Plenary Lecture

Plenary Lecture

Cross-Talk of Hypoxic and Map Kinase-Dependent Signalling Pathways in Toll-Like Receptor (TLR)-Mediated Inflammatory Reactions

Dr. Vadim Sumbayev
Medway School of Pharmacy
University of Kent
Anson Building, Central Avenue
Chatham Maritime, Kent ME4 4TB
United Kingdom

Abstract: TLRs are the key pattern recognition receptors that lie at the core of resistance to disease, initiating most of the phenomena that occur in the course of innate immune reactions. In our studies we found that ligand-induced TLR4 (cell membrane-associated receptor which recognises LPS of Gram-negative bacteria) signalling triggers cross-talk of ASK1 downstream pathway and HIF-1alpha in THP-1 human myeloid cells. Both pathways were activated via redox-dependent mechanism associated with tyrosine kinase/phospholipase C-1gamma-mediated activation of protein kinase C alpha/beta. The latter activated NADPH oxidase and, therefore, the production of ROS which up-regulate both HIF-1alpha and ASK1. ASK1 contributes to the stabilisation of HIF-1alpha protein via activation of p38 MAP kinase which directly phosphorylates HIF-1alpha. Knockdown of HIF-1alpha in THP-1 cells with siRNA suggested that this protein supports TLR4-dependent production of pro-inflammatory cytokines by protecting the cells against depletion of ATP and therefore against death. Ligand-induced activation of TLR7/8 (endosomal receptors which recognise viral ssRNA) leads to the accumulation of HIF-1alpha protein in THP-1 human myeloid macrophages via redox- and reactive nitrogen species-dependent mechanisms. ASK1 and its downstream MAP kinases as well as PI3-kinase are not involved in TLR7/8-mediated HIF-1alpha accumulation. Experiments with HIF-1alpha knockdown THP-1 cells have clearly demonstrated that this protein is?important for the protection of these cells against TLR7/8-induced depletion of ATP and for production of the pro-inflammatory cytokines. Therefore membrane-associated and endosomal TLRs use differential mechanisms of activation of HIF-1alpha but the function of the protein is similar in both cases.

Brief Biography of the Speaker:
I achieved my PhD degree in 1999 from the Palladin Institute of Biochemistry, National Academy of Science of the Ukraine. After graduating, I worked as Assistant, then Associate, Professor at the Department of Biochemistry, Mechnikov Odessa National University in the Ukraine. Then I moved to Germany where I received an Alexander von Humboldt research fellowship and worked as a Humboldt fellow in the Institute for Cell Biology, University of Kaiserslautern. Upon complete of my fellowship, I spent three years in Denmark at the University of Aarhus, working as Assistant Professor at the Department of Molecular Biology at the Interdisciplinary Nanoscience Centre. In December 2006, I joined the Medway School of Pharmacy, University of Kent as a Lecturer in Biochemistry where I have established my research group.



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