Suppression of tumor necrosis factor-alpha and inducible nitric oxide synthase gene expression by THI 52, a new synthetic naphthyl-benzylisoquinoline alkaloid.
The effects of THI 52 (1-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) on (a) inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) expression in RAW 264.7 cells stimulated by lipopolysaccharide (LPS)/interferon gamma (IFN-gamma), (b) plasma nitrate concentration as well as iNOS protein expression (lung) in vivo in LPS-treated rats, and (c) the restoration of vascular contractility to vasoconstrictor agents in LPS-treated vessels in vitro were investigated. THI 52 concentration-dependently reduced not only nitric oxide (NO) production (IC(50) value, 12.5 microM) but also the expression of TNF-alpha and iNOS mRNA in RAW 264.7 cells. Incubation of rat endothelium-denuded thoracic aorta with LPS (300 ng/mL) in vitro for 8 hr resulted in the suppression of vasoconstrictor effects to phenylephrine (PE), effects that were restored by co-incubation with THI 52. Administration of THI 52 (10 and 20mg/kg, i.p.) 30 min before injection of LPS (10mg/kg, i.p.) resulted in a significant reduction of the expression of iNOS protein in rat lung tissue and in the plasma nitrite/nitrate (NOx) level. Addition of THI 52-treated macrophage-conditioned medium to a TNF-sensitive L929 fibroblast cell line (CCL1) increased cell viability, depending on the concentration of THI 52. Finally, THI 52 inhibited the activation of nuclear factor kappaB (NF-kappaB) by inhibition of IkappaB degradation through the prevention of IkappaB phosphorylation. Collectively, these results strongly suggest that THI 52 suppresses both TNF-alpha and iNOS gene expression by inhibiting NF-kappaB. Thus, THI 52, a new synthetic isoquinoline alkaloid, may be beneficial in inflammatory disorders where the overproduction of NO and TNF-alpha is a matter of concern.
Kang
Young J
YJ
Department of Pharmacology, College of Medicine, Gyeongsang National University, Jinju, South Korea.
Lee
Bog K
BK
Lee
Young S
YS
Seo
Han G
HG
Park
Min K
MK
Kim
Hyo J
HJ
Pyo
Hyang S
HS
Chong
Won S
WS
Jung
Hye J
HJ
Yun-Choi
Hye S
HS
Lee
Duck H
DH
Chang
Ki C
KC
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects*; D020672:I-kappa B Proteins / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology*; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D044005:Tetrahydroisoquinolines; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics; D014661:Vasoconstriction / Q000187:drug effects
C471009:1-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; D000470:Alkaloids; D020672:I-kappa B Proteins; D007546:Isoquinolines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009281:Naphthalenes; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat