News From The Journal Of Clinical Investigation, Oct. 1, 2008

Main Category: Biology / Biochemistry
Also Included In: Cardiovascular / Cardiology;  Immune System / Vaccines;  Cancer / Oncology
Article Date: 02 Oct 2008 - 7:00 PDT

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Loss of the protein target of lithium disrupts normal mouse embryonic heart development

Individuals with bipolar disorder are usually treated with 'mood stabilizing' drugs, one of which is lithium - an inhibitor of GSK-3 proteins. As new drugs that are more powerful inhibitors of GSK-3 are under development despite controversial studies suggesting a link between lithium therapy and congenital heart defects, Thomas Force and colleagues, at Thomas Jefferson University, Philadelphia, set out to determine whether GSK-3 proteins are important for heart development in mice.

In the study, mice lacking GSK-3-alpha were born with a normal heart; however, mice lacking GSK-3-beta died before birth. Some of the embryos died of severe liver degeneration approximately half way through gestation, but most died at the late stages of development. These embryos exhibited numerous defects in the heart, including thickening of the heart muscle due to increased proliferation of the heart muscle cells. The authors therefore suggest that although controversy remains as to whether lithium is teratogenic, it would be wise to exercise caution when considering whether to treat women of childbearing age with the new generation of GSK-3 inhibitors.

TITLE: Deletion of GSK-3-beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation

AUTHOR CONTACT:
Thomas Force
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36245

HEMATOLOGY: Restoring PTEN protein function in leukemic cells

In many different human cancers, genetic mutations in the PTEN gene lead to an absence of PTEN protein. New data, generated by Joao T. Barata and colleagues, at Lisbon University Medical School, Portugal, have now shown that although PTEN protein is not functional in leukemic cells from individuals with a form of leukemia known as T-ALL, this is not because the PTEN gene is mutated; rather it is because the PTEN protein is modified such that it cannot function normally. As drugs targeting the pathways found to inactivate the PTEN protein restored PTEN signaling in T-ALL cells and led to T-ALL cell death, the authors hope that pharmacological manipulation of these pathways might provide new therapeutic approaches for T-ALL.

TITLE: PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability
AUTHOR CONTACT:
Joao T. Barata
Instituto de Medicina Molecular, Lisbon University Medical School, Lisbon, Portugal.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34616

CARDIOLOGY: Pinpointing a crucial role in the heart for one HDAC protein, HDAC3

Drugs known as HDAC inhibitors have been used successfully to treat various disorders, including several forms of cancer and cardiac hypertrophy (a condition that is characterized by thickening of the heart muscle and that often leads to heart failure). However, neither the contribution of each specific HDAC protein to the disorders nor their normal function in the tissues affected by these disorders has been determined. But now, using mice lacking HDAC3, Eric Olson and colleagues, at the University of Texas Southwestern Medical Center, Dallas, have identified a crucial role for this HDAC protein in maintaining heart function and the availability of cellular energy in heart muscle cells.

In the study, although mice lacking HDAC3 in all cells died before birth, mice lacking HDAC3 only in heart muscle cells lived for 3?? months. At this time, the mice were found to have extensive cardiac hypertrophy. Further, the mechanisms for generating cellular energy were markedly dysregulated in their heart muscle cells as a result of excessive activity of the protein PPAR-alpha. The authors therefore suggest that their data have implications for the future development of HDAC inhibitors. Current drugs do not discriminate between different HDAC proteins, but this study indicates that developing approaches that do not inhibit HDAC3 might be warranted in order to avoid unwanted toxicity in the heart.

TITLE: Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice

AUTHOR CONTACT:
Eric N. Olson
University of Texas Southwestern Medical Center, Dallas, Texas, USA.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35847

ONCOLOGY: Immune cells known as Tregs block the TRAIL to tumor destruction

One job of the immune system is to keep potential tumors in check. A wide range of mechanisms to escape antitumor immune responses is therefore observed in tumors that develop. For example, some tumors induce the generation and/or recruitment of CD4+CD25+ Tregs, immune cells that inhibit the function of immune cells known as CD8+ T cells and NK cells, which attack and destroy developing tumors. New data, generated in two rodent models of colon cancer, by François Ghiringhelli and colleagues, at CRI INSERM 866 and Centre Georges-Francois Leclerc, France, have now provided insight into yet another mechanism by which CD4+CD25+ Tregs inhibit the antitumor immune response.

In both models of cancer, treatment with a combination of agents (specifically, Mycobacterium bovis Bacillus Calmette-Guérin and cyclophosphamide) that activated immune cells known as DCs and eliminated CD4+CD25+ Tregs led to tumor eradication. Further analysis revealed the mechanism underlying tumor eradication: numbers of CD11b+ DCs in the tumors increased and they killed the tumor cells via a process known as TRAIL-mediated cell death. As an infusion of Tregs nullified this effect, the authors suggest that a two step approach of Treg elimination followed by tumor-associated DC activation might be therapeutically beneficial.

TITLE: CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer

AUTHOR CONTACT:
François Ghiringhelli
CRI INSERM 866, Dijon, France; or Centre Georges-Francois Leclerc, Dijon, France.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35890

IMMUNOLOGY: Detailed analysis of a human immune response

Immune cells known as natural Tregs are regulatory cells that are characterized as CD4+FoxP3+. They dampen immune responses and prevent the immune system attacking the body's own tissues. Arne Akbar and colleagues, at University College London, United Kingdom, have now provided new insight into the role of CD4+FoxP3+ cells in an ongoing immune response to part of the bacterium that causes tuberculosis (termed here PPD) in the skin of individuals previously immunized against tuberculosis.

In the study, the number of CD4+FoxP3+ T cells increased at the site of PPD injection in the skin at the same rate as the number of memory T cells. When the CD4+FoxP3+ T cells were isolated from the skin they were found to have several functional characteristics of natural Tregs. As the authors were able to take memory T cells from the site of PPD injection in the skin and generate natural Tregs in vitro, the authors suggest that it might be possible to isolate memory T cell from sites of unwanted inflammation and generate natural Tregs that could then be used to suppress the ongoing inflammatory response.

TITLE: The kinetics of CD4+FoxP3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo

AUTHOR CONTACT:
Arne N. Akbar
University College London, London, United Kingdom.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35834

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Article adapted by Medical News Today from original press release.
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Contact: Karen Honey
Journal of Clinical Investigation