title: Inhibition of lipopolysaccharide/ATP-induced release of interleukin-18 by KN-62 and glyburide.
abstract: Monocytes release interleukin-18 after activation by lipopolysaccharide/ATP. Since inflammatory conditions such as sepsis are characterized by augmented interleukin-18 in sera of patients, we sought to modulate lipopolysaccharide/ATP-induced interleukin-18 release by pharmacological means. Here we report that 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62), an inhibitor of ATP-mediated cellular activation by the purinoreceptor subtype P(2x7), potently suppresses interleukin-18 release from peripheral blood mononuclear cells. Interleukin-18 liberation was likewise inhibited by glyburide, a modulator of ion transport and inhibitor of ATP-binding cassette transporter 1. The data presented herein indicate that by pharmacologically interfering with the process of cytokine secretion agents such as KN-62 or glyburide have the potential to curb overproduction of interleukin-18 in septic patients.
authors.affiliation: Pharmazentrum frankfurt, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. H.Muehl@em.uni-frankfurt.de
authors.forename: Heiko
authors.initials: H
authors.lastname: Mühl
authors.forename: Sonja
authors.initials: S
authors.lastname: Höfler
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D020382:Interleukin-18; D008070:Lipopolysaccharides; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D005905:Glyburide