JCI table of contents, March 23, 2006

EDITOR'S PICK

Clarifying controversy in multiple sclerosis

Multiple sclerosis (MS) is a crippling autoimmune disease of the central nervous system (CNS) in which the protective nerve cell coating called myelin is damaged. Although uncontrolled CNS inflammation by immune cells called microglia (MG) and production of the protein TNF-alpha are considered important causes of demyelination and loss of nerve (neuron) function in MS, there is evidence to suggest that a controlled inflammatory response may actually restore damaged myelin and nerve function. Now, in a study appearing online on March 23 in advance of print publication in the April issue of the Journal of Clinical Investigation, researcher Michal Schwartz and colleagues at the Weizmann Institute of Science in Israel help clarify the controversy by reporting that it is the mechanism by which the MGs are activated that determines whether they are destructive or protective. Using both mouse and rat animal models of MS, the authors show that production by immune cells known as helper T cells of small amounts of a proinflammatory protein called IFN-gamma or production of an anti-inflammatory protein IL-4 could stimulate MGs to support nerve cell survival. In contrast, the researchers show that MGs fail to protect neurons when they are exposed to high doses of IFN-gamma, because high levels of IFN-gamma stimulate the MGs to produce TNF-alpha. The results demonstrate that the helper T cells can have direct control over MG action, stimulating them to either support or destroy nerve cell function through production of IL-4, and suggest that stimulation of MGs with IL-4 may help in MS clinical recovery.

TITLE: Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis

AUTHOR CONTACT:
Michal Schwartz
Weizmann Institute of Science, Rehovot, Israel
Phone: 972-8-93-42467; Fax: 972-8-93-46018; E-mail: michal.schwartz@weizmann.ac.il

View the PDF of this article at: https://www.the-jci.org/article.php?id=26836

CARDIOLOGY

A real heartbreaker: clues to the causes of heart-related birth defects

Congenital heart diseases and defects that result during fetal development are thought to occur from failure of cells called neural crest cells to survive, migrate, or mature into another cell type called smooth muscle cells (SMCs), which contribute a contractile property to blood vessels. Previous studies showed that a protein called semaphorin 3C guides the migration of neural crest cells to developing large blood vessels of the heart such as the aorta, but the mechanisms involved in semaphorin 3C signaling are unclear. In a study appearing online on March 23 in advance of print publication in the April issue of the Journal of Clinical Investigation, researcher Michael S. Parmacek and colleagues at the University of Pennsylvania School of Medicine in Philadelphia show that semaphorin 3C is regulated by a protein called GATA-6. The authors deleted the GATA-6 gene in mice specifically within the neural crest and in SMCs grown in a laboratory dish, in order to identify the function of GATA-6 in heart development. The authors found that mice without GATA-6 developed cardiac malformations similar to those seen in animals with defects in semaphorin 3C, suggesting that GATA-6 was involved in neural crest cell migration and semaphorin 3C signaling. When the researchers examined semaphorin 3C expression in the GATA-6 null mice, they found that semaphorin 3C was dramatically reduced in the SMCs of the aorta and pulmonary artery. These studies demonstrate that GATA-6 is an important regulator of semaphorin 3C levels in neural crest-derived SMCs during cardiac development, and that further study of this protein may provide insights into the causes of developmental heart defects.

TITLE: GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis

AUTHOR CONTACT:
Michael S. Parmacek
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Phone: (215) 662-3140; Fax: (215) 349-8017; E-mail: michael.parmacek@uphs.upenn.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=27363

AUTOIMMUNITY

Tweaking muscle weakness with MuSK

Myasthenia gravis (MG), an autoimmune disease characterized by muscle weakness mainly in the limbs and face, is caused by the body's production of antibodies against a protein involved in nerve-muscle communication called the nicotinic acetylcholine receptor (AChR), causing reduced "clustering" or grouping of these receptors on muscle cells and impaired muscle contraction. Approximately 70% of patients with generalized MG who lack detectable AChR autoantibodies have been shown to produce antibodies against a different protein, muscle-specific kinase (MuSK). Unfortunately, little evidence exists regarding the specific role of the MuSK antibodies in MG disease. In a study appearing online on March 23 in advance of print publication in the April issue of the Journal of Clinical Investigation, researcher Kazuhiro Shigemoto and colleagues at Ehime University School of Medicine in Japan demonstrate that MuSK autoantibodies are also pathogenic in MG. Immunization of rabbits with MuSK protein caused limb muscle weakness compatible with MG and consistent with a significant reduction in clustering of AChR at sites where electrical nerve impulses meet the muscle cell, called the neuromuscular junctions. MuSK antibodies also inhibited AChR clustering and function in response to various stimuli in isolated muscle cells grown in laboratory dishes. Thus, MuSK autoantibodies rigorously inhibit AChR clustering, an outcome that broadens our general comprehension of the pathogenesis of MG.

TITLE: Induction of myasthenia by immunization against muscle-specific kinase

AUTHOR CONTACT:
Kazuhiro Shigemoto
Ehime University School of Medicine, Ehime, Japan
Phone: 81-89-960-5278; Fax: 81-89-960-5279; E-mail: shigemot@m.ehime-u.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=21545

IMMUNOLOGY

When not to scratch: loss of Itch causes airway inflammation

Immune system T cells are able to tell that the body's own "self" cells are not harmful pathogens like bacteria by the use of a process called tolerance. Although extensive studies have been performed to understand the induction of T cell tolerance, the link between a type of tolerance called Th2 tolerance and the control of allergic inflammation is not well understood. In a study appearing online on March 23 in advance of print publication in the April issue of the Journal of Clinical Investigation, Yun-Cai Liu and colleagues at the La Jolla Institute for Allergy and Immunology in California provide evidence that a cell signaling pathway called MEKK1/JNK converges with another pathway called the Itch-mediated protein modification pathway in the control of Th2 tolerance and allergic asthma. The authors used a MEKK1 mutant and JNK1-deficient mice to demonstrate that, like T cells deficient in an important immune protein called Itch, T cells from MEKK1 mutant or JNK1-deficient mice are also resistant to the induction of tolerance. The authors then linked Th2 tolerance to asthma by combining a tolerance protocol using high-dose soluble antigen with a mouse model of asthma. Although asthma could be prevented with high-dose soluble antigen pretreatment in normal mice, Itch-deficient mice still developed an allergic reaction. Thus, these results highlight a novel genetic pathway linking MEKK1/JNK signaling to Itch–mediated protein modification, which is critical in the induction of Th2 tolerance and airway inflammation.

TITLE: Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation

AUTHOR CONTACT:
Yun-Cai Liu
La Jolla Institute for Allergy and Immunology, San Diego, California, USA
Phone: (858) 678-4604; Fax: (858) 558-3525; E-mail: yuncail@liai.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=26858

ENDOCRINOLOGY

Too fat, too sweet: impaired liver function in diabetes

The liver, kidney, and intestine express a special protein called the farnesoid X receptor (FXR), which binds to bile acids involved in fat digestion. In order to better understand the functions of FXR, researchers David D. Moore and colleagues at Baylor College of Medicine in Texas studied genetically altered mice that lacked FXR, which demonstrate high levels of the blood fats cholesterol and triglycerides, as well as increased rates of fatty liver disease. In addition, the authors found the surprising result that these FXR-deficient mice also suffer from increased blood sugar (glucose) levels and insulin resistance, similar to humans with diabetes. By measuring the functions of the liver and skeletal muscle, the authors were able to determine that the livers of the FXR-deficient mice have an impaired ability to shut-down glucose production following a rise in insulin. In addition, the uptake of glucose by skeletal muscle, which does not express FXR, from the blood was impaired in FXR-deficient mice. These two effects in distinct tissue types suggest that loss of FXR can mediate insulin resistance, an increasingly common metabolic disorder in developed countries in which the body fails to utilize blood glucose in response to insulin signaling. Together these data demonstrate that FXR, a protein long-considered central to proper regulation of fat and cholesterol levels, to be a critical regulator of blood glucose levels through direct and indirect control of liver and muscle glucose production and uptake, respectively. The study appears online on March 23 in advance of print publication in the April issue of the Journal of Clinical Investigation.

TITLE: Farnesoid X receptor is essential for normal glucose homeostasis

AUTHOR CONTACT:
David D. Moore
Baylor College of Medicine, Houston, Texas, USA
Phone: (713) 798-3313; Fax: (713) 798-3017; E-mail: moore@bcm.tmc.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=25604

HEPATOLOGY

Seeing the LIGHT: identification of a protein involved in hepatitis

In a study appearing online on March 23 in advance of print publication in the April issue of the Journal of Clinical Investigation, Koji Tamada and colleagues at Johns Hopkins University School of Medicine in Baltimore report that an inflammatory molecule called LIGHT, known to be associated with the death of tumor cells as well as lethal liver inflammation (hepatitis) acts to induce these effects, in part, through interaction with a cell receptor called LTbeta receptor (LTbetaR). The authors used a mouse model of liver inflammation to mimic a potent inflammatory response, and found that mice that did not express LIGHT had a reduced influx of inflammatory cells into the liver with significantly higher survival rates than normal mice (of which only 20% survived following hepatitis). Similarly, mice injected directly with DNA molecules that produced LIGHT protein had much lower survival rates and higher liver inflammation than mice injected with control DNA or mutated LIGHT DNA molecules. Using antibodies that block the specific interaction between LIGHT and LTbetaR, the authors discovered that LIGHT required LTbetaR interaction to mediate liver inflammation. These studies demonstrate a direct role for the proinflammatory LIGHT protein in liver inflammation (hepatitis), liver damage, and associated mortality.

TITLE: Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis

AUTHOR CONTACT:
Koji Tamada
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Phone: (410) 502-0958; Fax: (410) 502-0961; E-mail: ktamada1@jhmi.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=27083

NEPHROLOGY

Defying gravity: the ups and downs of blood pressure control in the kidney

In a study appearing online on March 23 in advance of print publication in the April issue of the Journal of Clinical Investigation, Scott Thomson and colleagues at the University of California, San Diego, California, report the surprising role for the peptide hormone angiotensin II (Ang II) in regulating blood pressure via kidney fluid reabsorption during high–dietary salt intake. The authors placed rats on high-salt diets and monitored the amount of fluid reabsorbed in the proximal tubule portion of the kidney (an important region for controlling blood volume and hence pressure). In addition, the researchers gave the rats a drug called losartan, which blocks the action of Ang II. Rats on a standard diet taking losartan demonstrated a 25% reduction in proximal fluid reabsorption, suggesting that Ang II signaling can mediate changes in fluid balance and transport within this kidney region. In addition, after seven days on a high-salt diet, rats exhibited suppressed blood (systemic, or whole-body) and whole-kidney levels of Ang II, demonstrating that Ang II levels are regulated through feedback from dietary salt levels directly. However, the authors found that a high-salt diet could not reduce the impact of losartan on proximal tubule fluid reabsorption, suggesting that the Ang II effect within the proximal tubule is independent of dietary salt levels. These results were confirmed when the researchers discovered that Ang II was able to prevent a dramatic increase in the rate of fluid flow in the proximal tubule in response to high salt intake. Together, these results demonstrate that the previously assumed notion that Ang II function was to balance systemic salt levels must be re-evaluated, and reveal a novel role for Ang II in stabilizing tubule reabsorption.

TITLE: An unexpected role for angiotensin II in the link between dietary salt and proximal reabsorption

AUTHOR CONTACT:
Scott Thomson
University of California, San Diego, California, USA
Phone: (858) 552-7528; Fax: (858) 642-1438; E-mail: sthomson@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=26092

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Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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