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CELLULAR AND MOLECULAR

Roflumilast Inhibits Lipopolysaccharide-Induced Inflammatory Mediators via Suppression of Nuclear Factor-B, p38 Mitogen-Activated Protein Kinase, and c-Jun NH₂-Terminal Kinase Activation

Laboratory of Molecular Pharmacology and Physiology, Medicinal Science Division, Korea Research Institute of Chemical Technology, Taejon, Korea (H.J.K., J.S.S., J.Y.H., J.-Y.N., H.G.C.); and Department of Bio-Chemical Engineering, Yanbian University of Science and Technology, Yanji City, China (S.D.Y.)

Roflumilast, a potent and selective phosphodiesterase 4 (PDE4) inhibitor, has been demonstrated to be an effective anti-inflammatory agent in airway inflammatory diseases. In the present study, we investigated the mechanism of anti-inflammatory effects of roflumilast in murine macrophage cell line RAW264.7 cells. Roflumilast inhibited NO, tumor necrosis factor (TNF)-, and interleukin (IL)-1 production via suppression of their gene expressions in lipopolysaccharide (LPS)-stimulated macrophages. To elucidate the mechanism by which roflumilast inhibits the production of inflammatory mediators, we examined the effect of roflumilast on the activation of nuclear factor-B (NF-B) in these cells. Roflumilast inhibited the DNA binding activity of NF-B by preventing inhibitor B phosphorylation and degradation. The phosphorylation of mitogen-activated protein (MAP) kinases, including stress-activated protein kinase/c-Jun NH₂-terminal kinase (JNK) and p38 MAP kinase, was also markedly inhibited by roflumilast. Similar to the effects of roflumilast, treatment of either SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole] or SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone], specific inhibitors of p38 MAP kinase and JNK, respectively, suppressed NO, TNF-, and IL-1 production. Consistent with in vitro results, administration of roflumilast recovered the survival rate of LPS-treated mice, with concurrent suppression of plasma levels of nitrite/nitrate, TNF-, and IL-1. These results suggest that the inhibitory activity of roflumilast on the production of inflammatory mediators seems to be mediated via inhibition of NF-B, p38 MAP kinase, and JNK activation in macrophages.

Address correspondence to: Dr. Hyae Gyeong Cheon, Laboratory of Molecular Pharmacology and Physiology, Medicinal Science Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yusung-Gu, Taejon 305-343, Korea. E-mail: hgcheon{at}krict.re.kr

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				K. McCluskie, U. Klein, C. Linnevers, Y.-h. Ji, A. Yang, C. Husfeld, and G. R. Thomas Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 468 - 476. [Abstract] [Full Text] [PDF]