engleski

Inflammation mediated by heat shock proteins

Heat shock proteins (hsps) are evolutionary highly conserved proteins which are expressed in various subcellular localizations, indicating their high biological significance. All of them are strongly cytoprotective for the host cell due to their chaperone functions. Hsps maintain “client” protein folding, translocation or degradation mediating in a signal transduction and cell survival, regardless of their structural differences and family affiliation due to the molecular mass (HSP 100, HSP 90, HSP 70, HSP 60 or smoll HSPs). In addition to temperature shock, hsps are induced in different human tissues after the “physiological” stress such as the influence of growth factors and hormones, cell and tissue differentiation, including mild pro-inflammatory events during tissue remodeling at the normal maternal-embryonal interface. Constitutive HSC70 and inducible HSP70 forms were detected in decidua basalis of normal early pregnancy, blighted ovum and missed abortion. They were always higher when compared to term placenta. Glycoprotein 96 was the lowest in decidua of missed abortion when compared to normal early pregnancy and term placenta. Pathological conditions, such as infection, tumorigenesis, various radiations and cytotoxic agents (chemotherapy), nutritional and oxidative stress, ischaemia and autoimmune processes significantly enhance expression and secretion of hsps from damaged viable and necrotic, but not apoptotic cells. The extracellular hsp/peptide complexes emerged as “danger” signals which might elicit strong innate and acquired immune response on unconventional manner. Members of HSP70, HSP 90 and Hsp27 bind to pattern recognition receptors including CD91 and Toll-like receptor-4 (TLR-4), expressed on antigen presenting dendritic cells and macrophages. In decidua of missed abortion labeling intensity of CD91 and TLR4 was lower than in decidua of normal pregnancy, blighted ovum and term placenta, suggesting less efficient gp96/peptide internalization. Internalized hsp-chaperoned peptides are presented in the context of MHC class I molecules (cross presentation) and MHC class II molecules to CD8+ or CD4+ T cells, respectively. Thus the expansion of cytotoxic hsp specific T cell clones was found in atherosclerotic plaque, autoimmune Behcet disease, infections and tumors mediating tissue damage. Large hsps might act as highly effective cancer vaccines when associated with cancer antigens. The internalization of hsp/peptide complexes in antigen presenting cells engage highly conserved pro-inflammatory and anti-apoptotic NF-kappa B signaling pathway with specific pattern of cytokine and chemokine secretion, and co-stimulatory or differentiation marker expression. However, the gp96, HSP90, HSP70 and Hsp27 act differentially, and each induces some, but not all molecules. Recently was shown that hsps/peptide complexes could also induce tolerogenic/regulatory effects depending on inflammation status of the surrounding tissues and probably concentration of hsp/peptide complexes. Thus the immune responses mediated by hsp/peptide complexes are not unique, particularly in antigen processing, and presentation, in maturation program of antigen presenting cells and immune orientation.

decidua ; heat shock proteins ; inflammation ; pregnancy

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