JCI table of contents: June 14, 2007

In a study appearing online on June 14 in advance of publication in the July print issue of the Journal of Clinical Investigation, researchers at Charite – Universitatsmedizin Berlin report that the molecule known as TRAIL can limit excessive immune responses in bacterial meningitis and as such may be of use to control inflammation of the spinal cord and brain, which causes brain cell death in this life-threatening disease.

Pneumococcal meningitis involves inflammation of the protective membranes covering the brain and spinal cord and is caused by infection with the bacterium Streptococcus pneumoniae. The observed swelling of the brain is largely the result of the excessive immune response to infection. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been previously reported to play a role in the regulation of the host immune response. In the current study, Joerg Weber and colleagues administered components of Streptococcus pneumoniae bacteria to the cerebrospinal fluid bathing the brain and spinal cord of mice lacking TRAIL. They found that these animals suffered from increased inflammation and brain cell death, however these effects were reversed by the administration of recombinant TRAIL (rTRAIL). Importantly, the application of rTRAIL to mice with intact TRAIL and meningitis also decreased inflammation and neuronal cell death. Finally, the authors observed that human patients with bacterial meningitis showed increased synthesis in the cerebrospinal fluid of TRAIL. The results of the study provide evidence that TRAIL acts to limit inflammation of the brain and spinal cord during bacterial meningitis, suggesting that it may be of use as an anti-inflammatory agent in invasive bacterial infections.

TITLE: TRAIL limits excessive host immune responses in bacterial meningitis

AUTHOR CONTACT:
Joerg Weber
Charite – Universitatsmedizin Berlin, Berlin, Germany.
Phone : 49-30-450-528002; Fax:40-30-450-528902; E-mail: joerg.weber@charite.de

View the PDF of this article at: https://www.the-jci.org/article.php?id=30356

Researchers have identified an interaction between the molecules transient receptor potential A1 (TRPA1) and proteinase-activated receptor 2 (PAR2) that may explain how we sense the pain caused by inflammation.

TRPA1 is present on a population of neurons and it forms channels that are important in sending signals in response to environmental irritants or other agents that cause inflammatory pain. PARs, also present on neurons, are known to play an important role in the response to tissue injury, notably in the process of inflammation and repair. Tryptase and trypsin, which are released from immune cells after injury, activate PAR2.

In their study appearing online on June 14 in advance of publication in the July print issue of the Journal of Clinical Investigation, Koichi Noguchi and colleagues from Hyogo College of Medicine, Japan, report that TRPA1 and PAR2 are significantly co-expressed in dorsal root ganglion neurons in rats and that PAR2 activation potentiates TRPA1 activity, resulting in the amplification of the pain sensation. They go on to show that this signaling pathway is dependent on the presence of the enzyme phospholipase C. The results represent a novel mechanism through which trypsin or tryptase released in response to tissue inflammation may trigger the sensation of pain through PAR2 activation. Therefore, compounds acting on TRPA1 or interfering with the interaction between TRPA1 and PAR2 may be useful in the treatment of inflammatory pain.

TITLE: Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain

AUTHOR CONTACT:
Koichi Noguchi
Hyogo College of Medicine, Hyugo, Japan.
Phone : 81-798-45-6415; Fax: 81-798-45-6417; E-mail: noguchi@hyo-med.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=30951

The hormone progesterone is vital to ovulation and pregnancy, however various aspects of its roles throughout pregnancy are not well understood. A hurdle to expanding our knowledge of the effects of progesterone is the fact that progesterone-deficient mice cannot produce offspring. However, as FKBP52 is a molecule that acts to optimize signaling through the progesterone receptor, Fkbp52-/- mice provide a unique opportunity to study the roles of progesterone signaling throughout pregnancy.

In a study appearing online on June 14 in advance of publication in the July print issue of the Journal of Clinical Investigation, Sudhansu Dey and colleagues from Vanderbilt University first established that embryo implantation in the uterus in female Fkbp52-/- mice was not successful, mimicking the effect of the loss of progesterone, however daily progesterone supplementation enabled successful implantation of embryos in female Fkbp52-/- mice of one genetic background (referred to as C57BL6/129 Fkbp52-/- mice), but not another (CD1 Fkbp52-/- mice). The results indicate that FKBP52 deficiency-induced loss of uterine progesterone signaling is genetic background-specific. The authors went on to show that while progesterone supplementation at higher than normal pregnancy levels enabled progesterone receptor signaling sufficient for embryo implantation in the uterus in female CD1 Fkbp52-/- mice, these levels were not sufficient to maintain pregnancy to full term. Progesterone levels had to be further elevated to achieve successful term pregnancy and a normal litter size.

In summary, the data reflect that the indispensability of FKBP52 in uterine progesterone signaling is genetic background- and pregnancy stage-specific. As there is evidence of a correlation between progesterone supplementation and a reduction in the risk of recurrent miscarriages and endometriosis in progesterone-deficient women, these findings have clinical implications for a genetically diverse population of women.

TITLE: FKBP52 deficiency-conferred uterine progesterone resistance is genetic background and pregnancy stage specific

AUTHOR CONTACT:
Sudhansu K. Dey
Vanderbilt University, Nashville, Tennessee, USA.
Phone: (615) 322-8642; Fax: (615) 322-4704; Email: sk.dey@vanderbilt.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31622

During dilated cardiomyopathy (DCM) the heart is weakened, enlarged, and no longer able to pump blood efficiently. In a study appearing online on June 14 in advance of publication in the July print issue of the Journal of Clinical Investigation, Naoki Mochizuki and colleagues from the National Cardiovascular Center Research Institute, Osaka, Japan, investigated the critical role of the proteins Gab1 and Gab2 in maintaining normal heart muscle function.

The authors examined mice lacking both Gab1 and Gab2, specifically in cardiomyocytes, and found that these animals exhibited dilated and malformed cardiac blood vessels and reduced cardiac contractility. They also found that Gab1 and Gab2 serve as essential mediators of signaling through the molecule neuroregulin-1beta (NRG-1beta). In their subsequent studies to better understand how the defect of NRG-1beta and Gab1/Gab2 signaling causes DCM, the authors found that angiopoietin 1 expression, which promotes blood vessel formation, is promoted by NRG-1beta and that this interaction is blocked in Gab1/Gab2 double-knockout mice. This lack of response to NRG-1beta may well account for the loss of cardiac contractility and malformed vessels observed in the hearts of these mice and provides insight into the signaling events that underlie DCM.

TITLE: Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling

AUTHOR CONTACT:
Naoki Mochizuki
National Cardiovascular Center Research Institute, Osaka, Japan.
Phone : 81-6-6833-5012 Ext: 2508; Fax :81-6-6835-5461; E-mail : nmochizu@ri.ncvc.go.jp

Yoshikazu Nakaoka
Osaka University Graduate School of Medicine, Osaka, Japan.
PhoneL 81-6-6879-3835; Fax: 81-6-6879-3839; Email: ynakaoka@imed3.med.osaka-u.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=30651

Niemann-Pick disease refers to a group of inherited metabolic disorders known as lipid storage diseases in which harmful amounts of fatty substances, such as cholesterol, build up in the spleen, liver, lungs, bone marrow, and brain, causing loss of muscle coordination and brain degeneration. The cholesterol-lowering drug Ezetimibe decreases cholesterol absorption in the intestine by targeting the protein Neimann-Pick C1-like 1 (NPC1L1). However, NPC1L1 is also expressed in the liver. In a study appearing online on June 14 in advance of publication in the July print issue of the Journal of Clinical Investigation, Liqing Yu and colleagues from Wake Forest University School of Medicine report that liver NPC1L1 allows the retention of cholesterol by liver cells and is also affected by Ezetimibe.

The authors found that mice created to overexpress human NPC1L1 in liver cells had a 30%-60% increase in plasma cholesterol levels. Administration to the mice of Ezetimibe normalized plasma cholesterol levels suggesting that Ezetimibe treatment in humans may reduce plasma cholesterol levels by inhibiting NPC1L1 in both intestine and liver and that liver NPC1L1 may have evolved to help protect the body from excessive changes in cholesterol levels.

TITLE: Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe

AUTHOR CONTACT:
Liqing Yu
Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Phone : (336) 716-0920; Fax : (336) 716-6279; E-mail: lyu@wfubmc.edu

Mark Wright
Director, Office of Public Relations
Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Phone: (336) 716-3382; Email: mwright@wfubmc.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=30060

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes and is strongly associated with obesity. In a study appearing online on June 14 in advance of publication in the July print issue of the Journal of Clinical Investigation, Gerald Shulman and colleagues from Yale University Medical School report that overexpression of uncoupling protein 3 (UCP3) in the skeletal muscle of mice is able to protect against the development of high-fat diet-induced insulin resistance.

Uncoupling proteins act to convert stored fat into thermal energy. In the current study the authors began by showing that mice fed a high-fat diet were markedly insulin resistant, a result of defects in insulin signaling in skeletal muscle and liver. In contrast, mice overexpressing UCP3 in skeletal muscle experienced increased whole body energy expenditure and were completely protected against fat-induced defects in insulin signaling and action in these tissues. They went on to delineate the events at the cellular levels that underlie this protective mechanism and suggest that some of these cellular events may serve as excellent therapeutic targets for the treatment of type 2 diabetes.

TITLE: Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance

AUTHOR CONTACT:
Gerald I. Shulman
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone : (203) 737-5447; Fax: (203) 737-4059; E-mail: gerald.shulman@yale.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=13579