Regulation of lipopolysaccharide-induced inducible nitric-oxide synthase expression through the nuclear factor-kappaB pathway and interferon-beta/tyrosine kinase 2/Janus tyrosine kinase 2-signal transducer and activator of transcription-1 signaling cascades by 2-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (THI 53), a new synthetic isoquinoline alkaloid.
The effects of 2-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (THI 53), on nitric oxide (NO) production and inducible nitric-oxide synthase (iNOS) protein induction by lipopolysaccharide (LPS) were investigated in RAW 264.7 cells and mice. In cells, THI 53 concentration dependently reduced NO production and iNOS protein induction by LPS. In addition, THI 53 inhibited NO production and iNOS protein induction in LPS-treated mice. LPS-mediated iNOS protein induction was inhibited significantly by the specific tyrosine kinase inhibitor alpha-cyano-(3-hydroxy-4-nitro)cinnamonitrile (AG126) as well as by THI 53. In addition, a c-Jun NH(2)-terminal kinase (JNK) inhibitor anthra[1,9-cd]pyrazole-6 (2H)-one) (SP600125) but not an extracellular regulated kinase inhibitor [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98029)] or a p38 inhibitor [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB230580)] reduced the iNOS protein level induced by LPS. Moreover, a Janus kinase 2 (JAK2) inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG490) dose-dependently prevented LPS-mediated iNOS protein induction. LPS activated phosphorylations of tyrosine kinases, especially tyrosine kinase 2 (Tyk2) and signal transducer and activator of transcription-1 (STAT-1); these were reduced by THI 53. LPS also phosphorylated the JNK pathway; however, this phosphorylation was unaffected by THI 53. Interestingly, a JNK inhibitor (SP600125) and another tyrosine kinase inhibitor (genistein) significantly inhibited STAT-1 phosphorylation, suggesting that the LPS-activated JNK pathway and a tyrosine kinase pathway (especially Tyk2) may link to the STAT-1 pathway, which is involved in iNOS induction. However, THI 53 regulates LPS-mediated iNOS protein induction by affecting the Tyk2/JAK2-STAT-1 pathway, not the JNK pathway. The inhibition by THI 53 of LPS-induced NO production was recovered by a tyrosine phosphatase inhibitor (Na(3)VO(4)), which supports the possibility that THI 53 inhibits the LPS-induced inflammatory response through regulation of tyrosine kinase pathways. THI 53 also inhibited LPS-mediated interferon (IFN)-beta production and nuclear factor-kappaB (NF-kappaB) activation. Thus, THI 53 may regulate LPS-mediated inflammatory response through both the NF-kappaB and IFN-beta/Tyk2/JAK2-STAT-1 pathways.
Kim
Hye Jung
HJ
Department of Pharmacology, College of Medicine, Gyeongsang National University, 92 Chilam-dong, Jinju, South Korea.
Tsoyi
Konstantin
K
Heo
Ja Myung
JM
Kang
Young Jin
YJ
Park
Min Kyu
MK
Lee
Young Soo
YS
Lee
Jae Heun
JH
Seo
Han Geuk
HG
Yun-Choi
Hye Sook
HS
Chang
Ki Churl
KC
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D016899:Interferon-beta / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D050794:STAT1 Transcription Factor / Q000502:physiology*; D053634:TYK2 Kinase / Q000502:physiology*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
C517917:2-naphthylethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; D007546:Isoquinolines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009281:Naphthalenes; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D044005:Tetrahydroisoquinolines; D009569:Nitric Oxide; D016899:Interferon-beta; D052247:Nitric Oxide Synthase Type II; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse