@article{JurrmannBrigeliusFloheBoel2005,
  author    = {Jurrmann, Nadine and Brigelius-Floh{\´e}, Regina and B{\"o}l, Gaby Fleur},
  title     = {Curcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cells},
  issn      = {0022-3166},
  year      = {2005},
  abstract  = {Curcumin is a dietary compound with diverse anti-inflammatory and anticarcinogenic effects in several experimental models. A mechanism by which curcumin exerts these actions might be the direct modification of protein thiols, thereby altering the activity of the affected proteins. An early event in inflammatory signaling cascades is the recruitment of the interleukin-1 (IL-1) receptor-associated kinase (IRAK) to the IL-1 receptor (IL-1 RI) upon stimulation with IL-1. IRAK recruitment was shown recently to be inhibited by agents that modify thiols of IRAK. We asked, therefore, whether IRAK is also a target for curcumin. Curcumin indeed blocked IRAK thiols in a murine T-cell line stably overexpressing IRAK (EL-4(IRAK)), which resulted in the inhibition of IRAK recruitment to the IL-1RI and phosphorylation of IRAK and IL-1RI-associated proteins. Inhibitory effects were not reversible by thiol-reducing agents. Thus, modification by curcumin did not occur by oxidation but rather by alkylation, as is typical for electrophilic compounds reacting as Michael addition acceptors. The block in one of the earliest events in the IL-1 signaling cascade can explain the often observed inhibition of IL-1-mediated signaling steps by curcumin further downstream. Hence, thiol modification might be a crucial step in the anti-inflammatory functions of curcumin},
  language  = {en}
}
@article{BoelJurrmannBrigeliusFlohe2005,
  author    = {B{\"o}l, Gaby Fleur and Jurrmann, Nadine and Brigelius-Floh{\´e}, Regina},
  title     = {Cellular trafficking of the IL-1RI-associated kinase-1 requires intact kinase activity},
  issn      = {0006-291X},
  year      = {2005},
  abstract  = {Upon stimulation of cells with interleukin-1 (IL-1) the IL-1 receptor type 1 (IL-1RI) associated kinase-1 (IRAK- 1) transiently associates to and dissociates front the IL-IRI and thereafter translocates into the nucleus. Here we show that nuclear translocation of IRAK-I depends on its kinase activity since translocation was not observed in EL-4 cells overexpressing a kinase negative IRAK-1 mutant (EL-4(IRAK-1-K239S)). IRAK-1 itself, an endogenous substrate with an apparent molecular weight of 24 kDa (p24). and exogenous substrates like histone and myelin basic protein are phosphorylated by nuclear located IRAK-1. Phosphorylation of p24 cannot be detected in EL-4(IRAK-1-K239S) cells. IL-1- dependent recruitment of IRAK-1 to the IL-1RI and subsequent phosphorylation of IRAK-l is a prerequisite for nuclear translocation of IRAK-1. It is therefore concluded that intracellular localization of IRAK-1 depends on its kinase activity and that IRAK-1 may also function as a kinase in the nucleus as shown by a new putative endogenous substrate. (c) 2005 Elsevier Inc. All rights reserved},
  language  = {en}
}
@article{BanningDeubelKluthetal.2005,
  author    = {Banning, Anja and Deubel, S. and Kluth, Dirk and Zhou, Z. W. and Brigelius-Floh{\´e}, Regina},
  title     = {The GI-GPx gene is a target for Nrf2},
  issn      = {0270-7306},
  year      = {2005},
  abstract  = {The gastrointestinal glutathione peroxidase (GI-GPx, GPx2) is a selenoprotein that was suggested to act as barrier against hydroperoxide absorption but has also been implicated in the control of inflammation and malignant growth. In CaCo-2 cells, GI-GPx was induced by t-butyl hydroquinone (tBHQ) and sulforaphane (SFN), i.e., "antioxidants" known to activate the "antioxidant response element" (ARE) via electrophilic thiol modification of Keap1 in the Nrf2/ Keap1 system. The functional significance of a putative ARE in the GI-GPx promoter was validated by transcriptional activation of reporter gene constructs upon exposure to electrophiles (tBHQ, SFN, and curcumin) or overexpression of Nrf2 and by reversal of these effects by mutation of the ARE in the promoter and by overexpressed Keap1. Binding of Nrf2 to the ARE sequence in authentic gpx2 was corroborated by chromatin immunoprecipitation. Thus, the presumed natural antioxidants sulforaphane and curcumin may exert their anti-inflammatory and anticarcinogenic effects not only by induction of phase 2 enzymes but also by the up-regulation of the selenoprotein GI-GPx},
  language  = {en}
}