The Role Of Heat Shock Protein 70 In Lps-activated Signaling Pathway

Inducible heat shock protein 70 ( Hsp70 ) is one of the most important HSPs for maintenance of cell integrity during normal cellular growth as well as pathophysiological conditions. Tumor necrosis factor receptor-associated factor 6 (TRAF6) was found by yeast two-hybrid assay using CD40 peptide as the probe in 1996. It is a crucial signaling transducer that regulates a diverse array of physiological and pathological processes and is essential for activating NF-κB signaling pathway in response to bacterial lipopolysaccharide (LPS). It is consisted of Ring finger domain, zinc finger domain in N-terminal and coiled-coil domain, TRAF-C domain in C-terminal. Our results show that Hsp70 can associate with TRAF6 physically in the TRAF-C domain. Upon stimulation, interaction of TRAF6 with CD40 or TRANCE-R activates NF-κB transcription factors and mitogen-activated protein kinase (MAPK). LPS(Lipopolysaccharide) is the principal component of the outer membrane of Gram-negative bacteria. Hsp70 inhibits LPS-induced NF-κB signaling cascade activation in heat-shock treated as well as Hsp70 stable transfected RAW264.7 cells. NF-κB is one of the key point in the regulation of gene expression of pro-immunity cytokines, which induces the expression of pro-immunity cytokines, chemokines, cell adhesion molecules, and etc. Hsp70 inhibits LPS-induced NF-κB activation by binding TRAF6, and results in inhibition of inflammatory mediators production, which provides a new insight for analyzing the effects of Hsp70 on LPS-triggered inflammatory signal transduction pathways.