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 IC value of 27 nM. Radicicol inhibited tyrosine phosphorylation of p53/56, 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 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.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				S. Papp, M. P. Fadel, H. Kim, C. A. McCulloch, and M. Opas Calreticulin Affects Fibronectin-based Cell-Substratum Adhesion via the Regulation of c-Src Activity J. Biol. Chem., June 1, 2007; 282(22): 16585 - 16598. [Abstract] [Full Text] [PDF]

				Y. Chen, M. Medhora, J. R. Falck, K. A. Pritchard Jr, and E. R. Jacobs Mechanisms of activation of eNOS by 20-HETE and VEGF in bovine pulmonary artery endothelial cells Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L378 - L385. [Abstract] [Full Text] [PDF]

				G. Yetik-Anacak, T. Xia, C. Dimitropoulou, R. C. Venema, and J. D. Catravas Effects of hsp90 binding inhibitors on sGC-mediated vascular relaxation Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H260 - H268. [Abstract] [Full Text] [PDF]

				J. Y. Lee, L. Zhao, H. S. Youn, A. R. Weatherill, R. Tapping, L. Feng, W. H. Lee, K. A. Fitzgerald, and D. H. Hwang Saturated Fatty Acid Activates but Polyunsaturated Fatty Acid Inhibits Toll-like Receptor 2 Dimerized with Toll-like Receptor 6 or 1 J. Biol. Chem., April 23, 2004; 279(17): 16971 - 16979. [Abstract] [Full Text] [PDF]

				J. Y. Lee, J. Ye, Z. Gao, H. S. Youn, W. H. Lee, L. Zhao, N. Sizemore, and D. H. Hwang Reciprocal Modulation of Toll-like Receptor-4 Signaling Pathways Involving MyD88 and Phosphatidylinositol 3-Kinase/AKT by Saturated and Polyunsaturated Fatty Acids J. Biol. Chem., September 26, 2003; 278(39): 37041 - 37051. [Abstract] [Full Text] [PDF]

				T. Takano, A. V. Cybulsky, W. A. Cupples, D. O. Ajikobi, J. Papillon, and L. Aoudjit Inhibition of Cyclooxygenases Reduces Complement-Induced Glomerular Epithelial Cell Injury and Proteinuria in Passive Heymann Nephritis J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 240 - 249. [Abstract] [Full Text]

				J. Y. Lee, A. Plakidas, W. H. Lee, A. Heikkinen, P. Chanmugam, G. Bray, and D. H. Hwang Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids J. Lipid Res., March 1, 2003; 44(3): 479 - 486. [Abstract] [Full Text] [PDF]

				H. Vliagoftis Thrombin Induces Mast Cell Adhesion to Fibronectin: Evidence for Involvement of Protease-Activated Receptor-1 J. Immunol., October 15, 2002; 169(8): 4551 - 4558. [Abstract] [Full Text] [PDF]

				R. Bolli, K. Shinmura, X.-L. Tang, E. Kodani, Y.-T. Xuan, Y. Guo, and B. Dawn Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning Cardiovasc Res, August 15, 2002; 55(3): 506 - 519. [Abstract] [Full Text] [PDF]

				K. Shinmura, Y.-T. Xuan, X.-L. Tang, E. Kodani, H. Han, Y. Zhu, and R. Bolli Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning Circ. Res., March 22, 2002; 90(5): 602 - 608. [Abstract] [Full Text] [PDF]

				M. D. Boudreau, K. H. Sohn, S. H. Rhee, S. W. Lee, J. D. Hunt, and D. H. Hwang Suppression of Tumor Cell Growth Both in Nude Mice and in Culture by n-3 Polyunsaturated Fatty Acids: Mediation through Cyclooxygenase-independent Pathways Cancer Res., February 1, 2001; 61(4): 1386 - 1391. [Abstract] [Full Text]

				C. Vogel, A.-M. J.F. Boerboom, C. Baechle, C. El-Bahay, R. Kahl, G. H. Degen, and J. Abel Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway Carcinogenesis, December 1, 2000; 21(12): 2267 - 2274. [Abstract] [Full Text] [PDF]

				Y.-W. E. Chang, R. Jakobi, A. McGinty, M. Foschi, M. J. Dunn, and A. Sorokin Cyclooxygenase 2 Promotes Cell Survival by Stimulation of Dynein Light Chain Expression and Inhibition of Neuronal Nitric Oxide Synthase Activity Mol. Cell. Biol., November 15, 2000; 20(22): 8571 - 8579. [Abstract] [Full Text]

				D. J. Wadleigh, S. T. Reddy, E. Kopp, S. Ghosh, and H. R. Herschman Transcriptional Activation of the Cyclooxygenase-2 Gene in Endotoxin-treated RAW 264.7 Macrophages J. Biol. Chem., February 25, 2000; 275(9): 6259 - 6266. [Abstract] [Full Text] [PDF]

				K. A. Lucas and J. T. Flynn Signal transduction pathways involved in lipopolysaccharide-induced production of PGE2 by human microvascular endothelial cells Innate Immunity, October 1, 1999; 5(5-6): 307 - 317. [Abstract] [PDF]

				S. Soga, L. M. Neckers, T. W. Schulte, Y. Shiotsu, K. Akasaka, H. Narumi, T. Agatsuma, Y. Ikuina, C. Murakata, T. Tamaoki, et al. KF25706, a Novel Oxime Derivative of Radicicol, Exhibits in Vivo Antitumor Activity via Selective Depletion of Hsp90 Binding Signaling Molecules Cancer Res., June 1, 1999; 59(12): 2931 - 2938. [Abstract] [Full Text] [PDF]

				W. Yu, K. Israel, Q. Y. Liao, C. M. Aldaz, B. G. Sanders, and K. Kline Vitamin E Succinate (VES) Induces Fas Sensitivity in Human Breast Cancer Cells: Role for Mr 43,000 Fas in VES-triggered Apoptosis Cancer Res., February 1, 1999; 59(4): 953 - 961. [Abstract] [Full Text] [PDF]

				T. Endo, F. Ogushi, T. Kawano, and S. Sone Comparison of the Regulations by Th2-type Cytokines of the Arachidonic-Acid Metabolic Pathway in Human Alveolar Macrophages and Monocytes Am. J. Respir. Cell Mol. Biol., August 1, 1998; 19(2): 300 - 307. [Abstract] [Full Text]

				M. Pouliot, M. J. James, S. R. McColl, P. H. Naccache, and L. G. Cleland Monosodium Urate Microcrystals Induce Cyclooxygenase-2 in Human Monocytes Blood, March 1, 1998; 91(5): 1769 - 1776. [Abstract] [Full Text] [PDF]

				H. Parfenova, L. Balabanova, and C. W. Leffler Posttranslational regulation of cyclooxygenase by tyrosine phosphorylation in cerebral endothelial cells Am J Physiol Cell Physiol, January 1, 1998; 274(1): C72 - C81. [Abstract] [Full Text] [PDF]

				M. T. Crowley, P. S. Costello, C. J. Fitzer-Attas, M. Turner, F. Meng, C. Lowell, V. L. J. Tybulewicz, and A. L. DeFranco A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fcgamma Receptors on Macrophages J. Exp. Med., October 6, 1997; 186(7): 1027 - 1039. [Abstract] [Full Text] [PDF]

				A. Ptasznik, E. R. Prossnitz, D. Yoshikawa, A. Smrcka, A. E. Traynor-Kaplan, and G. M. Bokoch A Tyrosine Kinase Signaling Pathway Accounts for the Majority of Phosphatidylinositol 3,4,5-Trisphosphate Formation in Chemoattractant-stimulated Human Neutrophils J. Biol. Chem., October 11, 1996; 271(41): 25204 - 25207. [Abstract] [Full Text] [PDF]

				J. H. Paik, J. H. Ju, J. Y. Lee, M. D. Boudreau, and D. H. Hwang Two Opposing Effects of Non-steroidal Anti-inflammatory Drugs on the Expression of the Inducible Cyclooxygenase. MEDIATION THROUGH DIFFERENT SIGNALING PATHWAYS J. Biol. Chem., September 1, 2000; 275(36): 28173 - 28179. [Abstract] [Full Text] [PDF]

				S. W. Ki, K. Ishigami, T. Kitahara, K. Kasahara, M. Yoshida, and S. Horinouchi Radicicol Binds and Inhibits Mammalian ATP Citrate Lyase J. Biol. Chem., December 8, 2000; 275(50): 39231 - 39236. [Abstract] [Full Text] [PDF]

				S. H. Rhee and D. Hwang Murine TOLL-like Receptor 4 Confers Lipopolysaccharide Responsiveness as Determined by Activation of NFkappa B and Expression of the Inducible Cyclooxygenase J. Biol. Chem., October 27, 2000; 275(44): 34035 - 34040. [Abstract] [Full Text] [PDF]

				K. Shinmura, Y.-T. Xuan, X.-L. Tang, E. Kodani, H. Han, Y. Zhu, and R. Bolli Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning Circ. Res., March 22, 2002; 90(5): 602 - 608. [Abstract] [Full Text] [PDF]