Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells.
Viral infection generally results in the activation of inducible nitric oxide synthase (iNOS or NOS2) in respiratory epithelial cells by inflammatory cytokines. Activated NOS2 catalyzes synthesis of nitric oxide (NO), which in excess can cause cellular injury. On the other hand, lysophosphatidic acid (LPA), a lipid mediator released from epithelial cells, platelets, and fibroblasts in injured tissue, functions in repair of cell injury. However, details of the mechanism for repair by LPA remain unknown. We demonstrated one effect of LPA favoring repair, specifically inhibition by LPA of cytokine-induced NOS2 protein and mRNA expression by human respiratory epithelial cells in vitro. NO production by LPA-treated, cytokine-stimulated cells was also reduced. These decreases were prevented by Rho kinase inhibition with Y-27632. Thus, down-regulation by LPA of cytokine-induced increases in NOS2 activity is likely to involve a Rho-dependent signaling pathway. Harmful biologic effects of NO in viral respiratory infection might be modified by therapeutic manipulations involving LPA or Rho.
Kadowaki
Saori
S
Division of Internal Medicine and Molecular Therapeutics, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago Tottori, Japan.
Chikumi
Hiroki
H
Yamamoto
Hiroyuki
H
Yoneda
Kazuhiko
K
Yamasaki
Akira
A
Sato
Kenzo
K
Shimizu
Eiji
E
D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000201:enzymology* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007249:Inflammation; D008246:Lysophospholipids / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D012038:Regeneration; D012137:Respiratory System / Q000166:cytology*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000502:physiology
D016207:Cytokines; D008246:Lysophospholipids; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D020741:rho GTP-Binding Proteins; C032881:lysophosphatidic acid