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News From The Journal Of Clinical Investigation: Oct. 15, 2012

Hypertension: It’s all in your head

Hypertension affects nearly 1 billion people worldwide and increases the risk for diseases of the heart, kidney, and brain. Endoplasmic reticulum (ER) stress in brain cells has been linked to hypertension, but the exact pathological mechanisms are unknown. In a study published in the Journal of Clinical Investigation, researchers led by Robin Davisson at Cornell University examined the role of ER stress in hypertensive mice. They determined that the circumventricular subfornical organ (SFO) was the primary location of hypertension-linked ER stress. Further, reducing ER stress in the SFO could prevent hypertension in mice. In a companion article, David Harrison of Vanderbilt University discusses the implications of these findings for the treatment of hypertension.

TITLE: ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension


ACCOMPANYING COMMENTARY TITLE: Endoplasmic reticulum stress and hypertension – a new paradigm?


Turning on Natural Killer T cells

Natural Killer T (NKT) cells are a subset of immune cells that defend the body against infectious agents. They are activated by molecules found on the surface of bacteria, known as glycolipids, which are taken up and presented to the NKTs by Cd1d cells. There is great interest in using glycolipids in a clinical setting to activate an immune response in cancer patients; however, little is known about the factors that allow glycolipids to be presented to NKT cells. In a study published in the Journal of Clinical Investigation, researchers led by Luc Teyton at Scripps Research Institute in La Jolla, California investigated the uptake pathways and structural characteristics of a panel of glycolipids. This study will allow for the rational development of glycolipid molecules that can be used for the therapeutic activation of NKT cells.

TITLE: Scavenger receptors target glycolipids for natural killer T cell activation


Tumor necrosis factor helps cancer cells evade the immune system

Tumor necrosis factor (TNF) induces inflammation, promotes tumor growth, and helps tumor cells evade immune system detection. Tumor cells implanted in mice that lack a TNF receptor are spontaneously rejected, but the immune mechanisms that underlie the rejection are unknown. In a study published in the Journal of Clinical Investigation, researchers led by Zihai Qin at the Chinese National Academy of Sciences report that TNF drives the accumulation of a population of myeloid-derived suppressor cells (MDSCs) that repress the immune response to cancer. Mice lacking TNF did not develop MDSCs and the cancer cells were killed by the immune system. These results suggest that therapeutics targeting TNF could promote immune clearance of cancer cells.

TITLE: TNF signaling drives myeloid-derived suppressor cell accumulation


Specialized T-cells help the immune system target tumors

The immune system response to tumor cells is mediated by secreted factors known as interleukins. A subset of T-helper cells (Th9) produces an interleukin known as IL-9, which can both positively and negatively regulate immune responses. In a study published in the Journal of Clinical Investigation, Qing Yi and colleagues at MD Anderson Cancer Center determined the role of Th9 cells in a mouse model of pulmonary melanoma. Loss of IL-9 enhanced tumor growth, while Th9 cell treatment increased the immune response to tumor cells. In a companion article, Edgar Schmidt and Tobias Bopp of the Johannes Gutenberg University in Mainz, Germany discuss the implications of these findings for modulating the immune system antitumor response.

TITLE: Th9 cells promote antitumor immune responses in vivo


ACCOMPANYING COMMENTARY TITLE: Amazing IL-9: Revealing a new function for an “old” cytokine


Tpl2: A new regulator of inflammation-associated colon cancer

Colitis-associated colon cancer is driven by inflammation. Cells known as intestinal myoflibroblasts (IMFs) secrete factors that modulate cancer progression, but the specific mechanisms and signaling pathways that influence colon cancer are unknown. In a study published in the Journal of Clinical Investigation, researchers led by George Kollias at the Alexander Fleming Biomedical Sciences Research Center in Attica, Greece identified the protein Tpl2 as a regulator of IMF-mediated inflammation. In a mouse model of colon cancer, loss of Tpl2 in IMFs resulted in an increase in the number and size of tumors. Tpl2-deficient IMFs secreted greater amounts of an inflammatory protein known as HGF, which enhanced tumorigenesis. These findings establish Tpl2 as a regulator of colon cancer.

TITLE: Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis


Whole-organism metabolism influences neurons involved in appetite suppression and weight loss

Glial cells are non-neuronal brain cells that regulate the metabolism and activity of neurons. Leptin, a key regulator of metabolism, has previously been reported to influence the structure and activity of glial cells. In a study published in the Journal of Clinical Investigation, researchers led by Tamas Horvath at Yale University report that metabolic status and leptin modified neuronal uptake of glutamate and glucose. In mice, increased body weight or fasting altered glucose and glutamate transport in the hypothalamus, a region of the brain involved in appetite suppression and weight loss. These results demonstrate that whole-organism metabolism influences the activity of glial cells and suggest that these cells could play a role in obesity.

TITLE: Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes


Mouse model explains differences in the severity of polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, but the spectrum of disease symptoms in patients ranges from symptom onset in utero to adequate renal function at old age. In a study in the Journal of Clinical Investigation, researcher led by Peter Harris at the Mayo Clinic in Rochester, MN developed a PKD1 mutant mouse that models the different levels of disease severity seen in humans. Using this model, they were able to correlate disease severity with the level of functional PKD1. This study helps explain the variance seen in ADPKD patients and will be useful for therapeutic testing.

TITLE: Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity



Journal of Clinical Investigation