Recently, type I interferons IFN-α and IFN-β (IFN-α/β) have been evaluated in pilot clinical trials for the treatment of active ulcerative colitis. However, the underlying mechanisms that may contribute to a potential therapeutic effect are incompletely understood. A new study in this issue demonstrates a protective role for IFN-α/β, induced by activation of a Toll-like receptor 9–dependent pathway, in a rodent model of experimental colitis.
Stefan Wirtz, Markus F. Neurath
Remodeling of the arterial wall occurs mainly as a consequence of increased wall stress caused by hypertension. In this issue of the JCI, Azizi et al. report that in humans with a kallikrein gene polymorphism that lowers kallikrein activity, the brachial artery undergoes eutrophic inward remodeling in the absence of hypertension or other hemodynamic changes. It has also been reported that alterations of the kallikrein-kinin system are associated with formation of aortic aneurysms. Conversely, after vascular injury, kinins mediate the beneficial effect of angiotensin-converting enzyme inhibitors that prevent neointima formation. These findings raise the intriguing possibility that decreased kallikrein-kinin system activity may play an important role in the pathogenesis of vascular remodeling and disease, while increased activity may have a beneficial effect.
Oscar A. Carretero
Numerous viruses cause latent infections in humans, and reactivation often results in pain and suffering. While vaccines for several of these viruses are available or currently being studied in clinical trials, and antiviral therapies have been successful in preventing or treating active infection, therapy to eradicate latent infection has lagged behind. A new study reported in this issue of the JCI shows that treatment of cells latently infected with Kaposi sarcoma–associated herpesvirus (KSHV) with glycyrrhizic acid, a component of licorice, reduces synthesis of a viral latency protein and induces apoptosis of infected cells. This finding suggests a novel way to interrupt latency.
Jeffrey I. Cohen
The DEAD-box RNA helicases are enzymes involved in many critical aspects of RNA metabolism within both eukaryotic and prokaryotic organisms. Several studies have shown that these proteins may have important functions in mediating microbial pathogenesis. A new study in this issue of the JCI identifies the first DEAD-box RNA helicase in the pathogenic fungus Cryptococcus neoformans and proposes novel roles for this family of proteins in the development and progression of cryptococcosis.
Lena J. Heung, Maurizio Del Poeta
Recent evidence has demonstrated that endothelial-specific growth factors affect the development of apparently unrelated organs and cells. Expanding this evidence further, new findings in this issue of the JCI show that neurotrophic factors can affect neovascularization. Neurotrophic factors achieve proangiogenic effects not only by directly affecting endothelial cells, but also by recruiting hematopoietic precursors. Further understanding of the biology of angiogenic factors, as well as of the function of hematopoietic cells in tissue neovascularization, will lead to improved therapeutic strategies for the treatment of diseases ranging from ischemia to cancer.
Dan G. Duda, Rakesh K. Jain
Defective uptake of glucose into muscle and fat cells, or insulin resistance, is a central feature of obesity and type 2 diabetes. As we brace ourselves for the diabetes epidemic, it is reassuring to know that real progress is being made in defining the molecular biology of how insulin stimulates glucose uptake and what goes awry in obesity and type 2 diabetes. An understanding of the molecular determinants of insulin-stimulated glucose transport has been one of the holy grails of hormone action research. A major breakthrough was the discovery that insulin stimulates the translocation of a specific glucose transport protein, GLUT4, from intracellular vesicles to the cell surface. Elucidating how this process is regulated has remained a challenge because it represents a convergence of 2 disparate and complex fields of research — namely, vesicle transport and signal transduction. A study reported in this issue of the JCI using mice lacking Munc18c, one of the vesicle-trafficking proteins involved in GLUT4 translocation, has provided new insights into the signaling/trafficking intersection that controls insulin-stimulated GLUT4 movement.
David E. James
For 3 decades, terms such as synthetic phenotype and contractile phenotype have been used to imply the existence of a specific mechanism for smooth muscle cell (SMC) responses to injury. In this issue of the JCI, Hendrix et al. offer a far more precise approach to examining the mechanisms of SMC responses to injury, focused not on general changes in phenotype but on effects of injury on a single promoter element, the CArG [CC(A/T)6GG] box, in a single gene encoding smooth muscle (SM) α-actin. Since CArG box structures are present in some, but not all, SMC genes, these data suggest that we may be progressing toward establishing a systematic, molecular classification of both SMC subsets and the response of SMCs to different injuries.
William M. Mahoney Jr., Stephen M. Schwartz
Inositol-requiring enzyme 1 (IRE1) is a transmembrane protein that signals from the ER and contributes to the generation of an active spliced form of the transcriptional regulator X-box–binding protein 1 (XBP1). XBP1 is required for the terminal differentiation of B lymphocytes into plasma cells, and IRE1 also participates in this differentiation event. A study in this issue of the JCI reveals, quite unexpectedly, that IRE1 is also required early in B lymphocyte development for the induction of the machinery that mediates Ig gene rearrangement.
Shiv Pillai
In pancreatic β cells, not only insulin exocytosis per se, but translocation of β granules toward the plasma membrane — an event upstream of exocytosis — are under the control of glucose. However, the molecular basis of this translocation has been poorly understood. Rab27a-mediated translocation of glucose-induced β granules is reported in this issue of the JCI. Rab27a or its effector molecule may constitute a novel pharmacological target because potentiation of the Rab27a pathway is expected to restore β cell glucose competency in patients with diabetes mellitus.
Toru Aizawa, Mitsuhisa Komatsu
The potential threat of the smallpox virus as a bioterror weapon has long been recognized, and the need for developing suitable countermeasures has become especially acute following the events of September 2001. Traditional antiviral agents interfere with viral proteins or functions. In a new study, Yang et al. focus instead on host cellular pathways used by the virus. A drug that interferes with the cellular ErbB-1 signal transduction pathway, activated by smallpox growth factor, sheds new light on how the virus replicates in the cell. Drugs that target the ErbB-signaling pathways represent a promising new class of antiviral agents.
Anthony S. Fauci, Mark D. Challberg
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