The odd couple: unlikely receptor pair key to failed asthma treatments
During an asthma attack, a group of drugs known as beta2 agonists can activate the beta2-adrenergic receptor (beta2AR) present on airway smooth muscle cells, causing the airways to relax and the attack to subside. These receptors often exist in identical pairs called homodimers. More recently it has been revealed that some receptor types can exist in a pair with a different receptor, resulting in a heterodimer. In a study appearing in the May issue of the Journal of Clinical Investigation, Stephen Liggett and colleagues from the University of Maryland show that beta2AR can pair with another receptor on airway smooth muscle cells known as EP1R. Activation of this heterodimer causes beta2AR to become uncoupled from its normal signaling pathway, thereby reducing the ability of beta2 agonists to bring about airway relaxation during an asthma attack. This may be why some beta2AR–-activating drugs are not effective in some asthmatics.
Activation of EP1R by the hormone prostaglandin E2 (PGE2) causes airway smooth muscle cell constriction. In their current study, Liggett and colleagues found that PGE2 promotes the pairing or "dimerization" of EP1R with beta2AR, uncoupling b2AR from its signaling cascade, and reducing it's ability to cause muscle relaxation in response to beta2-AR–activating drugs. This may explain why in individuals with severe asthma whose PGE2 levels are elevated, some beta2-AR–-activating drugs are not effective.
In an accompanying commentary, Peter Barnes from Imperial College London reinforces how important the functional consequence of such receptor interactions can be. He muses about "the possibility of finding unexpected drug interactions or novel therapeutic agents that selectively activate certain heterodimer pairs" as well as the possibility of developing more selective drugs in the future for the treatment of asthma in individuals for whom current therapies have proven ineffective.
TITLE: Airway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-adrenergic receptors within a unique heterodimeric complex
AUTHOR CONTACT:
Stephen B. Liggett
University of Maryland School of Medicine, Baltimore, Maryland, USA.
Phone: (410) 706-6256; Fax: (410) 706-6262; E-mail: sligg001@umaryland.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=25840
ACCOMPANYING COMMENTARY
TITLE: Receptor heterodimerization: a new level of cross-talk
AUTHOR CONTACT:
Peter J. Barnes
National Heart and Lung Institute, Imperial College, London, United Kingdom.
Phone: 44-207-351-8174; Fax: 44-207-351-5675; E-mail: p.j.barnes@imperial.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28535
EDITOR'S PICK
Enzyme inhibitor may help lower cholesterol and unclog arteries
Atherosclerosis, the accumulation of cholesterol in the arteries that clogs the circulation and results in heart attacks and strokes, is a leading cause of death. One strategy for preventing heart disease and stroke is to clear out clogged arteries, restoring circulation. This process, known as reverse cholesterol transport is accomplished by the high-density lipoproteins (HDLs) in the blood. HDL transports excess cholesterol from the artery wall and macrophages and transports it to the liver, where it is excreted as bile salts and cholesterol. In a study appearing in the May issue of the Journal of Clinical Investigation, Fumihiko Matsuura and colleagues from Columbia University, New York, reveal new features of this pathway that suggest an enzyme inhibitor currently in phase III clinical trials may help reduce cholesterol levels and atherosclerosis in humans.
One proposal for boosting reverse cholesterol transport has been to elevate plasma HDL levels by inhibiting a protein called CETP that transfers cholesterol esters from HDL to lower-density lipoproteins. However, there has been controversy in the medical literature as to whether CETP deficiency is pro- or anti-atherogenic. Matsuura and colleagues assessed the ability of HDL-2 from individuals deficient in CETP to promote cholesterol removal from macrophages. They observed a 2–3-fold increase in cholesterol efflux in these individuals compared to controls and they demonstrated that this was dependent on a molecule known as ABCG1, which is present on macrophages and contributes to the formation of HDL. They also found that the enhanced ability to promote cholesterol removal in these CETP-deficient individuals was due to increased amounts of the enzyme LCAT and apolipoprotein E in HDL-2, which allow the inner cholesterol ester–rich core of HDL-2 to expand to carry greater amounts of cholesterol. In an accompanying commentary, Robert Mahley and colleagues from the University of California, San Francisco, comment that as CETP does not appear to be essential for reverse cholesterol transport in humans, this raises the hope of using a CETP inhibitor to elevate HDL levels and therefore reduce the incidence of atherosclerosis.
TITLE: HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway
AUTHOR CONTACT:
Fumihiko Matsuura
Osaka University, Osaka, Japan
Phone: 81-6-6879-3732; Fax: 81-6-6879-3739; E-mail: fc-mastu@fb4.so-net.ne.jp
View the PDF of this article at: https://www.the-jci.org/article.php?id=27602
ACCOMPANYING COMMENTARY
TITLE: Putting cholesterol in its place: apoE and reverse cholesterol transport
AUTHOR CONTACT:
Robert W. Mahley
Gladstone Institute of Neurological Disease, San Francisco, California, USA.
Phone: (415) 734-2000; Fax: (415) 355-0820; E-mail: rmahley@gladstone.ucsf.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=28632
HEMATOLOGY
Just go with the flow: how blood vessels sense and change in response to shear stress
Blood vessels must be able to quickly sense and adapt to increasing and decreasing rates of blood flow in order to maintain consistent blood pressure throughout the body. The endothelial cells (ECs) lining the vessel wall recognize shear stresses and transduce signals to vascular muscular cells and others in order to modify vessel shape and structure accordingly. In a study in the May issue of the Journal of Clinical Investigation, William Sessa and colleagues from Yale University show that the protein caveolin-1 (Cav-1) and structures known as caveolae act as sensors along the cell membrane of ECs in order to detect shear stress and help bring about appropriate reactionary remodeling of affected blood vessels.
Caveolae are distinct flask-shaped invaginated structures at the surface of ECs and consist of Cav-1 and other proteins. Sessa et al. used mice lacking Cav-1 as well as mice overexpressing Cav-1 specifically in ECs. After tying off the left carotid artery in these mice for 14 days, thereby modifying the blood flow, they found that the inside diameter of the ligated vessels was reduced in normal mice but not in Cav-1–deficient mice. In turn, re-expression of Cav-1 in ECs was sufficient to induce this change in Cav-1–deficient mice.
In an accompanying commentary, Michael Lisanti and Philippe Frank from Thomas Jefferson University further discuss the Cav-1–regulated signaling pathways in ECs and conclude that "these data suggest that endothelial caveolae and Cav-1 allow arteries to sense, organize, and mediate signal transduction, thereby giving arteries the ability to change their physical properties and to maintain/regulate normal blood flow in the face of altered shear stress conditions."
TITLE: Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels
AUTHOR CONTACT:
William C. Sessa
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 737-2213; Fax: (203) 737-2290; E-mail: william.sessa@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27100
ACCOMPANYING COMMENTARY
TITLE: Role of caveolin-1 in the regulation of the vascular shear stress response
AUTHOR CONTACT:
Michael P. Lisanti
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Phone: (215) 503-9295; Fax: (215) 923-1098; E-mail: michael.lisanti@jefferson.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28509
PULMONARY
All mice are not created equal: explanation for lung disease variability
A molecule known as IL-4 plays important roles in cell growth, inflammation, and immunity. In the lung, it is responsible for fibrosis and inflammation, which cause lung injury in conditions such as emphysema. Interestingly, researchers using animal models to study lung disease have noticed that IL-4 is capable of inducing different responses in different genetic strains of mice. In a study appearing in the May issue of the Journal of Clinical Investigation, Jack Elias and colleagues from Yale University demonstrate that genetic influences control IL-4–mediated inflammation and tissue remodeling in the lung.
The authors examined 2 different strains of mice known as Balb/c and C57BL/6 and found that IL-4 overexpression stimulates more severe allergic inflammation and fibrosis in the lungs of C57BL/6 mice than in Balb/c mice. They went on to show that these differences are, to great extent, due to differences in adenosine metabolism in these animals and can be regulated by interventions that modulate activity of the enzyme adenosine deaminase. The results of the study provide at least a partial explanation for the impressive patient-to-patient and animal-to-animal variability that is seen in the IL-4-mediated inflammatory response in humans and animal models of human disease.
TITLE: Adenosine metabolism and murine strain–specific IL-4–induced inflammation, emphysema, and fibrosis
AUTHOR CONTACT:
Jack A. Elias
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-4163; Fax: (203) 785-3826; E-mail: jack.elias@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=26372
AUTOIMMUNITY
Insulin-reactive T cells that reverse diabetes in mice
Insulin has been previously identified as the central autoantigen recognized by the destructive T cells that cause diabetes (diabetogenic T cells). In a study that appears in the May issue of the Journal of Clinical Investigation, Li Wen and colleagues from Yale University created mice possessing T cells with receptors that target a specific part of the insulin molecule, the B:9–23 peptide. Interestingly, these animals produce T cells that spontaneously revert diabetes. The authors go on to shown that these T cells protect the animal against the development of diabetes by producing the molecule TGF-beta1. They show that the ability of diabetogenic T cells to respond to TGF-beta1 is critical for protection against the autoimmune response. These animals represent an important experimental tool for the study of immune-mediated diabetes.
In an accompanying commentary, Dirk Homann and George Eisenbarth from the University of Colorado, Denver, discuss the challenges that lie ahead in the development of targeted immunotherapies for diabetes but stress the utility of this animal model for future studies.
TITLE: TGF-beta signaling is required for the function of insulin-reactive T regulatory cells
AUTHOR CONTACT:
Li Wen
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 785-7186; Fax: (203) 737-5558; E-mail: li.wen@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27030
ACCOMPANYING COMMENTARY
TITLE: An immunologic homunculus for type 1 diabetes
AUTHOR CONTACT:
George S. Eisenbarth
University of Colorado at Denver and Health Sciences Center, Aurora, Colorado, USA.
Phone: (303) 724-6847; Fax: (303) 724-6839; E-mail: george.eisenbarth@uchsc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28506
IMMUNOLOGY
IL-23 and IL-17: The inflammatory axis of evil
Inflammation is a hallmark symptom of many diseases, and can cause significant damage to the gastrointestinal tract in individuals with inflammatory bowel disease (IBD) as well as nerve degeneration in individuals with multiple sclerosis (MS). Two studies in the May issue of the Journal of Clinical Investigation from researchers at DNAX Research Inc. and Schering-Plough Biopharma, in Palo Alto, California, demonstrate that blocking IL-23, which promotes the differentiation of destructive T cells, and its downstream factor IL-17 can significantly suppress the development of IBD and MS in mice. In an accompanying commentary, Yoichiro Iwakura and Harumichi Ishigame from the University of Tokyo discuss how the studies demonstrate that the IL-23/IL-17 pathway is critical for the development of autoimmune diseases and suggest that this pathway may be a novel therapeutic target for the treatment of chronic inflammatory disorders.
TITLE: Anti–IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis
AUTHOR CONTACT:
Daniel J. Cua
DNAX Research Inc., Palo Alto, California, USA.
Phone: (650) 496-1261; Fax: (650) 496-1200; E-mail: daniel.cua@dnax.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=25308
COMPANION MANUSCRIPT
TITLE: IL-23 is essential for T cell–mediated colitis and promotes inflammation via IL-17 and IL-6
AUTHOR CONTACT:
Robert A. Kastelein
Schering-Plough Biopharma, Palo Alto, California, USA.
Phone: (650) 496-1271; Fax: (650) 496-1200; E-mail: rob.kastelein@dnax.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=21404
ACCOMPANYING COMMENTARY
TITLE: The Il-23/IL-17 axis in inflammation
AUTHOR CONTACT:
Yoichiro Iwakura
University of Tokyo, Japan.
Phone: 81-3-5449-5536; Fax: 81-3-5449-5430; E-mail: iwakura@ims.u-tokyo.ac.jp.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28508
IMMUNOLOGY
An evolutionary detour for the immune response
The complexity of the immune response has increased throughout evolution. Three pathways that activate the immune response are now known to exist – the classical, lectin, and alternative pathways. Deficiencies in components of these pathways (known as "complement components") may predispose us to infections or even cause the immune response to turn against us. Lectins are molecules that circulate throughout the body and recognize and bind to sugars on the surface of pathogens, triggering the immune response by the cleavage of 2 complement components, C4 and C2, to produce an enzyme known as C4b2a. This enzyme cleaves another complement component, C3, into C3a and C3b. C3b is then deposited on the surface of the pathogen, triggering activation of the alternative pathway, and targeting the pathogen for killing.
In a study appearing in the May issue of the Journal of Clinical Investigation, Anders Sjöholm and colleagues from the University Hospital of Lund, Sweden, investigated how individuals who suffer from a genetic immunodeficiency condition in which they lack C4 or C2, are still able to mount a substantial immune response. They found that in these individuals, C2 is bypassed and lectin binding to sugars on the pathogen instead engages the alternative pathway and formation of another C3-cleaving enzyme, C3bBb. This 'bypass' pathway may be functioning in individuals with acquired or naturally occurring complement deficiencies.
In an accompanying commentary, Peter Atkinson and Michael Frank from Washington and Duke Universities, respectively, comment that these results suggest that "individuals deficient in C4 or C2 possess a 'backup' or bypass complement activation system." The authors also stress that researchers using C4-deficient animals to rule out a contribution of certain pathways of complement activation in mouse models of human disease should be aware that 'bypass' pathways such as this may still be functioning.
TITLE: Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2
AUTHOR CONTACT:
Anders G. Sjöholm
University Hospital of Lund, Sweden.
Phone: 46-46-173281; Fax: 46-46-189117; E-mail: anders.sjoholm@med.lu.se.
View the PDF of this article at: https://www.the-jci.org/article.php?id=25982
ACCOMPANYING COMMENTARY
TITLE: Bypassing complement: evolutionary lessons and future implications
AUTHOR CONTACT:
John P. Atkinson
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-8391; Fax: (314) 362-1366; E-mail: jatkinso@im.wustl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28622
Journal
Journal of Clinical Investigation