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: Young Joo Oh, Ju Ho Youn, Hyun Jin Min, Dal-Hyun Kim, Sung-Sook Lee, In-Hong Choi, Jeon-Soo Shin
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 11 Issue 9 Pg. 1160-5 (Sep 2011) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 21457762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• HMGB1 Protein
• Lipopolysaccharides
• Phosphoinositide-3 Kinase Inhibitors
• Teichoic Acids
• Tetrahydroisoquinolines
• YS 49
• lipoteichoic acid
• Histone Acetyltransferases
• Protein Kinase C

Topics

• Animals
• Cell Line
• HMGB1 Protein (antagonists & inhibitors, metabolism)
• Histone Acetyltransferases (metabolism)
• Lipopolysaccharides (antagonists & inhibitors, pharmacology)
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Protein Transport (drug effects)
• Signal Transduction (drug effects)
• Teichoic Acids (pharmacology)
• Tetrahydroisoquinolines (pharmacology)