Cytokine-regulatory activity and therapeutic efficacy of cinnamyl derivatives in endotoxin shock.
We characterized the regulatory activity of cinnamyl derivatives and related compounds on pro-inflammatory cytokine production in vitro and in vivo. Among the 51 compounds examined, 7-amino-4-methylcoumarin (AMC) suppressed the production of interleukin-1alpha, interleukin-6 and tumor necrosis factor (TNF)-alpha, and their lipopolysaccharide-induced mRNAs in P388D1 cells. AMC suppressed pro-inflammatory cytokine transcription by reducing the DNA-binding amounts of nuclear factor-kappaB (NF-kappaB) and activator protein 1. Further, oral administration of AMC (30 mg/kg) as well as anti-TNF-alpha and anti-interleukin-1alpha antibodies significantly prevented death from endotoxin shock in mice without body weight loss and toxicity. AMC did not affect basal cytokine levels in control mice but suppressed the rise of systemic pro-inflammatory cytokine level, especially TNF-alpha. Thus, AMC might contribute to the recovery of endotoxin shock mainly by suppressing pro-inflammatory cytokine transcription. AMC may be useful in understanding the regulation and role of cytokine production in the pathogenesis of cytokine-mediated diseases.
Kurokawa
Masahiko
M
Toyama Medical and Pharmaceutical University, 2630 Sugitani, 930-0194 Toyama, Japan.
Brown
Jacqueline
J
Kagawa
Yoshinori
Y
Shiraki
Kimiyasu
K
D000818:Animals; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008811:Mice, Inbred DBA; D020005:Propanols / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*
D003374:Coumarins; D016207:Cytokines; D008070:Lipopolysaccharides; D020005:Propanols; C028743:7-amino-4-methylcoumarin; C020722:cinnamyl alcohol