on the NF-κB elements of the cPLA2 promoter. IL-1β-induced NF-κB transcriptional activity was mediated through a PI 3-kinase/Akt-dependent cascade. Up-regulation of cPLA2 by IL-1β increased PGE2 biosynthesis in RASFs. Conclusion IL-1β-induced cPLA2 expression is mediated through activation of the MyD88/c-Src, MMP/HB-EGF, EGFR/PI 3-kinase/Akt, p300, and NF-κB pathways. These results provide insights into the mechanisms underlying IL-1β-enhanced joint inflammatory responses in RA and may inspire new targeted therapeutic approaches.

AB - Objective Cytosolic phospholipase A2 (cPLA2) is a rate-limiting enzyme that plays a critical role in the biosynthesis of eicosanoids. The aim of this study was to investigate the mechanisms underlying interleukin-1β (IL-1β)-induced cPLA2 expression in human rheumatoid arthritis synovial fibroblasts (RASFs). Methods Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. In a mouse model of IL-1β-mediated inflammatory arthritis, neutrophil infiltration, bone erosion, and cPLA2 expression in ankle synovium were analyzed by immunohistochemistry. IL-1β-induced cPLA2 expression was determined by Western blotting, real-time polymerase chain reaction, and gene promoter assay using pharmacologic inhibitors and transfection with short hairpin RNAs or small interfering RNAs. The recruitment of NF-κB and p300 to the cPLA2 promoter was determined by chromatin immunoprecipitation assay. Prostaglandin E2 (PGE 2) biosynthesis was evaluated by enzyme-linked immunosorbent assay. Results IL-1β-induced cPLA2 expression and PGE2 release were mediated through a myeloid differentiation factor 88 (MyD88)/c-Src-dependent matrix metalloproteinase (MMP)/heparin-binding epidermal growth factor (HB-EGF) cascade linking to transactivation of the EGF receptor (EGFR)/phosphatidylinositol 3-kinase (PI 3-kinase)/Akt, p300, and NF-κB p65 pathways. IL-1β also stimulated Akt phosphorylation and nuclear translocation. Activation of Akt eventually led to the acetylation of histone residues by phosphorylation and recruitment of p300 and enhanced its histone acetyltransferase activity on the NF-κB elements of the cPLA2 promoter. IL-1β-induced NF-κB transcriptional activity was mediated through a PI 3-kinase/Akt-dependent cascade. Up-regulation of cPLA2 by IL-1β increased PGE2 biosynthesis in RASFs. Conclusion IL-1β-induced cPLA2 expression is mediated through activation of the MyD88/c-Src, MMP/HB-EGF, EGFR/PI 3-kinase/Akt, p300, and NF-κB pathways. These results provide insights into the mechanisms underlying IL-1β-enhanced joint inflammatory responses in RA and may inspire new targeted therapeutic approaches.

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