Publication: Heat shock protein-GP96 as an innate sensor of damage and activator of autoreactive NKT and regulatory T cells during liver regeneration
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Date
2008
Authors
Mrakovcic-Sutic, Ines ; Jakovac, Hrvoje ; Simin, Marija ; Grebic, Damir ; Cuk, Mira ; Trobonjaca, Zlatko ; Radosevic-Stasic, Biserka
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Tissue disintegration after injury leads, in the
endoplasmic reticulum (ER), to activation of adaptive
pathways known as the ER stress response. It is directed
to the correction of unfolded proteins and to the
activation of proteasome-dependent ER-associated
degradation of the misfolded proteins, but induces also a
rapid activation of natural and adaptive immunity, since
a ER resident heat shock protein-gp96 acts not only as a
molecular chaperone, but also as a strong adjuvant, able
to cross-present the antigenic peptides onto MHC class I
or MHC class II pathways.
Analyzing its potential role in processes of normal
growth, in mice subjected to 1/3 partial hepatectomy
(pHx) we determined the tissue expression of gp96
protein and mRNA in regenerating liver, thymus and
spleen, determining simultaneously the phenotypic
profile and spontaneous cytotoxic activity of intrahepatic
and splenic mononuclear lymphatic cells (MNLC)
against NKT- and NK-cells sensitive targets (syngeneic
thymocytes and YAC-1) in wild, perforin and FasL
deficient mice.
The data have shown that pHx induces fast
overexpression of gp96 protein and mRNA in
hepatocytes, spleen and thymus, with accumulation of
CD3intermediate/NK1.1+/CD69+ cells (liver) and
Foxp3+CD4+CD25+ cells (liver and thymus).
Simultaneously, intrahepatic MNLC acquired the FasLdependent
cytotoxic potential against NKT-sensitive
targets and both, intrahepatic and splenic MNLC,
acquired the perforin-dependent cytotoxic potential
against NK-sensitive targets, implying that during the
disturbance of morphostasis gp96 serves as a natural adjuvant for chaperoning antigenic self peptides into the
immune surveillance pathways, resulting in activation of
autoreactive NKT and regulatory cells, as well as NK
cells. Moreover, cell cycle analysis revealed that G2+M
phase of regenerating hepatocytes in PKO mice was
translocated from the 1st to the 7th p. o. day, as well as
that hepatocytes from FasL deficient mice were arrested
in G0/G1 phase.
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