Recruitment of the interleukin-1 receptor (IL-1RI)-associated kinase IRAK to the IL-1RI is redox regulated.
Interleukin-1 signaling is initiated by recruitment of adapter proteins and kinases to the type I interleukin-1 receptor (IL-1RI). It is modulated by accompanying redox processes at various levels, such as (auto-) phosphorylation of the IL-1RI-associated kinase IRAK, the phosphorylation of IkappaB and translocation and transcriptional activity of NF-kappaB. Here we demonstrate that the thiol-modifying agents diamide, menadione, and phenylarsine oxide (PAO) block the recruitment of IRAK to the receptor without inhibiting kinase activity in the immunoprecipitated IL-1RI complex in the human epithelial cell line ECV304 and the murine T cell line EL-4. Inhibition of IRAK receptor association by menadione is reversible in a GSH-dependent manner, while the PAO effect proved to be irreversible. Phospholipid hydroperoxide glutathione peroxidase attenuates inhibition by menadione. Recruitment correlates with the presence of thiol groups in IRAK that were available for IAIT-labeling. We conclude that recruitment of IRAK to the IL-1RI is redox regulated by the glutathione system, a reduced status being a prerequisite for an appropiate IL-1 response.
Department of Vitamins and Atherosclerosis, German Institute of Human Nutrition, D-14558 Potsdam-Rehbrücke, Germany.
Gaby-Fleur
GF
Böl
Nadine
N
Jurrmann
Regina
R
Brigelius-Flohé
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D001728:Dicumarol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases; D051379:Mice; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011233:Precipitin Tests; D011494:Protein Kinases / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D024483:Vitamin K 3 / Q000494:pharmacology
D004791:Enzyme Inhibitors; D017472:Receptors, Interleukin-1; D024483:Vitamin K 3; D001728:Dicumarol; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D005978:Glutathione