engleski

Morphogenetic and immunomodulatory functions of endoplasmic reticulum resident heat shock protein gp96

Owing to the findings that partial hepatectomy (pHx) induces a rapid activation of natural and adaptive immunity, in this study we attempted to analyze the possibilities that glycoprotein gp96 participates in these evens. Namely, this highly conserved endoplasmic reticulum (ER) resident heat shock protein, in involved in correction of the unfolded proteins and in activation of proteasome-dependent ER-associated degradation of misfolded proteins. Furthermore, it is also is a strong adjuvant, able to cross-present onto MHC class I or MHC class II pathways the antigenic peptides, derived from tumor, viral or bacterial antigens, eliciting the antigen-specific immunity. Additionally, it is able to deliver the maturation signal to the dendritic cells, regulating the production of pro-inflammatory cytokines and generation of regulatory cell clones. Analyses were done in early and late phase of liver regeneration i.e. on 1st, 2nd, 6th, 24th and 48th hour after 1/3 pHx or sham operation in C57Bl mice. Gp96 and phenotype of lymphoid cells were detected in regenerating liver, thymus and spleen by immunohistological staining, RT-PCR and FACScan analysis. Simultaneously the cytotoxicity of intrahepatic and splenic mononuclear lymphatic cells (MNLC) obtained pHx donors were tested against syngeneic thymocytes and NK-sensitive targets (YAC-1) in wild, perforin and FasL deficient mice. The data have shown that pHx induces upregulation of mRNA for gp96 in the regenerating liver, thymus and spleen, as well as the fast cytoplasmic over expression of gp96 staining in regenerating hepatocytes, followed by surface expression of gp96 on MNLC in the spleen, and in the thymus. FACS analysis showed that in the regenerating liver after 6th p. o. hour accumulated activated NKT cells (CD3intermediate/NK1.1+/CD69+cells). At that time hepatic MNLC became highly cytotoxic against syngeneic thymocytes, while later (at 24th and 48th hour) increased also the perforin and Fas/L-dependent cytotoxicity of hepatic and splenic MNLC against YAC-1 target. The data imply that during liver regeneration gp96 may serve as a natural adjuvant for chaperoning antigenic self peptides into the immune surveillance pathways, resulting in activation of autoreactive NKT cells, and NK and LAK cells, which might be involved in reestablishment of previous morphostasis. Supported by grant given by Croatian Ministry of Science.

endoplasmic reticulum; gp96; liver regeneration

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