Heme oxygenase-1 induction by (S)-enantiomer of YS-51 (YS-51S), a synthetic isoquinoline alkaloid, inhibits nitric oxide production and nuclear factor- mu B translocation in ROS 17/2.8 cells activated with inflammatory stimulants

• Published in: International immunopharmacology 2007-12, Vol.7 (12), p.1559-1568
• Main Authors: Chaea, Han-Jung, Kim, Hyung-Ryong, Kang, Young Jin, Hyun, Kwang Chul, Kim, Hye Jung, Seo, Han Geuk, Lee, Jae Heun, Yun-Choi, Hye Sook, Chang, Ki Churl
• Format: Article
• Language: English
• ISSN: 1567-5769
• DOI: 10.1016/j.intimp.2007.07.023

Activation of the inducible nitric oxide synthase (iNOS) pathway contributes to inflammation-induced osteoporosis by suppressing bone formation and causing osteoblast apoptosis. We investigated the mechanism of action by which YS-51S, a synthetic isoquinoline alkaloid, inhibits iNOS expression and nitric oxide (NO) production in ROS 17/28 osteoblast cells activated with the mixture of TNF-, IFN- gamma and LPS (MIX). YS-51S, concentration- and time-dependently, increased heme oxygenase (HO-1) expression. Treatment with YS-51S 1 h prior to MIX significantly reduced MIX-induced NO production and iNOS expression with the IC50 to NO production of 47 ± 3.3 is a subset of M. Electrophoretic mobility shift assay (EMSA) and western blot analysis showed that YS-51S inhibited MIX-mediated activation and translocation of NF- mu B to nucleus by suppressing the degradation of its inhibitory protein I mu B in cytoplasm. YS-51S also reduced NF- mu B-luciferase activity. In addition, an HO-1 inhibitor ZnPPIX, antagonized the inhibitory effect of YS-51S on iNOS expression and DNA strand break induced by MIX, indicating prevention of NO production by YS-51S is associated with HO-1 activity. Moreover, YS-51S inhibited the oxidation of cytochrome c2+ by peroxynitrite (PN). Our results indicated that YS-51S may be beneficial in NO-mediated inflammatory conditions such as rheumatoid arthritis by alleviating iNOS expression and NO-mediated cell death of osteoblast with 1) inducing HO-1 expression, 2) interfering the activation of NF- mu B and 3) quenching of PN.