title: Effects of sphondin, isolated from Heracleum laciniatum, on IL-1beta-induced cyclooxygenase-2 expression in human pulmonary epithelial cells.
abstract: Recently, under large-scale screening experiments, we found that sphondin, a furanocoumarin derivative isolated from Heracleum laciniatum, possessed an inhibitory effect on IL-1beta-induced increase in the level of COX-2 protein and PGE(2) release in A549 cells. Accordingly, we examined in the present study the action mechanism of sphondin on the inhibition of IL-1beta-induced COX-2 protein expression and PGE(2) release in a human pulmonary epithelial cell line (A549). Pretreatment of cells with sphondin (10-50 microM) concentration-dependently attenuated IL-1beta-induced COX-2 protein expression and PGE(2) release. The IL-1beta-induced increase in COX-2 mRNA expression was also attenuated by sphondin (50 microM). The selective COX-2 inhibitor, NS-398 (0.01-1 microM), inhibited the activity of the COX-2 enzyme in a concentration-dependent manner, while sphondin (10-50 microM) had no effect. Sphondin (50 microM) did not affect the IL-1beta-induced activations of p44/42 MAPK, p38 MAPK, and JNK. Treatment of cells with sphondin (50 microM) or the NF-kappaB inhibitor, PDTC (50 microM) partially inhibited IL-1beta-induced degradation of IkappaB-alpha in the cytosol and translocation of p65 NF-kappaB from the cytosol to the nucleus. Furthermore, IL-1beta-induced NF-kappaB-specific DNA-protein complex formation in the nucleus was partially inhibited by sphondin (50 microM) or PDTC (50 microM). Taken together, we demonstrate that sphondin inhibits IL-1beta-induced PGE(2) release in A549 cells; this inhibition is mediated by suppressing of COX-2 expression, rather than by inhibiting COX-2 enzyme activity. The inhibitory mechanism of sphondin on IL-1beta-induced COX-2 expression may be, at least in part, through suppression of NF-kappaB activity. We conclude that sphondin may have the therapeutic potential as an anti-inflammatory drug on airway inflammation.
authors.affiliation: Graduate Institute of Pharmacognosy Science, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: Yang
authors.forename: Yu Chih
authors.initials: YC
authors.lastname: Liang
authors.forename: Chia Wen
authors.initials: CW
authors.lastname: Chang
authors.forename: Wen Sen
authors.initials: WS
authors.lastname: Lee
authors.forename: Chen Tzu
authors.initials: CT
authors.lastname: Kuo
authors.forename: Ching Chiung
authors.initials: CC
authors.lastname: Wang
authors.forename: Horng Mo
authors.initials: HM
authors.lastname: Lee
authors.forename: Chien Huang
authors.initials: CH
authors.lastname: Lin
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004586:Electrophoresis; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology*; D030002:Heracleum / Q000737:chemistry*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008565:Membrane Proteins; D008730:Methoxsalen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C039410:sphondin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D008730:Methoxsalen