Exogenous heat shock protein HSP70 modulates lipopolysaccharide-induced macrophage activation

320 Innate immunity cells, including macrophages, play an important role in the defense of a mammalian body against pathogenic bacteria. Lipopolysacchaa rides (LPS) produced by Grammnegative bacteria actii vate macrophages. They begin to produce reactive oxygen species (ROS), synthesize and secrete proinn flammatory cytokines, and raise the production of heat shock proteins (HSP), including HSP70 [1]. After entering the bloodstream, LPSs interact with LPSSbinding protein and, subsequently, with the CD14 receptor of target cells. Then, LPSs are transs ferred from CD14 to lymphocyte antigen 96 (MDD2) to form two identical complexes including Tollllike receptor 4 (TLR4), MD2, and LPS. Then, a hett erodimeric receptor complex is formed in target cell membranes through interaction of the phosphate moii eties of LPS from one complex with TLR4 of the other complex [2]. The next step is the transduction of the signal from the receptor to transcription factors of tarr get cells to elicit the cell response. Early steps of the response are characterized by elevated ROS producc tion and adhesion factor expression. Then, proinflamm matory cytokines are produced. The first of them to be secreted is TNFFα [3]. Most enterobacteria E. coli contain the S form of LPSs. It includes hydrophobic lipid A, an oligosaccha ride core, and OOantigen. In addition to the S form, enterobacteria produce coreedeficient LPS molecules (R chemotypes) containing lipid A and cores of differr ent lengths. The molecules with abnormal cores are designated as Rb–Re chemotypes, and molecules with a fulllsize external core, as the Ra chemotype [4]. It is supposed that the LPS receptor complex can also bind heat shock proteins with M r = 70 kDa (HSP70) [5]. Our earlier results indicate that administration of exogenous recombinant HSP70 increases the survival of animals in the septic shock model and suppresses the activation of neutrophils and macrophages induced by the S form of LPS [6]. By now, the effect of S LPSs on myeloid cells has been studied in detail, but little is known about the action of R forms. Previously, we found an effect of various LPS chemotypes on ROS production and apoo ptosis in neutrophils [7]. Here, we studied the effect of exogenous HSP70 on ROS and TNFα production by macrophages exposed to various LPS chemotypes. We also studied the effect of exogenous HSP70 and LPSs on the TLR2 and TLR4 expression in macrophages. Earlier studies showed that administration of exogg enous HSP70 reduced …