Akt Cys-310-targeted Inhibition by Hydroxylated Benzene Derivatives Is Tightly Linked to Their Immunosuppressive Effects

Abstract

The hydroxylated benzene metabolite hydroquinone (HQ) is mainly generated from benzene, an important industrial chemical, and is also a common dietary component. Although numerous reports have addressed the tumorigenesis-inducing effects of HQ, few papers have explored its molecular regulatory mechanism in immunological responses. In this study we characterized Akt (protein kinase B)-targeted regulation by HQ and its derivatives, in suppressing inflammatory responses using cellular, molecular, biochemical, and immunopharmacological approaches. HQ down-regulated inflammatory responses such as NO production, surface levels of pattern recognition receptors, and cytokine gene expression with IC 50 values that ranged from 5 to 10 M. HQ inhibition was mediated by blocking NF-B activation via suppression of its translocation pathway, which is composed of Akt, IB␣ kinase ␤, and IB␣. Of the targets in this pathway, HQ directly targeted and bound to the sulfhydryl group of Cys-310 of Akt and sequentially interrupted the phosphorylation of both Thr-308 and Ser-473 by mediation of ␤-mercaptoethanol, according to the liquid chromatography/ mass spectroscopy analysis of the interaction of HQ with an Aktderived peptide. Therefore, our data suggest that Akt and its target site Cys-310 can be considered as a prime molecular target of HQ-mediated immunosuppression and for novel antiAkt-targeted immunosuppressive drugs.

Nuclear Factor-.KAPPA.B/Signal Transducers and Activators of Transcription-1-Mediated Inflammatory Responses in Lipopolysaccharide-Activated Macrophages Are a Major Inhibitory Target of Kahweol, a Coffee Diterpene

“…Therefore, kahweol inhibition seems to be mediated by modulating the levels of total or phospho-forms of nuclear NF-kB and STAT-1. Since it has been generally known that phosphorylation of an enzyme is essential for its kinase activity, 26) kahweol may be involved in direct suppression of JAK2 activity. Supportive evidence will be further obtained by a direct kinase assay with purified JAK2 and a molecular modeling study.…”

Ginsenoside F1 Modulates Cellular Responses of Skin Melanoma Cells

“…Cellular responses stimulated by chemical and biochemical stimulation accompany intracellular signaling events [15,23]. In general, the inhibition of cell proliferation, induction of cell cytoskeleton changes, and suppression of melanin generation by treatment with G-F1 could be managed either by G-F1-induced signaling or by G-F1 mediated inhibition of the cellular signaling cascade.…”

“…In general, the inhibition of cell proliferation, induction of cell cytoskeleton changes, and suppression of melanin generation by treatment with G-F1 could be managed either by G-F1-induced signaling or by G-F1 mediated inhibition of the cellular signaling cascade. Therefore, we fi nally investigated the effect of G-F1 on intracellular signaling in B16 melanoma cells in terms of MAPK (ERK, JNK, and p38) and Akt that are involved in the modulation of cell proliferation and morphological changes [15,24]. As Fig.…”

“…Whole cell lysates were then analyzed by immunoblotting as reported previously [15,16]. Proteins were separated on 10% sodium dodecyl sulfate-polyacrylamide gels and were transferred by electroblotting to a polyvinylidenedifluoride membrane.…”

Caracterização dos efeitos da exposição à hidroquinona sobre o recrutamento leucocitário para o pulmão inflamado

“…The HQ actions on different leukocytes types in vitro have shown impairment on secretory functions which are essential during an in vivo inflammatory response (Lee et al, 2010;. Leukocyteendothelial interactions are the initial and fundamental events to the leukocyte migration into an inflammatory focus.…”