Jean-Marque Elliot
Biochem
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Biochemistry (1362) Publish Paper: (Summery of a)
Review Article
Heat Shock Proteins and Regulatory T Cells
By
E. W. Brenu,1,2 D. R. Staines,2,3 L. Tajouri,4 T. Huth,1,2
K. J. Ashton,4 and S.M.Marshall-Gradisnik1,2
In the presence of tumors, concomitant relations between the extracellular HSPs
and the APCs following internalization of the tumor peptides via CD91 pathway generate both
anti-and proinflammatory immune response mediated by T cells.Extracellular HSPs, HSP70,
HSP90, and gp96 are peptide carriers, inducers of cytokines, and stimulants for immune cells
during stress.
Additionally, extracellular HSPs induce the maturation of dendritic cells and present
peptide molecules to antigen-presenting cells (APCs) thus, linking the innate immune and
adaptive immune systems.HSPs may indirectly or directly stimulate Tregs, via acetylation, TLR,
ligation or act as costimulatory molecules via the induction of other cells or molecules to
stimulate the Tregs.HSP70 derived from mycobacterium tuberculosis stimulates the proliferation
of Tregs by acting through dendritic cells causing a surge in IL-10 while dampening TNF-α
release.Intracellular HSPs including HSP27, HSP70, and HSP90 have direct roles in preventing
protein aggregation, induction of cell death pathways, cellular rescue and maintaining receptor
interactions.In the innate immune system, HSPs stimulate dendritic cells and macrophages, as
these are APCs, they consecutively stimulate adaptive immune cells.
Similarly, HSPs increase the effectiveness of cross-presentation between antigens and
APCs in the extracellular milieu, perpetrating in the presentation of peptides to major
histocompatibility complex class one (MHCI) or MHCII molecules on T cells.HSPs are
important in the induction, proliferation, suppressive function, and cytokine production of Tregs.
As HSPs regulate an extensive component of the immune system, it is likely that they have a role
in the optimal function of most immune cells.To date, the following HSPs have been investigated
in relation to Tregs, HSP60, HSP70, and HSP90.
Finally, In summary, despite the limited amount of research on Tregs and HSPs, the available
literature suggests an involvement of HSPs in the suppressive function and cytokine production
of Treg. Therapeutic strategies involving the use of HSPs to enhance the availability of
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Foxp3+.Tregs may be important in autoimmune diseases while in diseases like cancer it may be
necessary to inhibit Foxp3 acetylation. Cell-free or circulating HSPs, for instance, HSP70, are
released into the circulation by glial cells, B cells, PBMCs, or following necrosis.
Upon activation of the T cell receptor, Tregs suppress dendritic cells, B cells, macrophages,
osteoblasts, mast cells, NK cells, NKT cells, CD4+ T, and CD8+ T cells. I Tregs are generated
from naive CD4+ T cells subsequent to induction by IL-10 and TGF-β resulting in two
populations of iTregs, type 1 Tregs (Tr1), and T helper 3 (Th3) cells, respectively.The Role of
Heat Shock Proteins in Regulatory T Cell Function Regulatory T cells (Tregs) are a subset of
CD4+ T cells with suppressive functions.
Tregs may suppress the function of other cells via granzyme-mediated killing following
the release of granzymes into the target cells.The versatility in Treg effector function allows
them to modulate innate immune cells in particular APCs.High incidence of HSP70 decreases
endotoxin-induced protein and mRNA levels of TNF-α in heat-induced peritoneal macrophages
suggesting an influence of HSPs on the transcription of these genes.TLR4 interactions with
HSP70 may also augment effector T cell suppression by Tregs as this has been confirmed in
coculture experiments with other ligands.
The multifaceted nature of HSPs incorporates the regulation of reactive oxygen species (ROS)
and some chemokines from stimulated monocytes, macrophages, and dendritic cells. In
unstressed cells, HSPs are chaperone proteins that maintain protein configuration and transport.
HSPs may serve as immunogens released in response to an inflammatory episodes which
associates with particular surface receptors to induce adaptive immune reactions. HSP60
enhances the differentiation of cord blood cells into CD4+ CD25+ Foxp3+ Tregs.
In Tregs, the removal of HDAC6 results in the overexpression of HSP90 acetylation
resulting in an increase in HSF1-related genes instigating an increase in the suppressive function
of Tregs. Heat Shock Proteins and the Immune System The immune system is an intricate
network of cells and proteins, and bidirectional communication between different components of
the immune system is necessary for optimal homeostasis. Therapeutic administration of HSP60
increases the presence of nTregs, and this is often correlated with a decrease in atherosclerotic
plaques, the generation of Tregs, and an increase in the production of TGF-β.
Note: For any more information please see the original document.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612443/pdf/AD2013-813256.pdf
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Jean-Marque Elliot
Biochem
1362
Biochemistry (1362) Publish Paper: (Summery of a)
Research Paper
Liver autophagy contributes to the maintenance
of blood glucose and amino acid levels
By
Junji Ezaki,1 Naomi Matsumoto,1 Mitsue Takeda-Ezaki,1 Masaaki Komatsu,1–3 Katsuyuki Takahashi,1 Yuka
Hiraoka,4 Hikari Taka,4
Tsutomu Fujimura,4 Kenji Takehana,5 Mitsutaka Yoshida,6 Junichi Iwata,1,† Isei Tanida,1,7 Norihiko Furuya,1
Dong-Mei Zheng,1
Norihiro Tada,8 Keiji Tanaka,2 Eiki Kominami1 and Takashi Ueno1,4,*
The rationale for this conclusion is based on the following observations: (1)
whereas blood glucose levels were maintained within the normal range after the
amino acid surge provided by liver autophagic protein degradation in wild-type
mice (Fig. 4B), blood glucose levels continued to decrease and leveled off at onehalf the normal concentration in liver-specific autophagy-deficient mice (Fig. 4B);
and (2) when glucogenic amino acid, serine, was administered to wild-type and
liver-specific Atg7-deficient mice starved for 24 h, blood glucose concentrations
increased within 20 min (Fig. 4F), showing that both wild-type and autophagydeficient livers possess an equal ability to convert glucogenic amino acids to
glucose via gluconeogenesis.
To clarify this issue, we systematically investigated the fate of amino acids
produced by liver autophagic protein degradation by comparing normal wild-type
and liver-specific conditional autophagy (Atg7)-deficient mice. 20 We found that a
significant portion of the released amino acids was converted into glucose via
hepatic gluconeogenesis to maintain blood glucose levels, while the rest of the
amino acids were released into circulation to maintain plasma amino acids in wildtype mice.
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Earlier studies using perfused rat livers and in vivo experiments using mice have
revealed that autophagic protein degradation, which proceeds at a rate of ~1. 5% of
total liver protein/hour under nutrient-rich conditions, is enhanced approximately
two- to three-fold during starvation,16 resulting in the loss of nearly 40% of total
liver protein during a 48 h starvation period. 17 The conversion of glucogenic
amino acids generated during liver autophagy to glucose via gluconeogenesis has
long been proposed as a potential metabolic contribution.
The data also support the hypothesis that the amino acids generated by liver
autophagy were converted into glucose in the livers of starved wild-type mice and
that this glucose was released into the blood.
Using perfused rat liver, glucagon, which significantly stimulates autophagic
protein degradation,18 has enhanced intracellular utilization of glucogenic amino
acids through its effect on gluconeogenesis. 19 Because the liver is the major organ
that produces and supplies blood glucose, the utilization of glucogenic amino acids
for glucose production may be an important contribution of liver autophagy.
Transient increase in free amino acids in the liver, plasma and skeletal muscle
during starvation. (A) Plasma and tissue samples were collected from control wildtype mice starved for the indicated periods and were processed for amino acid
analyses as ...
Liver autophagy is controlled differently by plasma amino acids and
hormones, such as insulin and glucagon. 16,18,25,26 The suppressive effects of
amino acids on autophagy have been investigated mostly in perfusion experiments
using isolated rat livers or cultured hepatocytes. 16,25,36,37 However, either loss
of insulin action or stimulation by glucagon appears to play a more important role
in autophagy induction in vivo, because plasma amino acid concentrations do not
fluctuate enough in vivo to induce or suppress autophagy, in contrast with ex vivo
experiments. To test these possibilities, starvation-dependent changes in amino
acid levels in the liver, plasma and skeletal muscle were compared between control
wild-type mice and liver-specific autophagy (Atg7)-deficient mice.
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Because autophagy was induced after 24 h of starvation (Fig. 1), the levels of free
amino acids in the liver should increase as a result of autophagic protein
degradation.
The lack of a surge response in alanine may indicate a faster conversion of alanine
to pyruvic acid due to much higher alanine transferase activity compared with
serine dehydratase activity. 35 Taken together, these results indicate that the amino
acids produced through liver autophagy were efficiently converted into glucose
under starvation conditions.
In summary, the present study is the first to show that the amino acids
released as a result of starvation-induced autophagic proteolysis in the liver of
mice are metabolized, in part, via hepatic gluconeogenesis to glucose, which is
excreted into the circulation to maintain blood glucose concentrations.
Because the amino acid surge had metabolic effects on blood glucose via
gluconeogenesis in the livers of animals subjected to 24 h of starvation, it was
interesting to examine whether or not prior administration of glucose to starved
mice affects the amino acid surge or autophagic protein degradation.
To determine whether oral administration of amino acids to starved mice
could restore blood glucose concentrations, both control wild-type mice and liverspecific Atg7-deficient mice starved for 24 h were orally administered one regimen
of representative glucogenic amino acid serine (30 mg per animal), after which
blood glucose concentrations were monitored for 80 min. Herein, we report that, in
mice, liver autophagy makes a significant contribution to the maintenance of blood
glucose by converting amino acids to glucose via gluconeogenesis.
These results indicate that the transient increase in free amino acids in plasma and
skeletal muscle of wild-type mice starved for 24 h was due to liver autophagic
proteolysis.
Thus, the concentration of each of the 20 amino acids (except for two acid-labile
amino acids, cysteine and tryptophan) was examined in liver, plasma and skeletal
muscle isolated from control wild-type mice at various times after the induction of
starvation. Since the liver is known to supply blood glucose and hepatic glycogen
is a source of glucose, it would be reasonable to assume that the glucogenic amino
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Biochem
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acids generated in the liver through autophagy were converted into glucose and
that the resulting glucose was released into the blood to maintain blood glucose
levels. By contrast, in liver-specific Atg7-deficient mice, the inability to release
amino acids via autophagic proteolysis resulted in a significant reduction in blood
glucose levels during starvation.
In liver-specific autophagy (Atg7)-deficient mice, no amino acid release
occurred and blood glucose levels continued to decrease in contrast to those of
wild-type mice. Liver autophagy is suppressed by amino acids and insulin, while it
is enhanced by glucagon. 16,18,25,26 Hence, the concentrations of insulin,
glucagon, triacylglycerol and free fatty acids were measured in plasma collected
after various periods of starvation. In parallel with the amino acid surge in the
liver, free amino acids in plasma and skeletal muscles increased transiently in wildtype mice. These results may indicate that amino acids released by muscle
autophagy are secreted to the circulation to be transported to the liver in liverspecific Atg7-deficient mice.
Note: To see what the figure are about please see the original document
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149698/pdf/auto0707_0727.pdf
http://jme1005.wordpress.com/
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