A CYTOKINE NOT KIND TO AN INJURY OF THE SPINE
Transverse Myelitis (TM) is an autoimmune inflammatory disease of the central nervous system that is characterized by focal spinal cord demyelination and axonal injury. TM causes paralysis and other neurologic disabilities, but has limited treatment options due to a lack of understanding of its underlying mechanisms.
In a paper appearing online on September 22 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Douglas Kerr and colleagues from Johns Hopkins find that levels of the cytokine IL-6 are selectively increased in cerebrospinal fluid from TM patients. The researchers show that elevated IL-6 levels alone are necessary and sufficient to mediate injury to both neuronal and glial cells, in a manner that is dependent on nitric oxide.
This is the first description of IL-6 as a mediator of neural injury. Further, high levels of IL-6 were directly correlated with tissue injury and clinical disability, suggesting that IL-6 may be an important biomarker of TM. This new data may aid in the development of effective therapies against TM and other inflammatory diseases of the central nervous system.
TITLE: Interleukin-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder Transverse Myelitis
Johns Hopkins University School of Medicine, Baltimore, MD USA
Phone: 410-955-3129; Fax: 410-502-6736; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=25141
HOW CAN SOMETHING AS BAD AS ARSENIC BE SO GOOD FOR CANCER?
It has been shown that two treatments for acute promyelocytic leukemia (APL), Arsenic trioxide and retinoic acid (RA), can be antagonistic in vitro. In a paper appearing online on September 22 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, the same group describes a mechanism by which this occurs.
Wilson Miller and colleagues from Lady Davis Institute for Medical Research show that Arsenic trioxide inhibits transcription of the RA receptor, as well as other nuclear receptors that form complexes with the retinoid X receptor (RXR). The researchers show that this inhibition is mediated by phosphorylation of RXR on a specific serine residue in the N-terminal region, in a process that requires activation of SEK/JNK. These data may provide some insight into both the rational development of chemotherapeutic combinations involving Arsenic trioxide, as well as the molecular mechanisms of arsenic-induced carcinogenesis resulting from environmental exposure.
TITLE: Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXR phosphorylation
Lady Davis Institute for Medical Research, Montreal, CAN
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View the PDF of this article at: https://www.the-jci.org/article.php?id=23628
EPITHELIAL BARRIER DYSFUNCTION ON THE RUN
The intestinal epithelial permeability barrier is compromised in a variety of intestinal diseases, but the mechanism is not well defined. In a paper appearing online on September 22 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Jerrold Turner and colleagues from University of Chicago show that myosin light chain kinase (MLCK), an enzyme that helps regulate tight junction formation, is a critical checkpoint for T cell-mediated diarrhea.
The authors show that MLCK is a required intermediate by which T cell activation leads to intestinal epithelial barrier dysfunction. Diarrhea does not occur in epithelial MLCK knockout mice. Furthermore, the inhibitor prevents all intestinal signs and symptoms of disease. Thus, intestinal epithelial MLCK-dependent barrier dysfunction is required for T cell activation-induced diarrhea. These data demonstrate the mechanisms and critical role of barrier dysfunction in diarrheal disease. This work also identifies epithelial MLCK is a critical intermediate in intestinal barrier dysfunction and as a future therapeutic target.
TITLE: Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo.
The University of Chicago, Chicago, IL USA
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View the PDF of this article at: https://www.the-jci.org/article.php?id=24970
USING RESORPTION TO HONE THE BONE
Osteoclasts are the cells that resorb bone, and are generated from precursor cells when a protein called TRAF6 associates with the cytoplasmic domain of another protein called RANK. Understanding the process of bone resorption requires an understanding of how TRAF6 mediates RANK-induced osteoclastogenesis.
In a paper appearing online on September 22 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Steven Teitelbaum and colleagues from Washington University explore this process. The authors find that TRAF6 also interacts with a protein called FHL2, which is expressed only in activated osteoclasts. FHL2 can displace TRAF6 from RANK to decrease osteoclast formation. FHL2 therefore represents a physiological regulator of stimulated osteoclast differentiation and skeletal mass.
TITLE: FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner
Steven L. Teitelbaum
Washington University School of Medicine, St. Louis, MO USA
Phone: 314-454-8463; Fax: 314-454-5505; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=24921
UNEXPECTED ROLE FOR ENZYME IN AUTOIMMUNE DIABETES
Type 1 diabetes is an autoimmune disease characterized by destruction of insulin-producing cells in the pancreas. The animal model of this disease is a non-obese diabetic mouse, called NOD mice. In a paper appearing online on September 22 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Hidde Ploegh and colleagues from Harvard Medical School generate NOD mice that are also lacking a protein called Cathepsin L – a lysosomal protease involved in antigen presentation in the immune system.
The authors found that disrupting the Cathepsin L gene protected the usually diabetic mice from diabetes. This is because the mice have an increased proportion of regulatory T cells and decreased aggressive T cells compared to NOD mice. This protects them from developing the autoimmune disease. Therefore, Cathepsin L is an enzyme that is required for the development of type 1 diabetes in the NOD mouse model. This data shows that lysosomal proteases may contribute to the homeostasis of the T cell populations, and contribute to the development of autoimmune disease.
TITLE: Cathepsin L is essential for onset of autoimmune diabetes in NOD mice
Harvard Medical School, Boston, MA USA
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View the PDF of this article at: https://www.the-jci.org/article.php?id=25485
SKIN DISEASE AND STAPH: IT'S ALL ABOUT THE PAF
Staphylococcus aureus infections of the skin trigger inflammatory skin diseases, including atopic dermatitis. But the mechanisms by which this bacteria can modulate the immune system are not entirely clear. In a paper appearing online on September 22 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Jeffrey Travers and colleagues from Indiana University demonstrate a novel mechanism by which S. aureus, and presumably other gram-positive bacteria can evade the immune response.
In this paper, the authors show that lipoteichoic acid, a cell wall component of the S. aureus gram-positive bacteria, inhibits the induction and elicitation of delayed type hypersensitivity by binding to, and activating the platelet-activating factor (PAF) receptor. In addition, the authors demonstrate that the induction of immune suppression by lipoteichoic acid requires platelet activating factor binding and activation. Finally, lipoteichoic acid treatment induces the release of the cytokine IL-10. This work provides a novel mechanism by which staphylococcal infections can worsen skin diseases such as atopic dermatitis.
TITLE: Staphylococcal lipoteichoic acid inhibits delayed-type hypersensitivity reactions via the platelet-activating factor receptor
Indiana University School of Medicine, Indianapolis, IN USA
Phone: 317-274-8804; Fax: 317-274-5378; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25429
HOW POLYUNSATURATED FATTY ACIDS TRIM THE FAT
Dietary polyunsaturated fatty acids (PUFA) inhibit the conversion of carbohydrates and to fat. In a paper appearing online on September 22 in advance of print publication of the October 1 issue of the Journal of Clinical Investigation, Catherine Postic and colleagues from INSERM provide in vivo and in vitro evidence for a novel regulatory mechanism of the transcription factor ChREBP (carbohydrate-responsive element-binding protein) activity by PUFA in the liver and demonstrate the direct role of ChREBP in mediating the negative effect of PUFA on glycolytic and lipogenic genes.
Moreover, PUFA also alter the shuttling of ChREBP translocation from the cytosol to the nucleus, thus altering its ability to activate target genes in response to glucose. This occurs in conditions of high glucose and insulin. In contrast, the authors show that PUFA can keep ChREBP in the cytosol. This data show that ChREBP is a major player in the negative effects of PUFA on glyolytic and lipogenic genes.
TITLE: Polyunsaturated fatty acids suppress glycolytic and lipogenic gene expression through the inhibition of ChREBP nuclear protein translocation
Institut Cochin, INSERM, Paris, France
Phone: 33-1-53-73-27-07; Fax: 33-1-53-73-27-03; E-mail: email@example.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=25256
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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