engleski

The endoplasmic reticulum-resident heat shock protein Gp96 participates in the control of liver regeneration after partial hepatectomy in mice

Introduction: Owing to the findings that partial hepatectomy (pHx) induces a rapid activation of natural and adaptive immunity during which in the regenerating liver accumulate potentially autoreactive NKT cells, in this study we attempted to analyze the possibilities that heat shock protein gp96 participates in these evens. Namely, this highly conserved monomorphic glycoprotein, as molecular chaperone has the unique ability to target the peptides into the endogenous presentation pathway of APCs, representing them as MHC I-peptide complexes for recognition by antigen-specific T lymphocytes via T cell receptor. Furthermore, gp96 delivers also the maturation signal to the dendritic cells, inducing the expression of MHC antigens and co-stimulatory molecules, leading to induction of pro-inflammatory cytokines, simultaneously with the generation of immune response to gp96-chaperoned peptides. Material & Method: Analysis were done in early phase of liver regeneration i.e. on 1st, 2nd and 6th hour after 1/3 pHx in C57Bl mice. Gp96 and phenotype of lymphoid cells were detected in regenerating liver, thymus and spleen by immunohistological staining and FACScan analysis. Simultaneously the cytotoxicity of intrahepatic and splenic mononuclear lymphatic cells (MNLC) obtained pHx donors was tested against syngeneic thymocytes and NK-sensitive targets (YAC-1). Results: The data have shown that in intact mice gp96 is moderately expressed in the liver, as well as in the thymus and spleen. However, as early as 1h after pHx, upregulation of gp96 staining occurred, resulting at 6th p. o. in an impressive cytoplasmic overexpression in regenerating hepatocytes. On the 2nd p. o. hour increased also the surface expression of gp96 on MNLC in the spleen, as well as in the thymus, particularly at the cortico-medullar conjunction. 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 cytotoxicity of hepatic and splenic MNLC against YAC-1 target. Conclusion: 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, NK and LAK cells, which might be involved in the control of hepatic proliferation and reestablishment of previous morphostasis. (Supported by grants from Croatian Ministry of Science, project No 0062018).

liver regeneration; heat shock gp96; NKT cells; liver; thymus; spleen.

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