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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

Authors
 Young Joo Oh  ;  Ju Ho Youn  ;  Hyun Jin Min  ;  Dal-Hyun Kim  ;  Sung-Sook Lee  ;  In-Hong Choi  ;  Jeon-Soo Shin 
Citation
 INTERNATIONAL IMMUNOPHARMACOLOGY, Vol.11(9) : 1160-1165, 2011 
Journal Title
INTERNATIONAL IMMUNOPHARMACOLOGY
ISSN
 1567-5769 
Issue Date
2011
MeSH
Animals ; Cell Line ; HMGB1 Protein/antagonists & inhibitors* ; HMGB1 Protein/secretion* ; Histone Acetyltransferases/metabolism ; Lipopolysaccharides/antagonists & inhibitors ; Lipopolysaccharides/pharmacology* ; Mice ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors* ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation/drug effects ; Protein Kinase C/antagonists & inhibitors* ; Protein Kinase C/metabolism ; Protein Transport/drug effects ; Signal Transduction/drug effects ; Teichoic Acids/pharmacology ; Tetrahydroisoquinolines/pharmacology*
Keywords
Sepsis ; Inflammation ; Monocytes ; High mobility group box 1 (HMGB1) ; Protein kinase C ; Lipopolysaccharide
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.
Full Text
http://www.sciencedirect.com/science/article/pii/S1567576911001524
DOI
10.1016/j.intimp.2011.03.013
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Min, Hyun Jin(민현진)
Shin, Jeon Soo(신전수) ORCID logo https://orcid.org/0000-0002-8294-3234
Choi, In Hong(최인홍) ORCID logo https://orcid.org/0000-0001-9851-0137
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/93529
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