title: CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, inhibits the lipopolysaccharide-stimulated secretion of HMGB1 by inhibiting PI3K and classical protein kinase C.
abstract: CKD712, (S)-1-(α-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, was considered as a new effective drug candidate to sepsis, based on its anti-inflammatory activity. It was reported that CKD712 inhibited various signal pathways which play a key role in production of proinflammatory cytokines. Here, we examined the effect of CKD712 on the secretion of high mobility group box 1 (HMGB1), which is one of the proinflammatory cytokines. CKD712 can reduce Gram-negative lipopolysaccharide (LPS)- and Gram-positive lipoteichoic acid (LTA)-stimulated HMGB1 secretion in RAW264.7 and human peripheral blood monocytes (PBMo), and also reduce LPS-induced nucleocytoplasmic translocation of HMGB1 1h before or after LPS treatment. CKD712 could dose-dependently inhibit the activation of PI3K and PI3K-dependent kinase 1 (PDK1), which are involved in HMGB1 secretion signaling pathway. In addition, CKD712 inhibited classical protein kinase C (cPKC), the effective kinase for phosphorylation of HMGB1 for secretion, however, had no effect on histone acetyl-transferase activity, which is another mechanism known for HMGB1 secretion. Thus, we suggest that CKD712 could inhibit LPS- and LTA-stimulated HMGB1 secretion through the inhibition of HMGB1 phosphorylation by inhibiting PI3K-PKC signaling pathway.
authors: Department of Microbiology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors: Young Joo
authors: YJ
authors: Oh
authors: Ju Ho
authors: JH
authors: Youn
authors: Hyun Jin
authors: HJ
authors: Min
authors: Dal-Hyun
authors: DH
authors: Kim
authors: Sung-Sook
authors: SS
authors: Lee
authors: In-Hong
authors: IH
authors: Choi
authors: Jeon-Soo
authors: JS
authors: Shin
mesh_terms: D000818:Animals; D002460:Cell Line; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013682:Teichoic Acids / Q000494:pharmacology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
chemical_list: D024243:HMGB1 Protein; D051548:Histone Acetyltransferases; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D013682:Teichoic Acids; D044005:Tetrahydroisoquinolines; C090309:YS 49; C009900:lipoteichoic acid