Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis

Prithiva Chanmugan, Lili Feng, Shuenn Liou, Byeong C. Jang, Mary Boudreau, Gang Yu, Jong H. Lee, Ho J. Kwon, Teruhiko Beppu, Minoru Yoshida, Yiyang Xia, Curtis B. Wilson, Daniel Hwang

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Abstract

Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: a constitutively expressed COX-1 and mitogen-inducible COX-2, which is selectively expressed in response to various inflammatory stimuli. Thus, COX- 2 instead of COX-1 is implicated to produce prostanoids mediating inflammatory responses. Major efforts have been focused on identifying nonsteroidal anti-inflammatory drugs (NSAIDS) which can selectively inhibit the enzyme activity of COX-2. Such NSAIDS would be more desirable anti- inflammatory agents in comparison to NSAIDS which inhibit both COX-1 and COX- 2. Other than glucocorticoids, pharmacological agents which can selectively suppress the expression of COX-2 without affecting that of COX-1 have not been identified. We report here that radicicol, a fungal antibiotic, is a potent protein tyrosine kinase inhibitor, and that it inhibits the expression of COX-2 without affecting COX-1 expression in lipopolysaccharide (LPS)- stimulated macrophages with the IC50 value of 27 nM. Radicicol inhibited tyrosine phosphorylation of p53/56(lyn), a Src family tyrosine kinase and one of the major tyrosine-phosphorylated proteins in LPS-stimulated macrophages. Radicicol also inhibited COX-2 expression in vivo in glomeruli of rats with experimental glomerulonephritis induced by the anti-glomerular basement membrane antibodies, in which COX-2 expression is known to be enhanced. The enzyme activity of COX-1 or COX-2 was not affected by radicicol in macrophages. Radicicol also suppressed the COX-2 expression induced by IL- 1(β) in rat smooth muscle cells. Other protein tyrosine kinase inhibitors suppressed the LPS-induced COX-2 expression in macrophages but at much higher concentrations than needed for radicicol. Radicicol did not inhibit the COX- 2 expression induced by phorbol 12-myristate 13-acetate in macrophages. These results suggest that the activation of tyrosine-specific protein kinases is the proximal obligatory step in the LPS-induced signal transduction pathway leading to the induction of COX-2 expression in macrophages. The magnitude of the inhibition of COX-2 protein synthesis by radicicol was much greater than that of the steady state levels of COX-2 mRNA. These results suggest that radicicol inhibits COX-2 expression mainly at post-transcriptional steps.

Original languageEnglish (US)
Pages (from-to)5418-5426
Number of pages9
JournalJournal of Biological Chemistry
Volume270
Issue number10
DOIs
StatePublished - Mar 10 1995
Externally publishedYes

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Macrophages
Cyclooxygenase 2
Protein Kinase Inhibitors
Prostaglandin-Endoperoxide Synthases
Glomerulonephritis
Mitogens
Protein-Tyrosine Kinases
Lipopolysaccharides
Cyclooxygenase 1
Anti-Inflammatory Agents
monorden
Enzyme activity
Tyrosine
Rats
Pharmaceutical Preparations
Signal transduction
Glomerular Basement Membrane
Phosphorylation
src-Family Kinases
Eukaryotic Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis. / Chanmugan, Prithiva; Feng, Lili; Liou, Shuenn; Jang, Byeong C.; Boudreau, Mary; Yu, Gang; Lee, Jong H.; Kwon, Ho J.; Beppu, Teruhiko; Yoshida, Minoru; Xia, Yiyang; Wilson, Curtis B.; Hwang, Daniel.

In: Journal of Biological Chemistry, Vol. 270, No. 10, 10.03.1995, p. 5418-5426.

Research output: Contribution to journalArticle

Chanmugan, Prithiva ; Feng, Lili ; Liou, Shuenn ; Jang, Byeong C. ; Boudreau, Mary ; Yu, Gang ; Lee, Jong H. ; Kwon, Ho J. ; Beppu, Teruhiko ; Yoshida, Minoru ; Xia, Yiyang ; Wilson, Curtis B. ; Hwang, Daniel. / Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis. In: Journal of Biological Chemistry. 1995 ; Vol. 270, No. 10. pp. 5418-5426.
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abstract = "Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: a constitutively expressed COX-1 and mitogen-inducible COX-2, which is selectively expressed in response to various inflammatory stimuli. Thus, COX- 2 instead of COX-1 is implicated to produce prostanoids mediating inflammatory responses. Major efforts have been focused on identifying nonsteroidal anti-inflammatory drugs (NSAIDS) which can selectively inhibit the enzyme activity of COX-2. Such NSAIDS would be more desirable anti- inflammatory agents in comparison to NSAIDS which inhibit both COX-1 and COX- 2. Other than glucocorticoids, pharmacological agents which can selectively suppress the expression of COX-2 without affecting that of COX-1 have not been identified. We report here that radicicol, a fungal antibiotic, is a potent protein tyrosine kinase inhibitor, and that it inhibits the expression of COX-2 without affecting COX-1 expression in lipopolysaccharide (LPS)- stimulated macrophages with the IC50 value of 27 nM. Radicicol inhibited tyrosine phosphorylation of p53/56(lyn), a Src family tyrosine kinase and one of the major tyrosine-phosphorylated proteins in LPS-stimulated macrophages. Radicicol also inhibited COX-2 expression in vivo in glomeruli of rats with experimental glomerulonephritis induced by the anti-glomerular basement membrane antibodies, in which COX-2 expression is known to be enhanced. The enzyme activity of COX-1 or COX-2 was not affected by radicicol in macrophages. Radicicol also suppressed the COX-2 expression induced by IL- 1(β) in rat smooth muscle cells. Other protein tyrosine kinase inhibitors suppressed the LPS-induced COX-2 expression in macrophages but at much higher concentrations than needed for radicicol. Radicicol did not inhibit the COX- 2 expression induced by phorbol 12-myristate 13-acetate in macrophages. These results suggest that the activation of tyrosine-specific protein kinases is the proximal obligatory step in the LPS-induced signal transduction pathway leading to the induction of COX-2 expression in macrophages. The magnitude of the inhibition of COX-2 protein synthesis by radicicol was much greater than that of the steady state levels of COX-2 mRNA. These results suggest that radicicol inhibits COX-2 expression mainly at post-transcriptional steps.",
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T1 - Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis

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AU - Feng, Lili

AU - Liou, Shuenn

AU - Jang, Byeong C.

AU - Boudreau, Mary

AU - Yu, Gang

AU - Lee, Jong H.

AU - Kwon, Ho J.

AU - Beppu, Teruhiko

AU - Yoshida, Minoru

AU - Xia, Yiyang

AU - Wilson, Curtis B.

AU - Hwang, Daniel

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N2 - Two isoforms of cyclooxygenase (COX) have been identified in eukaryotic cells: a constitutively expressed COX-1 and mitogen-inducible COX-2, which is selectively expressed in response to various inflammatory stimuli. Thus, COX- 2 instead of COX-1 is implicated to produce prostanoids mediating inflammatory responses. Major efforts have been focused on identifying nonsteroidal anti-inflammatory drugs (NSAIDS) which can selectively inhibit the enzyme activity of COX-2. Such NSAIDS would be more desirable anti- inflammatory agents in comparison to NSAIDS which inhibit both COX-1 and COX- 2. Other than glucocorticoids, pharmacological agents which can selectively suppress the expression of COX-2 without affecting that of COX-1 have not been identified. We report here that radicicol, a fungal antibiotic, is a potent protein tyrosine kinase inhibitor, and that it inhibits the expression of COX-2 without affecting COX-1 expression in lipopolysaccharide (LPS)- stimulated macrophages with the IC50 value of 27 nM. Radicicol inhibited tyrosine phosphorylation of p53/56(lyn), a Src family tyrosine kinase and one of the major tyrosine-phosphorylated proteins in LPS-stimulated macrophages. Radicicol also inhibited COX-2 expression in vivo in glomeruli of rats with experimental glomerulonephritis induced by the anti-glomerular basement membrane antibodies, in which COX-2 expression is known to be enhanced. The enzyme activity of COX-1 or COX-2 was not affected by radicicol in macrophages. Radicicol also suppressed the COX-2 expression induced by IL- 1(β) in rat smooth muscle cells. Other protein tyrosine kinase inhibitors suppressed the LPS-induced COX-2 expression in macrophages but at much higher concentrations than needed for radicicol. Radicicol did not inhibit the COX- 2 expression induced by phorbol 12-myristate 13-acetate in macrophages. These results suggest that the activation of tyrosine-specific protein kinases is the proximal obligatory step in the LPS-induced signal transduction pathway leading to the induction of COX-2 expression in macrophages. The magnitude of the inhibition of COX-2 protein synthesis by radicicol was much greater than that of the steady state levels of COX-2 mRNA. These results suggest that radicicol inhibits COX-2 expression mainly at post-transcriptional steps.

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