Treatment with Y-40138, a multiple cytokine production modulator, inhibits lipopolysaccharide- or tumour necrosis factor-alpha-induced production of pro-inflammatory cytokines and augments interleukin-10.
N-[1-(4-[4-(pyrimidin-2-yl)piperazin-1-yl]methyl phenyl)cyclopropyl] acetamide . HCl (Y-40138) suppresses liver injury in concanavalin A- and D-galactosamine/lipopolysaccharide (LPS)-induced mouse hepatitis models. However, the mechanism of action of Y-40138 has not been fully investigated. In this study, we examined the effect of Y-40138 on cytokine production in mice. Cytokine production was induced by intraperitoneal injection of LPS (0.5 mg kg(-1)) or intravenous injection of recombinant mouse tumour necrosis factor (TNF)-alpha (10 mug mouse(-1)) in BALB/c mice. TNF-alpha and interleukin (IL)-10 reached maximum levels 1.5 h after the LPS injection. IL-12 and interferon-sigma (IFN-sigma) reached maximum levels 3 to 9 h after the injection. When Y-40138 was orally administered 30 min prior to the injection, it inhibited TNF-alpha, IL-12 and IFN-sigma production and augmented IL-10 production. Y-40138 also inhibited IL-12 production and augmented IL-10 production in TNF-alpha-stimulated mice. In IL-10 knockout mice, Y-40138 inhibited TNF-alpha and IL-12 production 1.5 h after the LPS injection but not after 3 h or later, unlike in wild mice. In addition, TNF-alpha production was inhibited by Y-40138 at concentrations that could not augment IL-10 production. These data suggest that Y-40138 modulates pro-inflammatory cytokine production by both IL-10-dependent and -independent mechanisms.
Fukuda
Tetsuko
T
Pharmaceuticals Research Unit, Research and Development Division, Mitsubishi Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Fukuda.Tetsuko@mf.m-pharma.co.jp
Hisadome
Masao
M
Komatsu
Hirotsugu
H
D000081:Acetamides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018664:Interleukin-12 / Q000097:blood; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D013154:Spleen / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000081:Acetamides; D016207:Cytokines; D008070:Lipopolysaccharides; D010879:Piperazines; D014409:Tumor Necrosis Factor-alpha; C406663:Y 39041; C482199:lipopolysaccharide, E coli O55-B5; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma