Normal cell growth requires well-coordinated balance between synthesis and breakdown. Autophagy is a regulated lysosomal pathway whereby long-lived cellular proteins and cytoplasmic organelles are degraded. The beclin 1 autophagy gene is monoallelically deleted in 40-75% of cases of human sporadic breast, ovarian, and prostate cancer. However, little is known about the role of autophagy in cancer biology. In the December 15 issue of the Journal of Clinical Investigation Beth Levine and colleagues studied a targeted mutant mouse model with a heterozygous disruption of beclin 1 and observed an increase in cellular proliferation and the frequency of spontaneous malignancies and a reduction in autophagy in vivo. The report demonstrates that beclin 1 is a haplo-insufficient tumor-suppressor gene and suggests that autophagy is a novel and important mechanism in the regulation of cell growth and tumor suppression.
TITLE: Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
AUTHOR CONTACT:
Beth Levine
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-305-7312
Fax: 212-305-7290
E-mail: levine@cancercenter.columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/20039.pdf
Inflammation of fat cells linked to obesity-related insulin resistance
Obesity is associated with a state of chronic, low-grade inflammation and alterations in fat mass are associated with changes in energy intake and storage, insulin sensitivity, and metabolism. However the molecular pathways underlying a link between chronic inflammation and insulin resistance are unknown. In the December 15 issue of the Journal of Clinical Investigation two studies from independent research groups at Novartis Institutes for Biomedical Research, Massachusetts, and the Naomi Berrie Diabetes Center at Columbia University, New York, report that obese fatty tissue is characterized by the infiltration of macrophages and that these macrophages are an important source of inflammation in this tissue.
Both studies utilized large-scale gene expression analysis and histological evidence to compare the differences in gene expression in multiple tissues of both lean mice and mice of varying degrees of obesity. They found that the largest class of genes significantly regulated in obesity consists of macrophage and inflammatory genes in fatty tissue. Anthony Ferrante, Jr., and colleagues provide evidence that macrophage infiltration of adipose tissue is characteristic of human obesity, by demonstrating that body mass index and average fat cell size were significant predictors of macrophage accumulation in adipose tissue.
Hong Chen and colleagues demonstrated that the upregulation of many inflammation and macrophage–specific genes precedes a dramatic increase in circulating insulin levels and treatment with an insulin-sensitizing drug triggered downregulation of these genes. The data suggests that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue.
In an accompanying commentary, Kathryn Wellen and Gökhan Hotamisligil from the Harvard School of Public Health discuss the inflammation of obese adipose tissue. While it remains to be shown how the inflammatory response in fatty tissue causes insulin resistance, these two studies prompt consideration of new models of the molecular changes that occur in fatty tissue in obesity in which macrophages play a major role.
TITLE: Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance
AUTHOR CONTACT:
Hong Chen
Novartis Institutes for Biomedical Research Inc., Cambridge, Massachusetts, USA.
Phone: 617-871-7344
Fax: 617-551-9540
E-mail: hong.chen@pharma.novartis.com
View the PDF of this article at: https://www.the-jci.org/press/19451.pdf
RELATED ARTICLE:
TITLE: Obesity is associated with macrophage accumulation in adipose tissue
AUTHOR CONTACT:
Anthony W. Ferrante, Jr.
The Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-851-5322
Fax: 212-851-5331
E-mail: awf7@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/19246.pdf
ACCOMPANYING COMMENTARY:
Obesity-induced inflammatory changes in adipose tissue
AUTHOR CONTACT:
Gökham S. Hotamisligil
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone: 617-432-1950
Fax: 617-432-1941
E-mail: ghotamis@hsph.harvard.edu
View the PDF of this commentary at: https://www.the-jci.org/press/20514.pdf
Chemokine ligand helps fight off fungi
Invasive pulmonary aspergillosis, a severe pneumonia with high mortality, almost exclusively afflicts immunocompromised patients despite intervention with antifungal agents. Molecules known as chemokine ligands are essential in recruiting white blood cells (WBCs) to sites of infection. In order to better understand the role of the immune response in aspergillosis, Borna Mehrad and colleagues from the University of Texas examined mice with low numbers of WBCs suffering from aspergillosis. Their report, in the December 15 issue of the Journal of Clinical Investigation, describes the observation of a rapid and marked induction of the chemokine ligand MCP-1/CCL2 in the lungs of these mice. Blocking MCP-1/CCL2 increased the severity of infection and mortality, and reduced the recruitment of specific types of WBCs to the lungs. The report indicates that MCP-1/CCL2–mediated recruitment of WBCs to the lungs is a critical and previously unrecognized early host defense mechanism in invasive aspergillosis.
TITLE: Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis
AUTHOR CONTACT:
Borna Mehrad
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214-648-3429
Fax: 214-648-3545
E-mail: Borna.Mehrad@UTSouthwestern.edu
View the PDF of this article at: https://www.the-jci.org/press/18125.pdf
Disease model will aid understanding of relapsing polychondritis
Relapsing polychondritis is a chronic multisystem autoimmune disease involving recurrent episodes of inflammation and destruction of cartilage including that of the ears, nose, joints, and spine. Damaged cartilage is replaced with scar tissue that, in the ear, can result in disfiguration known as "cauliflower ear". The cause of polychondritis is unknown. However, the human lymphocyte antigen DQ8 has been associated with various autoimmune diseases in humans and may be important in this condition. In the December 15 issue of the Journal of Clinical Investigation Veena Taneja and colleagues from the Mayo Clinic, Rochester, describe the development of a mouse model expressing DQ8, which developed clinical and histological symptoms similar to those seen in humans with relapsing polychondritis. These mice provide a unique model of relapsing polychondritis with a high disease incidence and involvement of multiple organs that will be useful for studying autoantigens and regulatory cells involved in the pathogenesis of this disease.
TITLE: Auricular chondritis in NOD.DQ8.Abo (Ag7–/–) transgenic mice resembles human relapsing polychondritis
AUTHOR CONTACT:
Veema Taneja
The Mayo Clinic, Rochester, Minnesota, USA.
Phone: 507-284-4541
Fax: 507-266-0981
E-mail: taneja.veena@mayo.edu
View the PDF of this article at: https://www.the-jci.org/press/17450.pdf
TRPV5: the calcium gatekeeper
Ca2+ ions play a fundamental role in many cellular processes, and their concentration is kept under strict control to allow proper physiological functions. The Ca2+ concentration in blood is tightly controlled despite variations in dietary intake and body demand. In the December 15 issue of the Journal of Clinical Investigation René Bindels and colleagues from University Medical Center Nijmegen, The Netherlands, show that the TRPV5 channel acts as the molecular gatekeeper in facilitating Ca2+ reabsorption in the kidney. Despite enhanced vitamin D levels, mice lacking TRPV5 displayed diminished active Ca2+ reabsorption, which caused severe hypercalciuria. In TRPV5–/– mice, Ca2+ reabsorption malfunctioned and these mice exhibited significant disturbances in bone structure, including reduced trabecular and cortical bone thickness. These data demonstrate the key function of TRPV5 in active Ca2+ reabsorption and its essential role in Ca2+ homeostasis.
TITLE: Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5
AUTHOR CONTACT:
René J.M Bindels
University Medical Center Nijmegen, Nijmegen, The Netherlands.
Phone: 31-24-3614211
Fax: 31-24-3616413
E-mail: r.bindels@ncmls.kun.nl
View the PDF of this article at: https://www.the-jci.org/press/19826.pdf
Schwann cells attract mast cells during neurofibroma development
Neurofibromas are benign tumors that develop on nerves and are primarily comprised of Schwann cells and fibroblasts. While the pathogenesis of neurofibroma formation is incompletely understood, investigators have hypothesized that inflammatory mast cells may also play a role in the progression of tumor formation. In the December 15 issue of the Journal of Clinical Investigation, D. Wade Clapp and colleagues from Indiana University demonstrate that Schwann cells deficient in neurofibromin 1 (Nf1-/-) instigate tumor development by secreting Kit ligand, which stimulates the migration of mast cells and neurofibroma formation.
In an accompanying commentary, David Viskochil from the University of Utah explores the mechanisms of these cellular interactions and suggests that "the development of medical treatment targeted to mast cell function may be a rational approach to decreasing neurofibroma formation."
This report sets the stage for rational development of therapeutics that could influence the microenvironments of neurofibromas in order to inhibit the development and/or progression of these benign tumors in human neurofibromatosis.
TITLE: Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/– mast cells
AUTHOR CONTACT:
Wade D. Clapp
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Phone: 317-274-4719
Fax: 317-274-8679
E-mail: dclapp@iupui.edu
View the PDF of this article at: https://www.the-jci.org/press/19195.pdf
ACCOMPANYING COMMENTARY:
It takes two to tango: mast cell and Schwann cell interactions in neurofibromas
AUTHOR CONTACT:
David Viskochil
University of Utah, Salt Lake City, Utah, USA.
Phone: 801-581-8943
Fax: 801-585-7252
E-mail: DAVE.VISKOCHIL@hsc.utah.edu
View the PDF of this commentary at: https://www.the-jci.org/press/20503.pdf
When genetic repair goes awry in the gut
Ulcerative colitis (UC), a chronic inflammatory condition associated with a predisposition to colon cancer, is frequently characterized by damage to short, repetitive DNA sequences, referred to as microsatellite instability (MSI). A report from Curtis Harris and colleagues from the National Cancer Institute in the December 15 issue of the Journal of Clinical Investigation links inflammation in UC with increases in 2 DNA repair enzymes: AGG and APE1. Paradoxically the authors found that the increased levels of these DNA repair enzymes actually caused greater DNA damage. The exact mechanism through which AAG and APE1 produce this instability remains to be elucidated, but it may be related to imbalances in components of the DNA repair pathway at work and the accumulation of mutant repair intermediates. This may represent a novel mechanism contributing to MSI in chronic inflammation.
In an accompanying commentary, Haiwei Guo and Lawrence Loeb from the University of Washington discuss the known links between UC, genetic instability, and cancer and further evaluate whether these DNA repair mechanisms are doing both good and harm.
TITLE: The adaptive imbalance in base excision–repair enzymes generates microsatellite instability in chronic inflammation
AUTHOR CONTACT:
Curtis C. Harris
National Cancer Institute, Bethesda, Maryland, USA.
Phone: 301-496-2048
Fax: 301-496-0497
E-mail: Curtis_Harris@nih.gov
View the PDF of this article at: https://www.the-jci.org/press/19757.pdf
ACCOMPANYING COMMENTARY:
Tumbling down a different pathway to genetic instability
AUTHOR CONTACT:
Lawrence A. Loeb
University of Washington, Seattle, Washington, USA.
Phone: 206-543-6015
Fax: 206-543-3967
E-mail: laloeb@u.washington.edu
View the PDF of this commentary at: https://www.the-jci.org/press/20502.pdf
In control of renal blood flow
Regulation of renal blood flow is an intrinsic property of the kidney, however the signaling mechanisms involved have not been identified. Autoregulatory capability is important to preserve renal structure and function and impaired autoregulation is a characteristic of hypertension and diabetes that ultimately progresses to kidney damage. Some controversy exists regarding the role of ATP or adenosine in mediating renal blood flow. In the December 15 issue of the Journal of Clinical Investigation Edward Inscho and colleagues from the Medical College of Georgia use both pharmacologic approaches and animals lacking P2X1 receptors to demonstrate that locally released ATP is the chemical mediator of this autoregulatory response through activation of P2X1 receptors.
TITLE: Physiological role for P2X1 receptors in renal microvascular autoregulatory behavior
AUTHOR CONTACT:
Edward Inscho
Medical College of Georgia, Augusta, Georgia, USA.
Phone: 706-721-5615
Fax: 706-721-7299
E-mail: einscho@mail.mcg.edu
View the PDF of this article at: https://www.the-jci.org/press/18499.pdf
Enzyme helps blood vessels relax
The endothelium, a layer of cells that lines the internal surface of blood vessels, synthesizes and releases many molecules that cause vessel dilation, including endothelium-derived hyperpolarizing factor (EDHF). Hydrogen peroxide (H2O2) has recently been reported to be an EDHF, however the mechanism of endothelial H2O2 production has not been defined.
In the December 15 issue of the Journal of Clinical Investigation, Hiroaki Shimokawa and colleagues from Kyushu University, Japan, demonstrate that the enzyme Cu,Zn-superoxidase dismutase (Cu,Zn-SOD) acts as an EDHF synthase by promoting the formation of H2O2 in small vessels. Cu,Zn-SOD mediates endothelium-dependent hyperopolarzation and subsequent vessel relaxation by converting superoxide anions into H2O2.
TITLE: Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization
AUTHOR CONTACT:
Hiroaki Shimokawa
Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Phone: 81-92-642-5360
Fax: 81-92-642-5374
E-mail: shimo@cardiol.med.kyushu-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/press/19351.pdf
A radical explanation for glucose-induced beta cell dysfunction in diabetes
The development of type 2 diabetes requires impaired beta cell function. Hyperglycemia (high blood glucose levels) causes further decreases in glucose-stimulated insulin secretion. A study by Bradford Lowell and colleagues from Harvard medical School appearing in the December 15 issue of the Journal of Clinical Investigation demonstrates that production of the toxic molecule superoxide by beta cell mitochondria activates uncoupling protein 2 (UCP2), which reduces the insulin-secretory response.
In an accompanying commentary Michael Brownlee from Albert Einstein College of Medicine in New York discusses the enormous therapeutic implications of this work: "[The authors] suggest that pharmacologic inhibition of mitochondrial superoxide overproduction in beta cells exposed to hyperglycemia could prevent the positive feed-forward loop of glucotoxicity that pushes impaired glucose tolerance into frank type 2 diabetes."
TITLE: Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction
AUTHOR CONTACT:
Bradford B. Lowell
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Phone: 617-667-5954
Fax: 617-667-2927
E-mail: blowell@bidmc.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/19774.pdf
ACCOMPANYING COMMENTARY:
A radical explanation for glucose-induced beta cell dysfunction
AUTHOR CONTACT:
Michael A. Brownlee
Albert Einstein College of Medicine, New York, New York, USA.
Phone: 718-430-3636
Fax: 718-430-8570
E-mail: Brownlee@aecom.yu.edu
View the PDF of this commentary at: https://www.the-jci.org/press/20501.pdf
Are your alloantigens histocompatible?
Bone marrow transplantation offers the hope of a complete cure for patients suffering from certain forms of cancer, such as leukemia or other immune deficiency diseases. However, there is a risk that transplanted cells may recognize the recipient patient's tissues as foreign and begin to attack them. This reaction, known as graft-versus-host disease (GVHD), can be lethal if it continues unchecked. In the December 15 issue of the Journal of Clinical Investigation Robert Korngold and colleagues from the Kimmel Cancer Center illuminate the difference between major and minor histocompatibility antigens in the pathogenesis of GVHD.
Most bone marrow transplants are between MHC-matched/minor histocompatibility antigen (miHA)–mismatched individuals. miHAs with expression restricted to the recipient hematopoietic compartment could be prospective targets for graft-versus-leukemia therapy, but it is unclear whether this would trigger graft-versus-host disease (GVHD). Using established bone marrow irradiation chimeras across multiple miHA-disparate mice, Robert Korngold and colleagues from the Kimmel Cancer Center studied the occurrence of lethal GVHD mediated by donor CD4+ T cells in recipient mice expressing only hematopoietically derived alloantigens. Acute GVHD failed to develop in this situation, although these mice did later develop significant chronic GVHD-like epidermal lesions. Importantly, acute lethal GVHD only occurred when nonhematopoietic cells expressed the alloantigens. These data suggest that GVHD across miHA barriers depends upon the expression of nonhematopoietically rather than hematopoietically-derived alloantigens for maximal acute target tissue infiltration and injury.
TITLE: Importance of minor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell–mediated graft-versus-host disease model
AUTHOR CONTACT:
Robert Korngold
Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
Phone: 215-503-4552
Fax: 215-923-4153
E-mail: R.Korngold@mail.jci.tju.edu
View the PDF of this article at: https://www.the-jci.org/press/19427.pdf
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