Tranilast, an orally active anti-allergic drug, up-regulates the anti-inflammatory heme oxygenase-1 expression but down-regulates the pro-inflammatory cyclooxygenase-2 and inducible nitric oxide synthase expression in RAW264.7 macrophages.
Tranilast (N-[3',4'-dimethoxycinnamonyl] anthranilic acid), an orally active anti-allergic drug, is reported to exert the anti-inflammatory effects, but the underlying mechanisms that could explain the anti-inflammatory actions of tranilast remain largely unknown. Here, we found that tranilast induces heme oxygenase-1 (HO-1) expression through the extracellular signal-regulated kinase-1/2 (ERK1/2) pathway in RAW264.7 macrophages. Tranilast suppressed cyclooxygenase-2 (COX-2) and inducible nitric oxide (NO) synthase (iNOS) expression, and thereby reduced COX-2-derived prostaglandin E(2) (PGE(2)) and iNOS-derived NO production in lipopolysaccharide (LPS)-stimulated macrophages. Similarly, tranilast diminished tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production. Interestingly, the effects of tranilast on LPS-induced PGE(2), NO, TNF-alpha, and IL-1beta production were partially reversed by the HO-1 inhibitor tin protoporphyrin, suggesting that tranilast-induced HO-1 expression is at least partly responsible for the resulting anti-inflammatory effects of the drug. Thus, HO-1 expression via ERK1/2 activation may be at least one of the possible mechanisms explaining the anti-inflammatory actions of tranilast.
Pae
Hyun-Ock
HO
Department of Microbiology and Immunology, Wonkwang University School of Medicine, Shinyong-Dong, 344-2, Iksan, Chonbuk 570-749, Republic of Korea.
Jeong
Sun-Oh
SO
Koo
Bon Soon
BS
Ha
Hun-Yong
HY
Lee
Kang-Min
KM
Chung
Hun-Taeg
HT
D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015854:Up-Regulation; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000494:pharmacology*
D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D062367:ortho-Aminobenzoates; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C012293:tranilast