THIOL MODULATION INHIBITS THE INTERLEUKIN (IL)-1-MEDIATED ACTIVATION OF AN IL-1 RECEPTOR-ASSOCIATED PROTEIN-KINASE AND NF-KAPPA-B

The interleukin-1 receptor type I (IL-IRI) is associated with other pr oteins 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 ea rliest events detectable (Martin et al., fur. J. Immunol. 1994. 24: 15 66). IL-1 signaling is commonly accompanied by oxidative processes and is thought to be subject to redox regulation. We therefore investigat ed whether the activation of the IL-1RI-associated protein kinase coul d be a target for redox regulation and whether an altered activity of the kinase could influence IL-1-mediated NF-chi B activation. A murine T cell line, EL4, was stimulated with IL-1 with and without pretreatm ent with different compounds known to influence the cellular redox sta tus. Thiol modifying agents like diamide, menadione, pyrrolidine dithi ocarbamate (PDTC), diethyl dithiocarbamate or phenylarsine oxide inhib ited the IL-1-induced activation of the IL-1RI-associated protein kina se. N-Acetylcysteine, alpha,alpha'-dipyridyl, aminotriazole or nitrofu rantoin did not show any effect. The inhibition by PDTC was reversible unless glutathione synthesis was blocked by buthionine sulfoximine. T he described conditions which inhibited or prevented the activation of the IL-1RI-associated kinase similarly impaired the activation of NF- chi B in EL4 cells. From these observations we conclude that free thio ls in the IL-1RI complex are essential for the activation of the IL-1R I-associated protein kinase and that this process is mandatory for IL- 1 signaling leading to NF-chi B activation.