From Journal of Clinical Investigation
JCI Table of Contents, 15 August 2003 Anti-asthma medications: too much of a good thing?
In an unusual paradox, asthmatics that are chronically treated with bronchodilating beta-agonist medications such as albuterol, ventolin, and salbutamol may ultimately develop increased sensitivity to airway constriction and experience exacerbation of their condition. A new study by Stephen Liggett and colleagues at the University of Cincinnati in the August 15 issue of the Journal of Clinical Investigation describes a responsible mechanism for this adverse reaction and reveals a potential new therapeutic target in the treatment of asthma.
Inhaled selective beta-agonists are the most widely used treatment for the acute relief of asthma symptoms. Administered to asthmatic patients via an inhaler, nebulizer, in tablet or liquid form, or injection, they cause airway relaxation and reduced airway responsiveness to nonspecific contractile stimuli. This is achieved by drug binding to the beta2-adrenergic receptor (beta2AR). Despite the ability of these agents to immediately reverse airway obstruction, there has been ongoing concern that the use of these drugs may be associated with harmful outcomes. Some, but not all, studies have revealed that regular scheduled use (e.g., multiple times daily, every day) of inhaled beta-agonists has resulted in a loss of control over the condition, which can manifest as longer asthmatic attacks and and post-treatment airway hyperresponsiveness.
To date, the evidence has suggested that a desensitization of the beta2AR is responsible. Liggett and colleagues suggest an alternative explanation. The authors demonstrate that persistent high-level activation of the beta2AR leads to increased expression of phospholipase C-beta (PLC-beta) in airway smooth muscle, inducing a crosstalk between beta2AR signaling pathways that ultimately results in airway hyperresponsiveness.
In their accompanying commentary, Stephanie Shore and Jeffrey Drazen from the Harvard School of Public Health and Brigham and Women's Hospital in Boston, Massachusetts, discuss additional explanations for the bronchoconstricting effects associated with chronic beta2AR stimulation. The commentary authors state that "it is interesting to note that the adverse effects of regular b-agonist use can be observed even weeks after their withdrawal, at a time when beta2AR desensitization should be resolved". These authors also indicate that studies of regular beta-agonist use have reported adverse effects only in subjects with a particular mutation in the beta2AR. The impact of this mutation has not been fully examined in any cell type.
Liggett and his research team suggest that therapeutics targeting PLCb may have substantial benefit in the treatment of asthma, particularly when chronic beta-agonist use is prescribed. Shore and Drazen suggest that it is possible that this is "just the tip of the iceberg" and that "understanding the panoply of beta2AR-mediated events in airway smooth muscle might lead to the design of new agonists that avoid negative effects of beta2AR activation while enhancing events that lead to relaxation".
TITLE: Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox
Stephen B. Liggett
University Of Cincinnati, Cincinnati, Ohio, USA.
Phone: (513) 558-4831
Fax 1: (513) 558-0835
View the PDF of this article at: https://www.the-jci.org/press/18193.pdf
Beta-agonists and asthma: too much of a good thing?
Harvard School of Public Health, Boston, Massachusetts, USA.
Phone 1: (617) 432-0199
Fax 1: (617) 432-3468
View the PDF of this commentary at: https://www.the-jci.org/press/19642.pdf
Decrypting the role of Cripto in tumor growth
The cell-surface associated molecule Cripto is overexpressed in a wide range of epithelial cancers, yet little is known about the potential mechanisms by which Cripto expression might enhance tumor growth. A new study by Michele Sanicola and colleagues at Biogen Inc. in the August 15 issue of the Journal of Clinical Investigation reveals that binding of Cripto to the TGFbeta ligand Activin B can block Activin B-mediated suppression of cell proliferation. Furthermore, this study also demonstrates that antibody blockade of Cripto function may prove useful in the inhibition of tumorigenesis.
Cripto was first discovered 15 years ago and was suitably named for its mysterious lack of relationship to known proteins and signaling pathways. Since then Cripto has been shown to play an essential role in embryonic development. It has also been shown to act as a coreceptor for Nodal, a member of the TGFbeta family. Cripto appears to recruit Nodal to the Activin receptor complex to mediate transcriptional responses. However there remains no explanation for the widespread overexpression of Cripto in human epithelial cancers. In attempting to determine whether Cripto activity is essential for tumor growth and/or maintenance, and what role, if any, that Nodal plays in this interaction, Sanicola and colleagues have revealed that Activin signaling can be blocked by Cripto overexpression in many cell types. They go on demonstrate that monoclonal antibodies specific for Cripto are capable of inhibiting tumor cell growth in models of testicular and colon cancer, and that this correlates with the ability to inhibit Activin signaling.
The study suggests that Cripto overexpression may play an early role in cancer progression through the inhibition of the tumor supressing effects of Activin. In an accompanying commentary, Michael Shen from the University of Medicine and Dentistry in Piscataway, New Jersey, discusses some of the proposed mechanisms of this inhibition. "The exciting finding that antibody blockade of Cripto has a strong effect in xenograft models indicates that Cripto functions in a central pathway for cell proliferation and/or maintenance of the transformed state. While much more analysis is needed to decode the molecular mechanisms of Cripto function, the work now provides a glimmer of understanding as to the functions of this enigmatic protein in tumorigenesis".
TITLE: Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo
Biogen Inc., Cambridge, Massachusetts, USA.
Phone: (617) 679-3307
Fax: (617) 914-7140
View the PDF of this article at: https://www.the-jci.org/press/17788.pdf
ACCOMPANING COMMENTARY: Decrypting the role of Cripto in tumorigenesis
Michael M. Shen
Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, USA.
Phone: (732) 235-5645
Fax: (732) 235-5373
View the PDF of this commentary at: https://www.the-jci.org/press/19546.pdf
Asthma, a complex inflammatory disease afflicting nearly 15 million Americans, is mediated by Th2 cells. Migration of Th2 cells to the lung is key to their inflammatory function and is regulated in large part by chemokine receptors. Robert Lefkowitz and colleagues from Duke University Medical Center in Durham, North Carolina, show that allergen-sensitized mice with a targeted deletion of the gene encoding beta-arrestin-2 (a G protein–coupled receptor regulator) do not accumulate lymphocytes in their airways, nor do they demonstrate other physiological and inflammatory features characteristic of asthma. Because beta-arrestin-2 regulates the development of allergic inflammation at a proximal step in the inflammatory cascade, targeting this protein may become a treatment for asthma.
TITLE: Beta-arrestin-2 regulates the development of allergic asthma
Robert J. Lefkowitz
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 684-2974
View the PDF of this article at: https://www.the-jci.org/press/17265.pdf
Muscling in on the specificity of anti-diabetic agents
Thiazolidinediones (TZDs) are pharmacologic agents that improve glucose balance by increasing insulin sensitivity in skeletal muscle in type 2 diabetes. The antidiabetic actions of TZDs are believed to be mediated by their interactions with the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma). As PPAR-gamma is expressed primarily in fat cells, with lower levels in skeletal muscle, it has remained debatable whether the effect of TZDs on muscle is direct or indirect. Using muscle-specific PPAR-gamma--–knockout mice, C. Ronald Kahn and colleagues at the Joslin Diabetes Center in Boston, Massachusetts, demonstrated that muscle PPAR-gamma is not required for a whole-animal response to TZDs. Disruption of PPAR-gamma led to increased fat mass and insulin resistance, however it did not block the beneficial effects of TZDs. The data indicate that the effects of TZDs on muscle are indirect, but that PPAR-gamma in muscle plays a previously unrecognized role in the regulation of whole-body lipid storage and insulin sensitivity through an inter-tissue crosstalk, perhaps due to altered lipid metabolism in muscle.
TITLE: Muscle-specific PPAR-gamma-–deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones
C. Ronald Kahn
Joslin Diabetes Center, Boston, Massachusetts, USA.
Phone: (617) 732-2635
Fax: (617) 732-2487
View the PDF of this article at: https://www.the-jci.org/press/17305.pdf
A new cathepsin in the thymus
CD4 cells detect extracellular pathogens that have been processed and presented on the surface of MHC class II molecules. This presentation process requires the activity of lysosomal proteases such as the cathepsins, which degrade the MHC class II chaperone invariant chain to generate class II–associated invariant chain peptides. Eva Tolosa and colleagues from Tübingen University Hospital, Germany, have now characterized the function of a new human cathepsin (Cathepsin V) exclusively expressed in the human thymus and testis. The authors show that Cathepsin V is the protease that mediates invariant chain release in the class II processing pathway in the human thymus. Comparison of Cathepsin V expression in thymi from myasthenia gravis patients and healthy controls revealed a significantly higher expression level in the pathological samples, suggesting a potential involvement of this protease in the immunopathogenesis of this disease.
TITLE: Cathepsin V is involved in the degradation of invariant chain in human thymus and is overexpressed in myasthenia gravis
Tüebingen University Hospital, Tüebingen, Germany.
View the PDF of this article at: https://www.the-jci.org/press/18028.pdf
Neurodegeneration and diabetes come together
Diabetes is caused by an absolute or relative deficiency of insulin-producing b cells. In order to elucidate the underlying mechanisms leading to the development of diabetes in humans, Michael Ristow and colleagues from the German Institute of Human Nutrition created a beta cell–specific knockout of the frataxin gene in mice. Reduced expression of frataxin is known to cause an autosomal recessively inherited disease, Friedreich ataxia, in humans. Mice were born healthy, but subsequently developed impaired glucose tolerance progressing to overt diabetes mellitus. The secretory defect was caused by reduced beta cell mass due to both decreased cell growth and an increase in programmed cell death, which was caused by the overproduction of toxic oxygen species in the absence of frataxin. These observations might provide insight into the deterioration of beta cell function observed in human type 2 diabetes.
TITLE: Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass
Free University of Berlin, Berlin, Germany.
View the PDF of this article at: https://www.the-jci.org/press/18107.pdf
Integrin-linked kinase mediates kidney fibrosis
Emerging evidence suggests that during certain disease states, epithelial cells within the kidney are capable of undergoing epithelial to mesenchymal transition (known as EMT), the process of transformation from epithelial cells to matrix-producing fibroblasts, that may ultimately result in renal interstitial fibrosis and renal failure. EMT is regulated by numerous hormones and growth factors, including tumor growth factor beta1 (TGF-beta1). Youhua Liu and colleagues from the University of Pittsburgh School of Medicine demonstrate that expression of the intracellular enzyme integrin-linked kinase (ILK) is specifically induced in renal tubular epithelial cells in response to TGFbeta1 and that ILK administration induces many key events in TGFbeta1-induced EMT. The data implicate ILK as a crucial mediator of EMT in renal interstitial fibrosis. The authors demonstrate that administration of a kinase-dead form of ILK abolishes TGFbeta1-induced EMT suggesting that this and other inhibitors of ILK signaling could be explored as potential therapies for chronic renal disease.
TITLE: Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Phone: (412) 648-8263
Fax: (412) 648-1916
View the PDF of this article at: https://www.the-jci.org/press/17913.pdf
Interfering interferons in medulloblastoma
Type I interferons (IFN-alpha and IFN-beta), crucial for fighting viral infection and regulating immune function, signal via activation of STAT1 and STAT2. Iain Campbell and colleagues from the Scripps Institute in La Jolla, California, show that in mice lacking STAT2, IFN-alpha retains potent biological activity in the central nervous system. IFN-alpha mediates a type I–like immune response with IFN-gamma gene expression and signaling in the brain associated with the development of medulloblastoma, the most common type of brain tumor. Further, the authors show that the Sonic hedgehog (Shh) signaling pathway, which is implicated in the development of medulloblastoma, is activated in granule neurons, and this process can be mediated by IFN-gamma. These findings show the dire consequences of STAT2-independent type I IFN signaling and reveal a previously unknown link between the immune system and the pathogenesis of developmental disorders and tumorigenesis of the central nervous system due to dysregulated Shh signaling mediated by IFN-gamma.
TITLE: Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-alpha–stimulated STAT2-independent production of IFN-gamma in the brain
Iain L. Campbell
The Scripps Research Institute, La Jolla, California, USA.
Phone: (858) 784-9306
Fax: (858) 784-9544
View the PDF of this article at: https://www.the-jci.org/press/18637.pdf
Thyroid hormones in a binding contract
Thyroid hormones are critical for differentiation, growth, and metabolism. Thyroid hormone receptor beta (TRbeta) has been implicated in the development of both auditory and visual systems. Interested in the biological role of TRbeta, Fredric Wondisford and colleagues from the University of Chicago have demonstrated that DNA binding is critical for most functions of this receptor. Their study also suggests that novel mechanisms independent of DNA binding may contribute to the regulation of auditory function by TRbeta. In his accompanying commentary Mitchell Lazar from the University of Pennsylvania School of Medicine discusses alternative mechanisms whereby thyroid hormones can regulate gene expression in a manner that does not involve binding to DNA.
TITLE: Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo
Fredric E. Wondisford
University of Chicago, Chicago, Illinois USA.
Phone: (773) 702-9653
Fax: (773) 834-0486
View the PDF of this article at: https://www.the-jci.org/press/18377.pdf
ACCOMPANYING COMMENTARY: Thyroid hormone action: a binding contract
Mitchell A. Lazar
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-0198
Fax: (215) 898-5408
View the PDF of this commentary at: https://www.the-jci.org/press/19479.pdf
A balancing act in the kidney
The epithelial sodium channel (ENaC) consists of alpha, beta, and gamma subunits present in many configurations, and facilitates sodium reabsorption and potassium secretion. ENaC regulation takes place in the kidney in the aldosterone-sensitive distal nephron, which comprises the end of the distal convoluted tubule (late DCT), the connecting tubule (CNT), and the collecting duct (CD). Bernard C. Rossier and colleagues at the Institut de Pharmacologie et de Toxicologie in Lausanne, Switzerland examined the consequence of inactivating the ENaC alpha subunit in the CD while leaving ENaC expression in the late DCT and CNT intact in mice. The authors found that ENaC expression in the CD is not a prerequisite for achieving sodium and potassium balance, stressing the more proximal nephron segments (late DCT and CNT) in achieving this equilibrium.
TITLE: Collecting duct–specific gene inactivation of alphaENaC in the mouse kidney does not impair sodium and potassium balance
Bernard C. Rossier
Institut de Pharmacologie et de Toxicologie, Lausanne, Switzerland.
View the PDF of this article at: https://www.the-jci.org/press/16956.pdf
Signaling interplay during inflammation
Interferon-gamma (IFN-gamma) plays a central role in controlling the host immune response, however the precise mechanisms contributing to this control have not been fully defined. Nicholas Topley and colleagues from the University of Wales College of Medicine utilized a mouse model of acute peritnoneal inflammation in order to demonstrate that IFN-gamma directly controls the infiltration of neutrophils to the site of infection and modulates interleukin-6 (IL-6) signaling through its soluble receptor (sIL-6R) in order to promote clearance of foreign invaders and resolve inflammation. This study adds to our understanding of acute inflammatory states and should aid in determining suitable therapeutic strategies.
TITLE: Interplay between IFN-gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation
University of Wales College of Medicine, Cardiff, United Kingdom.
View the PDF of this article at: https://www.the-jci.org/press/17129.pdf
MOG: a minor myelin protein, a major self-antigen
Myelin/oligodendrocyte glycoprotein (MOG) is a minor protein component of myelin, which provides a insulating sheath around neurons. MOG is involved in diseases such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Danielle Pham-Dinh and colleagues from Hôpital de la Salpêtrière in Paris have generated a mouse lacking a functional Mog gene in order to assess the role of MOG in EAE. In contrast to normal mice, which developed severe EAE following immunization with whole myelin, MOG–/– mice had a mild phenotype, demonstrating that the anti-MOG autoimmune response is a major pathogenic component of the anti-myelin immune response. The lack of tolerance to MOG may be responsible for the high level of pathogenicity of the anti-MOG immune response as well as the high susceptibility of most animal strains to EAE induced by MOG. Therefore, immunotherapy aimed at inducing tolerance to MOG might be beneficial in the treatment of MS.
TITLE: Myelin/oligodendrocyte glycoprotein–deficient (MOG-deficient) mice reveal lack of immune tolerance to MOG in wild-type mice
ISERM Hôpital de la Salpêtrière, Paris, France.
View the PDF of this article at: https://www.the-jci.org/press/15861.pdf