Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide

Mediation through both mitogen-activated protein kinase and NF-κB signaling pathways in macrophages

Daniel Hwang, Byeong C. Jang, Gang Yu, Mary Boudreau

Research output: Contribution to journalArticle

226 Citations (Scopus)

Abstract

The mitogen-inducible cyclooxygenase (COX-2) is selectively expressed in lipopolysaccharide (LPS)-stimulated macrophages. However, the signaling pathways that lead to the expression of COX-2 in LPS stimulated macrophages are not well understood. LPS activates members of mitogen-activated protein kinases (MAPKs) and NF-κB transcription factor in macrophages. We have shown that protein tyrosine kinase (PTK) inhibitors suppress the LPS induced expression of COX-2 in macrophages (Chanmugam et al., J Biol Chem 270: 5418-5426, 1995). These PTK inhibitors also inhibit LPS-induced activation of MAPKs. Thus, in the present study, we determined whether the activation of MAPKs and NF-κB is necessary for the signaling pathway for the LPS induced expression of COX-2 in the murine macrophage cell line RAW 264.7. The findings demonstrated that inhibition of extracellular signal regulated protein kinases 1 and 2 (ERK-1 and -2) by the selective inhibitor PD98059 or inhibition of P38 by the specific inhibitor SB203580 results in partial suppression of COX 2 expression. However, activation of MAPKs by phorbol 12-myristate 13-acetate, H2O2, sorbitol, sodium vanadate, or a combination of these agents failed to induce the expression of COX-2. Inhibitors of NF-κB suppressed COX-2 expression without affecting tyrosine phosphorylation of MAPKs. The PTK inhibitors that suppressed the activation of MAPKs and COX 2 expression also inhibited the degradation of IκB-α. Together, these results indicate that the activation of NF-κB is required to induce the expression of COX-2 in LPS stimulated RAW 264.7 cells. Inhibition of ERK-1 and 2 or P38 results in partial suppression of COX-2 expression. However, the activation of MAPKs alone is not sufficient to induce the expression of COX-2 in these cells.

Original languageEnglish (US)
Pages (from-to)87-96
Number of pages10
JournalBiochemical Pharmacology
Volume54
Issue number1
DOIs
StatePublished - Jul 1 1997
Externally publishedYes

Fingerprint

Proto-Oncogene Proteins c-akt
Macrophages
Prostaglandin-Endoperoxide Synthases
Mitogen-Activated Protein Kinases
Mitogens
Lipopolysaccharides
Chemical activation
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 12
Phosphorylation
Vanadates
Mitogen-Activated Protein Kinase 3
Sorbitol
Cyclooxygenase 2
Protein Kinases
Tyrosine
Acetates
Transcription Factors

Keywords

  • Cyclooxygenase
  • Lipopolysaccharide
  • Macrophages
  • Mitogen-activated protein kinases
  • NF-κB
  • Protein tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Pharmacology

Cite this

Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide : Mediation through both mitogen-activated protein kinase and NF-κB signaling pathways in macrophages. / Hwang, Daniel; Jang, Byeong C.; Yu, Gang; Boudreau, Mary.

In: Biochemical Pharmacology, Vol. 54, No. 1, 01.07.1997, p. 87-96.

Research output: Contribution to journalArticle

@article{ee1b8449f2274dc39ac8433f3531de5c,
title = "Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide: Mediation through both mitogen-activated protein kinase and NF-κB signaling pathways in macrophages",
abstract = "The mitogen-inducible cyclooxygenase (COX-2) is selectively expressed in lipopolysaccharide (LPS)-stimulated macrophages. However, the signaling pathways that lead to the expression of COX-2 in LPS stimulated macrophages are not well understood. LPS activates members of mitogen-activated protein kinases (MAPKs) and NF-κB transcription factor in macrophages. We have shown that protein tyrosine kinase (PTK) inhibitors suppress the LPS induced expression of COX-2 in macrophages (Chanmugam et al., J Biol Chem 270: 5418-5426, 1995). These PTK inhibitors also inhibit LPS-induced activation of MAPKs. Thus, in the present study, we determined whether the activation of MAPKs and NF-κB is necessary for the signaling pathway for the LPS induced expression of COX-2 in the murine macrophage cell line RAW 264.7. The findings demonstrated that inhibition of extracellular signal regulated protein kinases 1 and 2 (ERK-1 and -2) by the selective inhibitor PD98059 or inhibition of P38 by the specific inhibitor SB203580 results in partial suppression of COX 2 expression. However, activation of MAPKs by phorbol 12-myristate 13-acetate, H2O2, sorbitol, sodium vanadate, or a combination of these agents failed to induce the expression of COX-2. Inhibitors of NF-κB suppressed COX-2 expression without affecting tyrosine phosphorylation of MAPKs. The PTK inhibitors that suppressed the activation of MAPKs and COX 2 expression also inhibited the degradation of IκB-α. Together, these results indicate that the activation of NF-κB is required to induce the expression of COX-2 in LPS stimulated RAW 264.7 cells. Inhibition of ERK-1 and 2 or P38 results in partial suppression of COX-2 expression. However, the activation of MAPKs alone is not sufficient to induce the expression of COX-2 in these cells.",
keywords = "Cyclooxygenase, Lipopolysaccharide, Macrophages, Mitogen-activated protein kinases, NF-κB, Protein tyrosine kinase inhibitors",
author = "Daniel Hwang and Jang, {Byeong C.} and Gang Yu and Mary Boudreau",
year = "1997",
month = "7",
day = "1",
doi = "10.1016/S0006-2952(97)00154-8",
language = "English (US)",
volume = "54",
pages = "87--96",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Expression of mitogen-inducible cyclooxygenase induced by lipopolysaccharide

T2 - Mediation through both mitogen-activated protein kinase and NF-κB signaling pathways in macrophages

AU - Hwang, Daniel

AU - Jang, Byeong C.

AU - Yu, Gang

AU - Boudreau, Mary

PY - 1997/7/1

Y1 - 1997/7/1

N2 - The mitogen-inducible cyclooxygenase (COX-2) is selectively expressed in lipopolysaccharide (LPS)-stimulated macrophages. However, the signaling pathways that lead to the expression of COX-2 in LPS stimulated macrophages are not well understood. LPS activates members of mitogen-activated protein kinases (MAPKs) and NF-κB transcription factor in macrophages. We have shown that protein tyrosine kinase (PTK) inhibitors suppress the LPS induced expression of COX-2 in macrophages (Chanmugam et al., J Biol Chem 270: 5418-5426, 1995). These PTK inhibitors also inhibit LPS-induced activation of MAPKs. Thus, in the present study, we determined whether the activation of MAPKs and NF-κB is necessary for the signaling pathway for the LPS induced expression of COX-2 in the murine macrophage cell line RAW 264.7. The findings demonstrated that inhibition of extracellular signal regulated protein kinases 1 and 2 (ERK-1 and -2) by the selective inhibitor PD98059 or inhibition of P38 by the specific inhibitor SB203580 results in partial suppression of COX 2 expression. However, activation of MAPKs by phorbol 12-myristate 13-acetate, H2O2, sorbitol, sodium vanadate, or a combination of these agents failed to induce the expression of COX-2. Inhibitors of NF-κB suppressed COX-2 expression without affecting tyrosine phosphorylation of MAPKs. The PTK inhibitors that suppressed the activation of MAPKs and COX 2 expression also inhibited the degradation of IκB-α. Together, these results indicate that the activation of NF-κB is required to induce the expression of COX-2 in LPS stimulated RAW 264.7 cells. Inhibition of ERK-1 and 2 or P38 results in partial suppression of COX-2 expression. However, the activation of MAPKs alone is not sufficient to induce the expression of COX-2 in these cells.

AB - The mitogen-inducible cyclooxygenase (COX-2) is selectively expressed in lipopolysaccharide (LPS)-stimulated macrophages. However, the signaling pathways that lead to the expression of COX-2 in LPS stimulated macrophages are not well understood. LPS activates members of mitogen-activated protein kinases (MAPKs) and NF-κB transcription factor in macrophages. We have shown that protein tyrosine kinase (PTK) inhibitors suppress the LPS induced expression of COX-2 in macrophages (Chanmugam et al., J Biol Chem 270: 5418-5426, 1995). These PTK inhibitors also inhibit LPS-induced activation of MAPKs. Thus, in the present study, we determined whether the activation of MAPKs and NF-κB is necessary for the signaling pathway for the LPS induced expression of COX-2 in the murine macrophage cell line RAW 264.7. The findings demonstrated that inhibition of extracellular signal regulated protein kinases 1 and 2 (ERK-1 and -2) by the selective inhibitor PD98059 or inhibition of P38 by the specific inhibitor SB203580 results in partial suppression of COX 2 expression. However, activation of MAPKs by phorbol 12-myristate 13-acetate, H2O2, sorbitol, sodium vanadate, or a combination of these agents failed to induce the expression of COX-2. Inhibitors of NF-κB suppressed COX-2 expression without affecting tyrosine phosphorylation of MAPKs. The PTK inhibitors that suppressed the activation of MAPKs and COX 2 expression also inhibited the degradation of IκB-α. Together, these results indicate that the activation of NF-κB is required to induce the expression of COX-2 in LPS stimulated RAW 264.7 cells. Inhibition of ERK-1 and 2 or P38 results in partial suppression of COX-2 expression. However, the activation of MAPKs alone is not sufficient to induce the expression of COX-2 in these cells.

KW - Cyclooxygenase

KW - Lipopolysaccharide

KW - Macrophages

KW - Mitogen-activated protein kinases

KW - NF-κB

KW - Protein tyrosine kinase inhibitors

UR - http://www.scopus.com/inward/record.url?scp=0030805596&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030805596&partnerID=8YFLogxK

U2 - 10.1016/S0006-2952(97)00154-8

DO - 10.1016/S0006-2952(97)00154-8

M3 - Article

VL - 54

SP - 87

EP - 96

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 1

ER -