JCI table of contents: July 19, 2007

Mucins are large proteins that are secreted on the surface of the gut, and while long regarded as having a role as a barrier to mucosal infection, data to support this theory have been lacking. In a study appearing online on July 19 in advance of publication in the August print issue of the Journal of Clinical Investigation, Michael McGuckin and colleagues from the University of Queensland, Australia, show that cell surface mucin 1 (Muc1) plays a critical role in protecting the mucosal lining of the gut from bacterial infection.

These authors orally infected mice with the bacterial pathogen Campylobacter jejuni (a common cause of diarrhea) and found that 1 week after infection this organism could be detected in the organs of the vast majority of mice lacking Muc1, but never in mice with intact Muc1. Although this organism was able to enter the gastrointestinal epithelial cells lining the gut of both Muc1-deficient and Muc1-intact mice, intestinal damage was more common in Muc1-deficient animals, and the authors determined that the prevention of the spread of infection was exclusively due to Muc1 on the surface of gut epithelial cells. This is believed to be the first study in animals to demonstrate that cell surface mucins are a critical component of mucosal defense, and the role of these proteins in epithelial infections and inflammatory disease should be further examined.

TITLE: MUC1 cell surface mucin is a critical element of the mucosal barrier to infection

AUTHOR CONTACT:
Michael A. McGuckin
University of Queensland, South Brisbane, Queensland, Australia.
Phone : 61-7-3840-2568; Fax: 61-7-3840-2550; E-mail: mmcguckin@mmri.mater.org.au

View the PDF of this article at: https://www.the-jci.org/article.php?id=26705

Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease in which the immune system attacks the body’s cells and tissues. Although B cells are known to play a role in this disease, the exact way in which their function is disrupted remains poorly understood. In a study appearing online on July 19 in advance of publication in the August print issue of the Journal of Clinical Investigation, Chandra Mohan and colleagues from UT Southwestern Medical Center examined different strains of lupus-prone mice in order to address this question. They report that different signaling pathways are upregulated in lupus B cells as the disease evolves. However, the very same pathways are shown to be upregulated in B cells from mice with different lupus-prone genetic backgrounds, indicating that although the genetic trigger of the disease may differ, these different triggers ultimately converge upon a shared set of signaling pathways to induce disease. Finally, the authors were able to treat lupus in these animals using a derivative of the drug rapamycin, thereby identifying one of these pathways (involving the molecules known as AKT and mTOR) as being an attractive therapeutic target in lupus.

TITLE: Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus

AUTHOR CONTACT:
Chandra Mohan
UT Southwestern Medical Center, Dallas, Texas, USA.
Phone : (214) 648-9675; Fax : (214) 648-7995; E-mail: chandra.mohan@utsouthwestern.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=30398

Noonan Syndrome (NS) is a relatively common congenital genetic condition characterized by congenital heart malformation, short stature, learning problems, indentation of the chest, impaired blood clotting, and a characteristic configuration of facial features. In a study in mice appearing online on July 19 in advance of publication in the August print issue of the Journal of Clinical Investigation, Jeffrey Robbins and colleagues from Cincinnati Children’s Hospital Medical Center show that blocking the activation of the molecule ERK1/2 can prevent the development of NS-associated heart abnormalities.

Mutations in the protein SHP2 (Scr homology region 2, phosphatase 2) occur in approximately half of all NS patients with cardiac abnormalities. Robbins et al. used transgenic mice bred to express a mutated form of SHP2 in heart muscle cells during gestation or following birth. Embryonic hearts containing the mutated SHP2 had altered cardiomyocyte cell cycling and structural defects, while expression of the mutant protein in postnatal cardiomyocytes had no effect. Fetal expression of this mutated protein was found to activate the ERK1/2 pathway and further studies confirmed that activation by mutant SHP2 was necessary and sufficient to cause the heart abnormalities. The authors went on to show that prevention of ERK1/2 activation was able to prevent the development of cardiac abnormalities, suggesting that therapeutic modulation of ERK1/2 could be a useful strategy during embryonic development for preventing this form of congenital heart disease.

TITLE: Mediating ERK1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome

AUTHOR CONTACT:
Jeffrey Robbins
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA.
Phone : (513) 636-8098; Fax: (513) 636-5958; E-mail: jef.robbins@cchmc.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=30756

Obesity, the metabolic syndrome, and type 2 diabetes are frequently characterized by insulin resistance – a condition in which normal amounts of insulin are not adequate to produce a normal insulin response from fat, muscle, and liver cells. The result is an elevation in blood glucose levels. While the causes of insulin resistance are not completely defined, previous studies have suggested that an atypical protein kinase C (aPKC), PKC-lambda, regulates insulin-stimulated glucose transport. In a study appearing online on July 19 in advance of publication in the August print issue of the Journal of Clinical Investigation, a team led by Robert Farese at the University of South Florida generated mice lacking PKC-lambda specifically in muscle tissue and found that glucose transport and the activity of the glucose transporter GLUT4 were reduced in these animals and accompanied by body-wide insulin resistance, diabetes, abnormal insulin-producing beta cells, high cholesterol, and excess fat deposition in the abdomen and liver. The results show that insulin resistance and resultant effects, owing to a specific defect in muscle PKC-lambda, is sufficient to cause abdominal obesity and other abnormalities characteristic of the metabolic syndrome and type 2 diabetes.

TITLE: Muscle-specific knockout of PCK-lambda impairs glucose transport and induces metabolic and diabetic sydnromes

AUTHOR CONTACT:
Robert V. Farese
University of South Florida College of Medicine, Tampa, Florida, USA.
Phone: (813) 972-7662; Fax: (813) 972-7623; E-mail: rfarese@health.usf.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31408

Natural killer (NK) T cells (of which type I and type II exist) are a small group of T cells in the blood that recognize and bind self- and foreign lipids. They rapidly release cytokines that can promote or suppress different immune responses, however the regulation of these responses is not well understood. In a study appearing online on July 19 in advance of publication in the August print issue of the Journal of Clinical Investigation, Vipin Kumar and colleagues from the Torrey Pines Institute for Molecular Studies examined the responses of these cells following their recognition of a self-glycolipid, sulfatide, and their relevance to inflammatory liver disease. They show that activation of sulfatide-reactive type II NKT cells caused recruitment of type I NKT cells into the liver in mice. These recruited type I NKT cells were anergic (ie. they were not able to mount a normal immune response against this self antigen) and as such were able to prevent experimentally-induced hepatitis in these animals. The authors went on to show that secretion of the cytokine IL-12 by dendritic cells in the liver and interaction of these dendritic cells with type II NKT cells was able to regulate the activity of type I NKT cells. The authors suggest that this activity could be exploited for the purpose of devising therapeutic interventions for inflammatory disease, including autoimmune diseases and asthma.

TITLE: Type II NKT cell–mediated anergy induction in type I NKT cells prevents inflammatory liver disease

AUTHOR CONTACT:
Vipin Kumar
Torrey Pines Institute for Molecular Studies, San Diego, California, USA.
Phone: (858) 455-3870; Fax: (858) 455-3804; E-mail: vkumar@tpims.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=31602

The formation of new blood vessels (angiogenesis) is essential to provide nutrients to growing tumors. In the past, some researchers have hypothesized that the growth factor PDGF-BB (platelet-derived growth factor BB) contributes to tumor growth and spread by enhancing the envelopment of newly formed vessels with stabilizing pericytes, and rendering new vessels more resistant to anti-angiogenic therapies. In a surprising study appearing online on July 19 in advance of publication in the August print issue of the Journal of Clinical Investigation, a team led by Lee Ellis from The University of Texas MD Anderson Cancer Center found that when PDGF-BB was overexpressed in gastrointestinal cancer cells in the lab and then injected into mice, tumor growth was actually inhibited. In additional studies they treated PDGF-BB–overexpressing tumors with the drug imatinib mesylate (also known as Gleevec), which inhibits the PDGF-BB receptor, and this resulted in reduced pericyte content and increased tumor growth compared to tumors left untreated. They believe that these effects are due to an increased number of pericytes in the tumor, which can actually limit tumor angiogenesis, and in turn limit tumor growth. The authors conclude that the use of drugs that specifically target the PDGF receptor must therefore be used with caution for the treatment of tumors in which the PDGF receptor is not the target on the tumor cell itself.

TITLE: Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content

AUTHOR CONTACT:
Lee M. Ellis
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 792-6926; Fax: (713) 792-4689; E-mail: lellis@mdanderson.org

View the PDF of this article at: https://www.the-jci.org/article.php?id=31334