Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages.
We previously reported that nobiletin (5,6,7,8,3',4'-hexamethoxy flavone), a citrus polymethoxy flavonoid, effectively interferes with the production of promatrix metalloproteinase (proMMP)-9/progelatinase B in rabbit synovial fibroblasts [J. Rheumatol. 27 (2000) 20]. In this paper, we further examine the effects of nobiletin on the production of cyclooxygenases (COXs), prostaglandin (PG) E(2), and proinflammatory cytokines in human synovial fibroblasts and the mouse macrophage J774A.1 cell line. Nobiletin suppressed the interleukin (IL)-1-induced production of PGE(2) in human synovial cells in a dose-dependent manner (<64 microM). Additionally, it selectively downregulated COX-2, but not COX-1 mRNA expression. Nobiletin also interfered with the lipopolysaccharide-induced production of PGE(2) and the gene expression of proinflammatory cytokines including IL-1alpha, IL-1beta, TNF-alpha and IL-6 in mouse J774A.1 macrophages. In addition, nobiletin downregulated the IL-1-induced gene expression and production of proMMP-1/procollagenase-1 and proMMP-3/prostromelysin-1 in human synovial fibroblasts. In contrast, production of the endogenous MMP inhibitor, TIMP-1, was augmented by nobiletin. These anti-inflammatory actions of nobiletin are very similar to those of anti-inflammatory steroids such as dexamethasone, and the upregulation of TIMP-1 production is a unique action of nobiletin. Therefore, these results further support the notion that nobiletin is likely to be a candidate for characterization as a novel immunomodulatory and anti-inflammatory drug.
Lin
Na
N
Department of Biochemistry and Molecular Biology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
Sato
Takashi
T
Takayama
Yuji
Y
Mimaki
Yoshihiro
Y
Sashida
Yutaka
Y
Yano
Masamichi
M
Ito
Akira
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002957:Citrus / Q000737:chemistry*; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects*; D047309:Flavones; D005419:Flavonoids / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D047309:Flavones; D005419:Flavonoids; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; C008661:nobiletin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone