From Journal of Clinical Investigation
JCI table of contents, July 15, 2003 1. An aspirin a day keeps Staphylococcus aureus away
In the July 15 issue of The Journal of Clinical Investigation, Ambrose Cheung and colleagues at Dartmouth School of Medicine in New Hampshire, USA, report that salicylic acid (SAL), the major metabolite of aspirin, downregulates two Staphylococcus aureus genes key to this organism's pathogenesis.
Over 100 years have passed since S. aureus was first described as the organism responsible for causing sepsis and abscesses. Today it remains a leading cause of serious infections such as endocarditis, pneumonia, and septicemia and requires intensive antibiotic therapy, which is often unsuccessful due to the rise of antibiotic resistant strains.
Aspirin has previously been shown to reduce the virulence of S. aureus in models of endocarditis. In an earlier study, this same group found that while administration of aspirin or its metabolite, SAL, was capable of reducing the ability of S. aureus to attach to host cells, the effect was significantly enhanced following SAL administration.
In this issue of the JCI, Cheung and colleagues extend these earlier findings and report that treatment with SAL induced activation of the S. aureus stress response gene sigB, resulting in downregulation of regulons sarA and agr, which control the expression of the genes encoding a-hemolysin and fibronectin. This downregulation resulted in decreased ability of the bacteria to adhere to host cells, and reduced S. aureus toxin-mediated hemolysis and thrombolysis of host cells.
"The establishing of a straightforward, unequivocal strategy to downregulate staphylococcal virulence using a cheap, simple, relatively non-toxic, resorbable compound such as SAL may be seen as major progress in the development of intervening strategies in addition to antimicrobial drugs" stated Professor Mathias Herrmann, Director of the Department of Bacteriology and Hygiene at the University of Saarland, Germany in his accompanying commentary. The report is the first description of aspirin-mediated genetic effects against S. aureus and represents an exciting new prospect for this widely used and established drug.
TITLE: Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus
Ambrose L. Cheung
Dartmouth Medical School, Hanover, New Hampshire, USA.
View the PDF of this article at: https://www.the-jci.org/press/16876.pdf
Salicylic acid: an old dog, new tricks, and staphylococcal disease
University of Saarland Hospital, Homburg/Saar, Germany.
View the PDF of this commentary at: https://www.the-jci.org/press/19143.pdf
2. Epitope plays a key role in the development of rheumatoid arthritis
Rheumatoid arthritis is a chronic inflammatory disease characterized by joint destruction. It has been suggested that the extracellular matrix protein osteopontin (OPN), which is expressed by a number of different mediators of the immune response, may facilitate this destruction. In the July 15 issue of The Journal of Clinical Investigation, Nobuchika Yamamoto and colleagues from the Fujisawa Pharmaceutical Company in Japan, provide important new evidence indicating a role for OPN in the pathogenesis of inflammatory arthritis and associated joint destruction.
OPN is abundant in bone, where it facilitates cell adhesion and modulation of the immune response. This adhesion is facilitated by interaction with a variety of cell surface molecules known as integrins. Binding of OPN to these cell surface molecules generally occurs at a specific integrin-binding motif. A second sequence, (SLAYGLR in mice and SVVYGLR in humans) within OPN has also been shown to mediate this cell adhesion. The site is the result of cleavage of human OPN by the protease thrombin and promotes the adherence of cells expressing intergrins a4 and a9.
In their latest report, Yamamoto and colleagues observed that monocytes of arthritic mice had a greater tendency to migrate toward thrombin-cleaved OPN, than full-length OPN, and that these monocytes expressed integrins a4 and a9 that bind the SLAYGLR epitope. Furthermore, the authors demonstrated that antibody blockade of the SLAYGLR sequence stopped monocyte migration to the cleaved OPN and significantly suppressed the development of arthritis in mice. The study indicates the critical role of the SLAYGLR sequence in the pathogenesis of rheumatoid arthritis in mice.
"The effects on the clinical and histologic parameters studied provide convincing additional evidence for a role of OPN in arthritic inflammation, and specifically in the recruitment of inflammatory cells to arthritic joints" stated Dr. Ellen Gravallese from Beth Israel Deaconess Medical Center and Harvard Institutes of Medicine in her accompanying commentary. She continues "given the clear and important role of OPN in inflammatory processes and bone remodeling, it will be of considerable interest to resolve some of the remaining controversies regarding the role of OPN in this disease".
TITLE: Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Ibaraki, Japan.
View the PDF of this article at: https://www.the-jci.org/press/17778.pdf
Osteopontin: a bridge between bone and the immune system
Ellen M. Gravellese
Harvard University, Boston, Massachusetts, USA.
View the PDF of this commentary at: https://www.the-jci.org/press/19190.pdf
3. Stem cells found to home towards the injured liver
The now recognized plasticity of stem cells challenges researchers to further define the mechanisms responsible for their recruitment and differentiation, so that they may ultimately become clinically useful in the repair of injured organs.
In the July 15 issue of The Journal of Clinical Investigation, a collaborative research team led by Tsvee Lapidot and colleagues at the Weizmann Institute of Science in Israel, and also including researchers from the Albert Einstein College of Medicine and Mount Sinai Medical Center in New York, Institut Pasteur in Paris, and the Chaim Sheba Medical Center, Israel, have reported a study that greatly contributes to our understanding of how hematopoietic stem cells (HSCs) home to injured liver tissue and contribute to tissue repair. The authors reveal that migration of HSCs to the liver is a selective, non-random event, requiring the expression of the signaling chemokine SDF-1 and the receptor CXCR4. The pathways that facilitate crosstalk between HSCs and injured liver tissue may serve as targets for future therapeutic protocols in the field of liver regeneration and transplantation.
TITLE: HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver
The Weizmann Institute of Science, Rehovot, Israel.
View the PDF of this article at: https://www.the-jci.org/press/17902.pdf
Online First articles
Increasing tolerance to contact allergens
Common contact allergies are triggered by allergens that affect the skin such as poison oak, poisin ivy, latex, dyes, fragrances, and metals. Researchers at the University of Mainz, Germany, have now shown that IL-10, a critical mediator of the immune response, is required in order to build-up tolerance to such allergens. The authors achieve what is known as low zone tolerance (LZT), in which repeated applications of low doses of contact allergens hinders the development of the allergic reaction. They demonstrate that mice lacking IL-10 cannot achieve LZT to allergens, suggesting that this IL-10–driven response may be utilized in allergic therapies.
TITLE: Critical role of IL-10 in the induction of low zone tolerance to contact allergens
Department of Dermatology, University of Mainz, Mainz, Germany.
View the PDF of this article at: https://www.the-jci.org/press/18106.pdf
Obesity results from a massive expansion of fat cells. This expansion involves the differentiation of early precursor fat cells, known as preadipocytes, into mature fat cells. Researchers at Rockefeller University in New York have revealed that preadipocytes stably expressing the Foxa-2 protein do not differentiate into mature fat cells. Furthermore, in multiple rodent models of obesity they observed that Foxa-2 production is increased, in what may be an important counterregulatory mechanism to prevent the expansion of fat cell numbers. While the stimuli that induce Foxa-2 expression in mature fat cells is unknown, the authors propose that the pathways involved may serve as a new target for pharmaceutical interventions of both obesity and diabetes.
TITLE: The role of Foxa-2 in adipocyte metabolism and differentiation
Laboratory of Metabolic Diseases, Rockefeller University, New York, New York, USA.
View the PDF of this article at: https://www.the-jci.org/press/18698.pdf
During cancer the IFN-a battle plan is: attack the host
High dose cytokine therapy is used for cancer treatment, but little is known regarding the targets of these drugs or the intracellular signaling pathways they activate within the body. Researchers at The Ohio State University in Columbus, Ohio, report that the cytokine IFN-a exerts its antitumor actions primarily via its ability to stimulate immune effectors in the host rather than through a direct effect on malignant cells. Using a mouse model of malignant melanoma, the team demonstrated that it is the STAT1 signaling pathway within the host, and not within the tumor cells, which mediates the antitumor effects of IFN-a therapy. These investigations may ultimately permit the identification of characteristics or symptoms of the patient that correlate with their responsiveness to IFN-a therapy.
TITLE: The antitumor effects of IFN-a are abrogated in a STAT1-deficient mouse
William E. Carson III
The Ohio State University, Columbus, Ohio, USA.
View the PDF of this article at: https://www.the-jci.org/press/16603.pdf
Another piece of the puzzle by which insulin controls blood sugar and fat mass
The serine/threonine kinase Akt/PKB has three mammalian isoforms: Akt1 (PKBa), Akt2 (PKBb), and Akt3 (PKBg). The three isoforms show broad tissue distribution, with the Akt2 isoform predominating in insulin-responsive tissues. Researchers at Pfizer have now generated Akt2 knockout (KO) mice that show similar growth retardation to that previously reported in Akt1 KO mice. The Akt2 KO mice exhibit impaired glucose metabolism, pancreatic b cell failure, and loss of fat mass, which were not previously reported in mice lacking Akt1. The authors conclude that both Akt1 and Akt2 play a role in the regulation of growth, but only Akt2 regulates glucose metabolism and fatty tissue mass. In addition, Akt2 is critical for the adaptive response of pancreatic b cells to insulin resistance and hyperglycemia.
TITLE: Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBb
Robert S. Garofalo
Pfizer Global Research and Development, Groton, Connecticut, USA.
View the PDF of this article at: https://www.the-jci.org/press/16885.pdf
Mathematics predicts antibiotic resistance and how to avoid it
As the discovery of new antibiotics lags, we are faced with a growing number of bacteria that have become resistant to commonly used antibiotics. Researchers from Albany Medical College and the Ordway Research Institute in Albany, New York, analyzed the response of defined bacterial populations to increasing drug exposure and devised a mathematical model that predicts the response of drug-sensitive and -resistant bacteria and ultimately identifies the drug concentration necessary to suppress a resistant mutant population. Directly applicable to a clinical setting, the model would allow easy determination of the antibiotic dose required to treat infection and also suppress the development of antibiotic-resistant organisms.
TITLE: Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy
George L. Drusano
Ordway Research Institute, Albany, New York.
View the PDF of this article at: https://www.the-jci.org/press/16814.pdf
Fighting fibrosis in liver disease
Liver injury and fibrosis are cardinal features of most chronic human liver diseases and they result from inflammation and the self-programmed death (apoptosis) of hepatocyte cells in the liver. Researchers at the Mayo Clinic in Rochester, Minnesota report that it is the lysosomal pathway that primarily dominates hepatocyte apoptosis. They also demonstrate a direct link between hepatocyte apoptosis and fibrosis. The data suggests that inhibition of apoptosis and perhaps the lysosomal pathway of apoptosis are important in the prevention of fibrosis and a number of other liver diseases.
TITLE: Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis
Gregory J. Gores
Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota, USA.
View the PDF of this article at: https://www.the-jci.org/press/17740.pdf
Blocking the immune response to transplanted tissue: it's all in the timing
Controlling a recipient's immune response to transplanted tissue, in order to negate transplant rejection, is an ongoing challenge in the field of transplantation. The inducible costimulatory molecule (ICOS) participates in T cell activation and differentiation and blockade of this molecule has been shown to prolong graft survival. Researchers at Brigham and Women's Hospital in Boston, Massachusetts, now report that the timing of ICOS pathway blockade is important in determining the clinical outcome of graft survival. The authors demonstrate that while both early and delayed ICOS blockade prolonged graft survival, the effect was significantly greater following delayed blockade. The data have important implications when considering the development of tolerance-inducing transplantation protocols with the aim of achieving long-term graft survival.
TITLE: The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity
Mohamed H. Sayegh
Brigham and Women's Hospital, Boston, Massachusetts, USA.
View the PDF of this article at: https://www.the-jci.org/press/17008.pdf
Neph1 as the gatekeeper in the kidney
Recent studies have identified a central role for the podocyte slit diaphragm as a size-selective barrier for plasma macromolecules in the kidney, and extensive progress has been made in identifying key proteins contributing to the structure and function of this filter. Researchers from Northwestern University, Chicago, Illinois, now show that Neph1 is localized to the slit diaphragm and is directly involved in determining permeability through interactions with resident anchoring proteins ZO-1 and nephrin. Antibody-induced disruption of the Neph1-Nephrin interaction in vivo resulted in complement- and leukocyte-independent proteinuria. This study points to new possibilities for studying the pathogenesis of proteinuria.
TITLE: Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability
Sumant S. Chugh
Northwestern University, Chicago, Illinois, USA.
View the PDF of this article at: https://www.the-jci.org/press/18242.pdf
Speeding surfactant production with KGF
Pulmonary surfactant lowers the surface tension at the air/liquid interface in the lung and prevents alveolar instability and small airway closure. Produced by type II alveolar epithelial cells, surfactant is composed predominantly of phospholipids. Understanding the regulation of lipid synthesis is important for developing new therapeutic strategies for increasing endogenous surfactant production. In order to characterize this system, researchers at the National Jewish Medical and Research Center in Denver, Colorado, identified culture conditions that stimulate lipogenesis in type II cells. Keratinocyte growth factor (KGF) increased synthesis of surfactant phospholipids and was found to regulate the expression of key transcription factors, lipogenic enzymes, and transport proteins responsible for lipid production. This data may stimulate further work on the regulation of surfactant phospholipid biosynthesis.
TITLE: Keratinocyte growth factor and the transcription factors C/EBPa, C/EBPd, and SREBP-1c regulate fatty acid synthesis in alveolar type II cells
Robert J. Mason
National Jewish Medical and Research Center, Denver, Colorado, USA.
View the PDF of this article at: https://www.the-jci.org/press/16793.pdf
Antibodies regulating myasthenia gravis
Specific regulatory T (Treg) cells play a major role in keeping T cells from responding to self antigens. Researchers at Université Paris, France, now show that one type of Treg cell, T cell receptor (TCR) peptide-specific regulatory CD4 T cells, may play a key role in the control of the autoimmune disease myasthenia gravis (MG). The authors explore the occurrence, reactivity, and regulatory role of anti-TCR antibodies against a T cell population expressing the V_5.1 TCR gene, which is responsible for the production of pathogenic antiacetylcholine receptor autoantibodies in patients with early-onset MG. High levels of anti-V_5.1 IgG antibodies in HLA-DR3+ MG patients were present, providing evidence for their spontaneous increase in the absence of prior TCR vaccination. These data suggest that there is a natural regulatory process involving B cells directed to TCR determinants, which may be boosted by TCR peptide vaccines for treatment of MG.
TITLE: Circulating regulatory anti–T cell receptor antibodies in patients with myasthenia gravis
Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
View the PDF of this article at: https://www.the-jci.org/press/16039.pdf
High acid levels may contribute to vascular disease
Nitric oxide (NO) is generally protective against the thickening and fatty degeneration of the interior walls of blood vessels, known as atherosclerosis. This vessel degeneration is a common cause of morbidity and mortality in chronic renal failure. Reduced NO expression results from reduced epithelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS) expression. Researchers at Freie Universität Berlin, Germany, report that patients with end-stage renal failure accumulate high levels of phenylacetic acid (PAA) in their plasma, capable of inhibiting iNOS expression. The authors suggest that the PAA-induced inhibition of iNOS in patients with chronic renal failure may contribute to increased atherosclerosis and cardiovascular morbidity.
TITLE: Increased plasma phenylacetic acid in patients with end-stage renal failure inhibits iNOS expression
Freie Universität Berlin, Berlin, Germany.
View the PDF of this article at: https://www.the-jci.org/press/15524.pdf
BAFF aids survival of differentiated B cells
BAFF is a key regulator of B cell homeostasis. It has been demonstrated that in BAFF-deficient mice, B cell development is arrested at the immature stage. Conversely, mice with elevated serum levels of BAFF develop autoimmune diseases resembling human lupus. Researchers at the Centenary Institute of Cancer Medicine and Cell Biology in Sydney, Australia, have identified a novel function for BAFF: it acts as a specific survival factor for Ig-secreting cells derived from memory B cells. The study suggest that in human autoimmune diseases, elevated levels of serum BAFF may contribute to the disease process by not only breaking tolerance at the immature/transitional B cell stage of development, but by also enhancing plasmablast survival.
TITLE: BAFF selectively enhances the survival of plasmablasts generated from human memory B cells
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia.
View the PDF of this article at: https://www.the-jci.org/press/18025.pdf
Secret to controlling thyroid hormone production
Originating in the thyroid, the prohormone thyroxine is converted to triiodothyronine, which is essential in brain development, growth, and metabolism. A study from researchers at Brigham and Women's Hospital in Boston, reveals a novel mechanism for controlling triiodothyronine production that demonstrates the first example of enzyme activity being restored by deubiquitination.
TITLE: Deubiquitination of type 2 iodothyronine deiodinase by von Hippel–Lindau protein–interacting deubiquitinating enzymes regulates thyroid hormone activation
Antonio C. Bianco
Harvard University, Boston, Massachusetts, USA.
View the PDF of this article at: https://www.the-jci.org/press/18348.pdf
Ubiquitinated deiodinase: not dead yet
Ronald J. Koenig
University of Michigan Medical Center, Ann Arbor, Michigan, USA.
View the PDF of this commentary at: https://www.the-jci.org/press/19157.pdf
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