Protein potentially links diet, obesity, and asthma
Australian researchers have identified a new protein in human airway epithelial cells that regulates allergic airway inflammation. This protein – adipocyte/macrophage fatty acid–binding protein aP2 – is known to regulate the uptake by fat cells of fatty acids and has been previously linked to insulin resistance in diabetes and the development of atherosclerosis. This new study suggests that in addition to its role in type 2 diabetes and hardening of the arteries, aP2 plays an essential role in allergic airway diseases such as asthma, and offers an additional intriguing link between the immune and metabolic systems. The study will appear online on July 13 in advance of print publication in the August issue of the Journal of Clinical Investigation.
The "hygiene hypothesis" currently dominates thinking in the medical field about the underlying causes of asthma. The hypothesis proposes that childhood infection and environmental factors such as diet and airborne pollution contribute to a predisposition to this condition. Michael Rolph and colleagues from The Garvan Institute of Medical Research, Sydney, now show for the first time that the protein aP2 is present in human epithelial cells lining the tubes that carry air from the windpipe to the lungs (bronchi), and that aP2 expression is significantly increased when these cells are stimulated with the molecules interleukin-4 and –13. This finding is very unexpected as aP2 has previously been considered to be a specific marker for fat cells. The group went on to show that mice lacking aP2 have a dramatic reduction in airway inflammation in a model of asthma. In addition, the infiltration into the airways of inflammatory molecules such as leukocytes and eosinophils was highly dependent on aP2 function in mice. The data emphasize the importance of lipids in the inflammatory response and contribute to the emerging theme that an overlap exists between the pathways that regulate inflammation and those that govern metabolism. Finally, the study suggests that blocking aP2 function may be a novel approach for the treatment of asthma and other inflammatory lung diseases.
TITLE: The adipocyte fatty acid–binding protein aP2 is required in allergic airway inflammation
AUTHOR CONTACT:
Michael S. Rolph
The Garvan Institute of Medical Research, Sydney, NSW, Australia.
Phone: 61-2-9295-8531; Fax: 61-2-9295-8404; E-mail: m.rolph@garvan.org.au.
OR
Gokhan S. Hotamisligil
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone (617) 432-1950; Fax: (617) 432-1941; Email: ghotamis@hsph.harvard.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=24767
GASTROENTEROLOGY
A gut reaction: neonatal Fc receptor guards against intestinal infection
The neonatal Fc receptor (FcRn) is involved in binding IgG and the embryonic acquisition of IgG from the mother through absorption across the lining of the intestine. Until now, the role that FcRn played in the intestine beyond neonatal life has remained a mystery. In a study in mice appearing online on July 13 in advance of print publication in the August issue of the Journal of Clinical Investigation, Richard Blumberg and colleagues at Harvard Medical School demonstrate for the first time that FcRn, through it's ability to secrete IgG, provides defense against infection by the gut bacterium Citrobacter rodentium. Animals that lacked FcRn were sensitive to Citrobacter rodentium infection. The ability to clear Citrobacter was associated with significant enhancement of the adaptive immune response in regional lymphoid organs. These data define the physiologic function of FcRn in the intestinal epithelium as a means to provide host immune surveillance against encounters with luminal and epithelial pathogens.
TITLE: Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria
AUTHOR CONTACT:
Richard S. Blumberg
Harvard Medical School, Boston, Massachusetts, USA.
Phone : (617) 732-6917; Fax: (617) 264-5185; E-mail: rblumberg@partners.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=27821
DERMATOLOGY
Embryonic mutation of FGFR3 gene linked to thickening of the skin
Approximately 1 in 1,000 people suffer from localized areas of thickened skin called epidermal nevi. However, the genetic basis of this condition has remained elusive, until now. In a study appearing online on July 13 in advance of print publication in the August issue of the Journal of Clinical Investigation, Christian Hafner and colleagues from the University of Regensburg examined epidermal nevi from 33 patients and found that in 33% of patients studied the epidermal nevi were caused by mosaicism of activating mutations in the human epidermis of the gene FGFR3 (fibroblast growth factor receptor 3). These appeared to result from mutations that occurred during embryonic development of these individuals. Since molecular-targeted inhibitors of FGFR3 are already available, topical treatment of the sometimes very disfiguring epidermal nevi with these inhibitors may represent a promising non-invasive therapeutic option, especially in children.
TITLE: Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi
AUTHOR CONTACT:
Christian Hafner
University of Regensburg, Regensburg, Germany.
Phone: 49-941-944-9610; Fax: 49-941-944-9611; E-mail: christian.hafner@klinik.uni-regensburg.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28163
PULMONARY
Inflamed about the A2B adenosine receptor in the lung
Adenosine is a signaling molecule that is generated at sites of tissue injury and inflammation. In a study appearing online on July 13 in advance of print publication in the August issue of the Journal of Clinical Investigation, Michael Blackburn and colleagues from University of Texas Medical School demonstrate that adenosine signaling through the A2B adenosine receptor (A2BAR) plays a role in the regulation of pulmonary inflammation. The authors examined mice lacking the enzyme adenosine deaminase (ADA), which metabolizes adenosine, and found that they develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. When ADA-deficient mice were treated with a selective blocker of A2BAR they experienced less pulmonary inflammation, fibrosis, and enlargement of alveolar airspace, compared to untreated mice. The results of this study suggest that A2BAR signaling influences pathways critical for lung inflammation and injury. Therefore, in chronic lung diseases associated with increased levels of adenosine, blocking A2BAR-mediated responses may prove to be a beneficial therapy.
TITLE: Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury
AUTHOR CONTACT:
Michael, R. Blackburn
University of Texas Medical School at Houston, Texas, USA.
Phone: (713) 500-6087; Fax: (713) 500-0652; E-mail: michael.r.blackburn@uth.tmc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27303
IMMUNOLOGY
SXR and NF-kappaB crosstalk links drug metabolism and inflammation
The enzyme CYP3A4 is responsible for the metabolism of more than 50% of clinically used drugs and other chemicals not normally found within the human body (known as xenobiotics). CYP3A4 expression is regulated in part by the steroid and xenobiotic receptor (SXR). It has long been known that inflammation and infection inhibit the expression of CYP genes, and exposure to xenobiotic chemicals can impair immune function. However, the molecular bases for these 2 phenomena have remained unknown.
In a study appearing online on July 13 in advance of print publication in the August issue of the Journal of Clinical Investigation, Bruce Blumberg and colleagues from the University of California, Irvine, show that activation of SXR by drugs commonly used by humans inhibits the activity of NF-kappaB in mice, a key regulator of inflammation and the immune response. They go on to show that activation of the NF-kappaB pathway reciprocally inhibits SXR activity and SXR target genes. The crosstalk between SXR and NF-kappaB signaling pathways establishes an important relationship between drug/xenobiotic metabolism and the inflammatory and immune responses. The results of this study also suggest that there may be clinical consequences, particularly the observation of anti-inflammatory effects, in individuals undergoing exposure to the wide variety of drugs that are also SXR agonists.
TITLE: Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation
AUTHOR CONTACT:
Bruce Blumberg
University of California, Irvine, California, USA.
Phone: (949) 824-8573; Fax: (949) 824-4709; E-mail: blumberg@uci.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=26283
Journal
Journal of Clinical Investigation