EDITOR'S PICK: Hunger hormone fights aging in the thymus
The deterioration in immune function that occurs as an individual ages is thought to occur because the thymus involutes with age, causing a dramatic decrease in T cell output. New data generated by Dennis Taub and colleagues from the National Institutes of Health, Baltimore, suggest that in mice, thymic involution is caused by a decrease upon aging in thymic expression of both a hormone that is better known as a stimulator of food intake (ghrelin) and its receptor. These results led them to caution that care should be taken when considering blocking ghrelin as a potential approach for treating individuals who are obese and to suggest that harnessing this pathway might provide a new approach to boost immune function in individuals who are elderly or immunocompromised.
The physiological relevance of the decrease, with age, in expression in the mouse thymus of both ghrelin and its receptor was highlighted by the observation that infusion of ghrelin into old, but not young, mice markedly increased thymic mass, improved thymic architecture, and increased thymocyte and thymic epithelial cell numbers. These changes were associated with increased T cell output and increased diversity of the TCR repertoire of the peripheral T cell population. Consistent with these observations, age-associated thymic involution was accelerated in mice lacking either ghrelin or its receptor.
TITLE: Ghrelin promotes thymopoiesis during aging
AUTHOR CONTACT:
Dennis D. Taub
National Institutes of Health, Baltimore, Maryland, USA.
Phone: (410) 558-8159; Fax: 410) 558-8284); E-mail: taubd@grc.nia.nih.gov.
Vishwa Deep Dixit
Louisiana State University, Baton Rouge, Louisiana, USA.
Phone: (225) 763-2719; Fax: (225) 763-0261; E-mail: vishwa.dixit@pbrc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30248
EDITOR'S PICK: Drug's potential adverse side effect explained
Drugs that are agonists of the receptor PPAR-gamma are used to treat individuals with diabetes. However, it has been suggested that their use is associated with a slightly increased risk of heart failure. In a new study, Ira Goldberg and colleagues at Columbia University, New York, outline a potential explanation for the adverse effects observed in a minority of patients being treated with PPAR-gamma agonists.
To directly determine the effects of increased PPAR-gamma activity in the heart, the authors generated mice expressing increased amounts of PPAR-gamma in the heart compared with normal mice. Fat and carbohydrates accumulated in the heart muscle cells of these mice causing a deterioration in heart function (a process known as glucolipotoxicity). Administration of a PPAR-gamma agonist to these mice exacerbated their heart dysfunction. The authors therefore conclude that the adverse effect of PPAR-gamma agonists on heart function in humans might be due to glucolipotoxocity.
TITLE: Cardiomyocyte expression of PPAR-gamma leads to cardiac dysfunction in mice
AUTHOR CONTACT:
Ira J. Goldberg
Columbia University, New York, New York, USA.
Phone: (212) 305-5961; Fax: (212) 305-5384; E-mail: ijg3@columbia.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30335
ONCOLOGY: To kill or not kill that is the question for IFN-alpha
Although individuals with myeloma are often treated with IFN-alpha, the effectiveness of this therapeutic is variable. A new report from Ernest Borden and colleagues at The Cleveland Clinic, Taussig Cancer Center provides a potential explanation as to why the effectiveness of IFN-alpha treatment varies.
IFN-alpha is thought to kill myeloma cells by making them susceptible to TRAIL-mediated apoptosis. The authors observed that 24 hours of exposure to IFN-alpha2b antagonized TRAIL-mediated apoptosis in myeloma cell lines and primary myeloma cells. By contrast, after 72 hours of exposure TRAIL-mediated apoptosis was augmented. Further analysis revealed that the anti-apoptotic effects of IFN-alpha2b were mediated by upregulation of a protein known as G1P3, which stabilized mitochondria and thereby inhibited TAIL-mediated apoptosis. The authors therefore suggest that these distinct effects of IFN-alpha2b on TRAIL-mediated apoptosis might account for discrepancies in the effectiveness of IFN-alpha treatment in individuals with myeloma.
TITLE: G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells
AUTHOR CONTACT:
Ernest C. Borden
The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.
Phone: (216) 444-8183; Fax: (216) 636-2498; E-mail: bordene@ccf.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31122
METABOLIC DISEASE: When does being obese not lead to diabetes? When mice lack osteopontin
Obesity is one of the biggest risk factors for type 2 diabetes. One reason for this is thought to be the chronic inflammation characterized by macrophage infiltration into adipose tissue that accompanies obesity, because it has been linked to the development of insulin resistance (which in turn often leads to type 2 diabetes). New data generated in mice by Dennis Bruemmer and colleagues at the University of Kentucky College of Medicine, Lexington, provides support for this hypothesis.
Osteopontin is an extracellular matrix protein and proinflammatory cytokine that is required for macrophage infiltration of a tissue during an immune response. Bruemmer and colleagues found that although mice lacking osteopontin became obese when fed a high-fat diet, they did not become as insulin resistant as normal mice fed the same diet. This decrease in insulin resistance was associated with decreased accumulation of macrophages in the adipose tissue leading the authors to conclude that osteopontin has a key role in linking obesity to the development of insulin resistance in mice.
TITLE: Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice
AUTHOR CONTACT:
Dennis Bruemmer
University of Kentucky College of Medicine, Lexington, Kentucky, USA.
Phone: (859) 323-4933, ext. 81418; Fax: (859) 257-3646; E-mail:dennis.bruemmer@uky.edu.
Melanie P. Jackson
Senior Information Specialist
University of Kentucky, Lexington, Kentucky, USA.
Phone: (859) 323-6363, ext. 253; Fax: (859) 323-6132; E-mail: mpjack0@email.uky.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31986
VIROLOGY: Understanding why infection with HIV-2 is not as bad as HIV-1
There are two distinct, but related, HIV viruses that humans can become infected with — HIV-1 and HIV-2. Individuals infected with HIV-2 progress to AIDS at a dramatically reduced rate compared with individuals infected with HIV-1; in fact, most individuals infected with HIV-2 die of unrelated causes. It is hoped that understanding why individuals infected with HIV-2 rarely progress to AIDS will help with the design of therapeutics and vaccine strategies for the treatment and prevention, respectively, of infection with HIV-1.
A new study by Aleksandra Leligdowicz and colleagues at the Weatherall Institute of Molecular Medicine, Oxford, demonstrates that individuals infected with HIV-2 mount a strong immune response to a specific region of the viral protein Gag. The robustness of this response was inversely correlated with the amount of virus detected in the individual. In turn, individuals with high levels of detectable virus had fewer CD4+ T cells, indicating that they were progressing towards AIDS. The authors therefore suggest that T cell responses to Gag are important in determining the better outcome of infection with HIV-2 than infection with HIV-1.
TITLE: Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection
AUTHOR CONTACT:
Aleksandra Leligdowicz
Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
Phone: 44-1865-222312; Fax: 44-1865-222502; E-mail: aleksandra.leligdowicz@balliol.ox.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32380
METABOLIC DISEASE: Expanding beta-cell numbers
The underlying cause of both type 1 and type 2 diabetes is that there are insufficient pancreatic beta-cells to control the level of glucose in the blood. Given its potential impact on the treatment of diabetes, deciphering the molecular pathways that control beta-cell proliferation is an area of intensive investigation. In a new study, Anil Bhushan and colleagues from the David Geffen School of Medicine, Los Angeles, show that the protein Skp2 has a critical role in regulating beta-cell proliferation in mice.
The authors observed that mice lacking Skp2 developed more severe insulin resistance and more overt diabetes after being fed a high-fat diet than normal mice. This was associated with decreased degradation of p27 in beta-cells, which prevented the cells from proliferating. The authors therefore suggest that Skp2-mediated p27 degradation in beta-cells might have a role in regulating beta-cell proliferation in response to metabolic needs.
TITLE: Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta-cells
AUTHOR CONTACT:
Anil Bhushan
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
Phone: (310) 206-5750; Fax: (310) 206-5368; E-mail: ABhushan@mednet.ucla.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32198
CARDIOLOGY: Getting the inside story: new mouse model of adult-onset muscular dystrophy allows disease mechanisms to be determined
The most common form of adult-onset muscular dystrophy is myotonic dystrophin type 1 (DM1). DM1 is an inherited disease that has many symptoms including progressive muscle wasting and heart problems. Heart problems occur in most individuals with DM1 and account for a substantial proportion of disease-related deaths. In a new study, Thomas Cooper and colleagues at Baylor College of Medicine, Houston, describe how they have developed a mouse model of DM1 heart problems that has enabled them to garner more insight into the molecular mechanisms of the disease.
DM1 is characterized by an accumulation of RNA in the nucleus, which alters the functions of proteins known as CUGBPs causing aberrant alternative slicing of certain pre-mRNAs. Using their new mouse model of DM1 Cooper and colleagues were able to show that upregulation of CUGBP1 correlated with alteration in alternative splicing patterns, indicating that this is an early step in the pathogenesis of DM1.
TITLE: Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy
AUTHOR CONTACT:
Thomas A. Cooper
Baylor College of Medicine, Houston, Texas, USA.
Phone: (713) 798-3141; Fax: (713) 798-5838; E-mail: tcooper@bcm.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32308
ONCOLOGY: Vehicle and driver important for gene therapy for primary cutaneous lymphomas
Primary cutaneous lymphoma (CL) is a form of non-Hodgkin lymphoma. Prognosis is good for individuals with primary CL as the disease progresses very slowly and treatment with cytokines can help slow progression further. Recent studies have indicated that gene therapy might provide an alternative to the administration of recombinant cytokines. In a new study, Mirjana Urosevic and colleagues from University Hospital Zurich, Switzerland, show why IFN-gamma gene therapy delivered using an adenoviral vector (Ad–IFN-gamma) benefits individuals with CL.
The authors determined the gene expression profile of tumors of individuals with CL treated with Ad–IFN-gamma. Expression of genes characteristic of both an IFN-gamma (type II IFN) and a type I IFN response was detected. The type I IFN response was induced by the adenoviral vector and enhanced by the IFN-gamma gene carried by the vector. This combined response was crucial for the anticancer effects of Ad–IFN-gamma treatment.
TITLE: Type I IFN innate immune response to adenovirus-mediated IFN-gene gene transfer contributes to the regression of cutaneous lymphomas
AUTHOR CONTACT:
Mirjana Urosevic
University Hospital Zurich, Zurich, Switzerland.
Phone: 41-44-255-11-11; Fax: 41-44-255-89-88; E-mail: mirjana.urosevic@usz.ch.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32077
PHYSIOLOGY: Zebrafish provide insight into human joint disease
Progressive pseudorheumatoid dysplasia (PPD), which causes joint failure in early adulthood, results from genetic mutations in the WISP3 gene that lead to the generation of nonfunctional WISP3 protein. Understanding why WISP3 deficiency causes PPD has been difficult because mice lacking WISP3 have no apparent symptoms. In a new study, Matthew Warman and colleagues from Case Western Reserve University, Cleveland, provide insight into the functions of WISP3 by studying its function in zebrafish.
It was shown that overexpression of WISP3 in zebrafish inhibited signaling through two proteins — BMP and Wnt. Zebrafish and human WISP3 were also shown to inhibit BMP and Wnt signaling in mammalian cells. Importantly, WISP3 resembling that found in individuals with PPD was not as effective at inhibiting BMP and Wnt signaling. As cartilage development in zebrafish in which WISP3 expression was eliminated was defective, the authors conclude that dysregulated BMP and/or Wnt signaling contributes to the cartilage defects, and thereby joint failure, observed in individuals with PPD.
TITLE: The CCN family member Wisp3, mutant in progressive pseudorheumatoid dysplasia, modulates BMP and Wnt signaling
AUTHOR CONTACT:
Matthew L. Warman
Children's Hospital Boston, Boston, Massachusetts, USA.
Phone: (617) 919-2371; Fax: (617) 730-0789; E-mail: matthew.warman@childrens.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32001
Journal
Journal of Clinical Investigation