EDITOR'S PICK: Carbon monoxide protects mice from multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disorder that causes degeneration of the nerves in the brain and spinal cord, leading to various symptoms including muscle weakness and pain. Most individuals with MS go through cycles of disease and remission, leading to the suggestion that there are regulatory mechanisms that counter the disease-causing inflammation. Using a mouse model of MS (known as EAE), researchers from the Gulbenkian Institute in Portugal show that increased expression of a protein known as HO-1, as well as administration of carbon monoxide, protect mice from disease.
In the study, which appears online on January 25 in advance of publication in the February print issue of the Journal of Clinical Investigation, Miguel Soares and colleagues show that mice lacking HO-1 develop more severe EAE than wild-type mice. Conversely, in mice already suffering the symptoms of EAE, disease is reversed if HO-1 expression is induced. The function of HO-1 is to degrade excess heme (a component of many important cellular proteins) and one of the by-products of heme degradation is carbon monoxoide. Surprisingly, like the induction of HO-1 expression, administration of carbon monoxide to mice already suffering the symptoms of EAE decreased disease. The authors therefore suggest that modulating HO-1 expression or administering carbon monoxide might be useful therapeutic strategies to treat patients with MS.
TITLE: Heme oxygenase–1 and carbon monoxide suppress autoimmune neuroinflammation
AUTHOR CONTACT:
Miguel P. Soares
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Phone: +351-214464520; Fax: +351-214407970; E-mail: mpsoares@igc.gulbenkian.pt.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28844
EDITOR'S PICK: New antibody for EGFR causes lung cancer regression
Mutant forms of the protein EGFR are important for the development of lung cancer in a substantial proportion of individuals with this disease. However, not all individuals express the same mutant EGFR, for example, some have a mutation that affects the intracellular part of EGFR and some have a mutation that affects the extracellular part of EGFR (known as the EGFRvIII mutant). The potential of therapeutics to benefit individuals with lung cancer caused by the distinct EGFR mutants can be examined using two mouse models of lung cancer, one driven by expression of EGFR with a mutation in the intracellular part of the protein and one driven by expression of the EGFRvIII mutant.
In a study appearing online on January 25 in advance of publication in the February print issue of the Journal of Clinical Investigation, Kwok-Kin Wong and colleagues from the Dana-Farber Cancer Institute in Boston show that a mouse antibody that binds EGFR (mAb806) causes the regression of lung tumors in both models of lung cancer. By contrast, a second antibody that binds EGFR (cetuximab), and that is already in clinical use for the treatment of a specific subset of patients with lung cancer, only induced tumor regression in mice with lung tumors driven by expression of EGFR with a mutation in the intracellular part of the protein. Importantly, the humanized form of mAb806 (ch806) caused regression of lung tumors in both models of lung cancer. The data presented in this study therefore indicate that ch806 might provide a new therapeutic for the treatment of patients with lung cancer driven by mutant forms of EGFR, in particular the EGFRvIII mutant.
TITLE: Therapeutic anti-EGFR antibody 806 generates responses in murine de novo EGFR mutant–dependent lung carcinomas
AUTHOR CONTACT:
Kwok-Kin Wong
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 632-6084; Fax: (617) 582-7839; E-mail: Kwong1@partners.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30446
METABOLIC DISEASE: Adiponectin helps clear away apoptotic cells
Although it is becoming clear that inflammation induced by obesity is an important factor linking obesity to type 2 diabetes, the effects of one of the most abundant soluble factors known to have both anti-inflammatory and anti-diabetic effects (adiponectin) remain to be completely determined. But now, in a study appearing online on January 25 in advance of publication in the February print issue of the Journal of Clinical Investigation, researchers from Boston University show that in mice, adiponectin facilitates the uptake, by immune cells known as macrophages, of cells dying by a process known as apoptosis.
Kenneth Walsh and colleagues found that mice lacking adiponectin were impaired in their ability to clear apoptotic cells when there were very high numbers of apoptotic cells present. By contrast, mice administered adiponectin exhibited enhanced macrophage uptake of apoptotic cells when there were very high numbers of apoptotic cells present. Further analysis showed that adiponectin bound the apoptotic cells and provided a bridge between the apoptotic cells and a protein on the surface of the macrophages known as calreticulin. As the accumulation of large numbers of apoptotic cells triggers inflammation, the authors of this study have identified another anti-inflammatory mechanism of adiponectin. This might contribute to the link between inflammation and diabetes because adiponectin levels are decreased in individuals who are obese.
TITLE: Adiponectin modulates inflammatory reactions via calreticulin receptor–dependent clearance of early apoptotic bodies
PRESS CONTACT:
Gina DiGravio
Media Relations
Boston Medical Center, Boston, Massachusetts, USA.
Phone: (617)-638-8491; E-mail: gina.digravio@bmc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29709
ONCOLOGY: Ha-ras goes it alone in bladder cancer
Cancer occurs when a particular cell or group of cells begins to grow in an uncontrolled manner. Such uncontrolled growth can be caused by an increase in the activity of proteins that promote cell growth, by a decrease in the activity of proteins that inhibit cell growth, or a combination of these two. In most tumors of the bladder, the activity of the protein Ha-ras, which promotes cell growth, is increased. However, it has been unclear whether increased Ha-ras activity is sufficient to cause bladder cancer, or even if it is necessary for bladder cancer to develop.
In a study appearing online on January 25 in advance of publication in the February print issue of the Journal of Clinical Investigation, Xue-Ru Wu and colleagues from New York University show that low levels of increased Ha-ras activity are insufficient to induce bladder tumors in mice. Surprisingly, combining this low level increase in Ha-ras activity with loss of a protein that inhibits cell growth (Ink4a/Arf) did not induce bladder tumors. However, doubling the activity of Ha-ras rapidly induced the growth of bladder tumors in all the mice analyzed, indicating that the extent of Ha-ras increased activity influences whether or not it induces the development of bladder tumors. The authors therefore suggest that targeting this molecule, as well as signaling molecules downstream of it, might provide a new avenue of research for the development of agents to treat bladder cancer in humans.
TITLE: Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis
AUTHOR CONTACT:
Xue-Ru Wu
New York University School of Medicine, Manhattan Veterans Affairs Medical Center, New York, New York, USA.
Phone: (212) 951-5429; Fax: (212) 951-5424; Email: xue-ru.wu@med.nyu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30062
BACTERIOLOGY: How one bacterium causes diarrhea
Infection with enteropathogenic E. coli (EPEC) is a major cause of diarrhea in infants and has a high rate of mortality. Developing new approaches to treat individuals infected with this bacterium requires increasing our understanding of the mechanisms by which it causes diarrhea. In a study appearing online on January 25 in advance of publication in the February print issue of the Journal of Clinical Investigation, Ravinder Gill and colleagues from the University of Illinois at Chicago, show that the exchange of Cl– and OH– by intestinal cells (something that if disturbed can lead to diarrhea) is inhibited by the bacterial proteins EspG and EspG2 in both human cells infected with EPEC in vitro and mice infected with EPEC. Further analysis revealed that EspG and EspG2 inhibit the exchange of Cl– and OH– by decreasing the amount of a protein known as DRA at the surface of intestinal cells. This study therefore identifies a potential mechanism by which infection with EPEC could cause diarrhea.
TITLE: Mechanism underlying inhibition of intestinal apical Cl–/OH– exchange following infection with enteropathogenic E. coli
AUTHOR CONTACT:
Ravinder K. Gill
University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois, USA.
Phone: (312) 569-6498; Fax: (312) 569-6487; E-mail: rgill@uic.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29625
Journal
Journal of Clinical Investigation