title: Thiol modulation inhibits the interleukin (IL)-1-mediated activation of an IL-1 receptor-associated protein kinase and NF-kappa B.
abstract: The interleukin-1 receptor type I (IL-1RI) is associated with other proteins thus forming a complex system by which IL-1 exerts its various signals. The initiating event is still uncertain, but activation of a recently described receptor-associated protein kinase is one of the earliest events detectable (Martin et al., Eur. J. Immunol. 1994. 24: 1566). IL-1 signaling is commonly accompanied by oxidative processes and is thought to be subject to redox regulation. We therefore investigated whether the activation of the IL-1RI-associated protein kinase could be a target for redox regulation and whether an altered activity of the kinase could influence IL-1-mediated NF-kappa B activation. A murine T cell line, EL4, was stimulated with IL-1 with and without pretreatment with different compounds known to influence the cellular redox status. Thiol modifying agents like diamide, menadione, pyrrolidine dithiocarbamate (PDTC), diethyl dithiocarbamate or phenylarsine oxide inhibited the IL-1-induced activation of the IL-1RI-associated protein kinase. N-Acetylcysteine, alpha,alpha'-dipyridyl, aminotriazole or nitrofurantoin did not show any effect. The inhibition by PDTC was reversible unless glutathione synthesis was blocked by buthionine sulfoximine. The described conditions which inhibited or prevented the activation of the IL-1RI-associated kinase similarly impaired the activation of NF-kappa B in EL4 cells. From these observations we conclude that free thiols in the IL-1RI complex are essential for the activation of the IL-1RI-associated protein kinase and that this process is mandatory for IL-1 signaling leading to NF-kappa B activation.
authors.affiliation: German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Tewes
authors.forename: G F
authors.initials: GF
authors.lastname: Böl
authors.forename: R
authors.initials: R
authors.lastname: Brigelius-Flohé
mesh_terms: D000818:Animals; D004050:Ditiocarb / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D013859:Thiocarbamates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013945:Thymoma; D013953:Thymus Neoplasms; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000494:pharmacology
chemical_list: D007375:Interleukin-1; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D017472:Receptors, Interleukin-1; D013438:Sulfhydryl Compounds; D013859:Thiocarbamates; D014812:Vitamin K; C020972:pyrrolidine dithiocarbamic acid; D004050:Ditiocarb; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D005978:Glutathione