News From The Journal Of Clinical Investigation: July 18, 2011
One of the reasons that tumors are able to grow rapidly is that they actively prevent immune cells from generating effective antitumor immune responses. Researchers are developing approaches to combat the mechanisms used by tumors to inhibit immune responses, but such approaches don't kill tumor cells directly. A team of researchers, led by Jolanda de Vries and Joost Lesterhuis, at Radboud University Nijmegen Medical Centre, Netherlands, has identified a mechanism by which some tumor cell-killing chemotherapeutic drugs currently in use (specifically, platinum-based drugs such as cisplatin) oppose the immune inhibitory mechanisms employed by tumors and thereby promote anticancer immune responses. The authors therefore suggest that their data provide rationale for the use of platinum-based anticancer chemotherapeutic drugs together with immune-modulating approaches to increase the effectiveness of cancer treatment.
TITLE: Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice
BONE BIOLOGY: The protein 3BP2 performs a balancing act in bone
Cherubism is a genetic disorder characterized by facial abnormalities that result from excessive bone destruction by activated bone cells known as osteoclasts. It is caused by mutations in the SH3BP2 gene that result in gain-of-function effects on the protein templated by the gene, the protein 3BP2. A team of researchers, led by Robert Rottapel, at the University of Toronto, Toronto, has now defined in mice the function of normal 3BP2 in bones, something about which little was previously known.
Rottapel and colleagues found that mice lacking 3BP2 developed osteoporosis as a result of reduced bone formation by bone cells known as osteoblasts. Further analysis revealed cell-intrinsic defects in both osteoblasts and osteoclasts in vivo and in vitro and determined the underlying molecular mechanism. These data indicate that 3BP2 has a key role in maintaining normal bone composition because it is essential for the normal function of both osteoblasts and osteoclasts.
TITLE: 3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions
PULMONARY: Home for progenitor cells modified in cystic fibrosis airways
Individuals with cystic fibrosis (CF) suffer persistent bacterial infections of the lungs as a result of impaired secretion of mucus from glands in the airways known as submucosal glands. These glands are also home to slow-cycling progenitor cells, which are thought to be involved in repairing CF airways damaged by the persistent bacterial infections. A team of researchers, led by John Engelhardt, at The University of Iowa Carver College of Medicine, Iowa City, has now identified a role for the protein CGRP in regulating both mucus secretion from submucosal glands and their ability to house slow-cycling progenitor cells.
Mucus secretion stimulated by CGRP is impaired in individuals with CF. Therefore, submucosal glands respond by producing more and more CGRP. Consistent with this, Engelhardt and colleagues found that signaling downstream of CGRP was hyperactivated in CF human, pig, ferret, and mouse submucosal glands. In turn, the increased levels of CGRP promoted slow-cycling progenitor cell proliferation, and this altered the properties of the slow-cycling progenitor cell niche. These data have important implications for understanding the airway injury and repair in individuals with CF.
TITLE: CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice
NEPHROLOGY: New mechanistic insight into salt-induced high blood pressure
High blood pressure (hypertension) is a risk factor for numerous severe medical conditions, including heart attack, stroke, and kidney failure. Increased sensitivity to salt is a contributing factor to high blood pressure in some individuals, but the underlying mechanism is not clear. Now, a team of researchers, led by Toshiro Fujita, at the University of Tokyo Graduate School of Medicine, Japan, has determined that high-salt loading activates the protein Rac1 in the kidneys in rodent models of salt-sensitive high blood pressure and that this elevates blood pressure and leads to kidney damage. The chain of events downstream of Rac1 activation required the protein MR (mineralocorticoid receptor). These data provide new insight into the mechanism underlying salt-induced high blood pressure and kidney injury, and provide potential new therapeutic targets for treating these conditions.
TITLE: Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway
VASCULAR DISEASE: New cause of blood vessel abnormalities identified
Hereditary hemorrhagic telangiectasia is a genetic disorder that results in the development of abnormalities in the blood vessels in organs such as the lungs, intestines, and brain. These abnormalities are known as arteriovenous malformations and they are associated with a high risk of potentially devastating bleeding episodes. New data, generated in mice, by Kristina I. Boström, Yucheng Yao, and colleagues, at the David Geffen School of Medicine, Los Angeles, suggests that deficiency of the protein MGP could be a previously unknown cause of AVMs. The authors therefore suggest that abnormalities in MGP function could contribute to the triggering of AVMs in individuals with hereditary hemorrhagic telangiectasia.
TITLE: Matrix Gla protein deficiency causes arteriovenous malformations in mice
VASCULAR BIOLOGY: Understanding the formation of valves in veins
Most veins have one-way flaps called venous valves that ensure that blood flows in one direction. Dysfunction of venous valves leads to serious clinical conditions, including leg swelling and chronic ulceration. Despite this, little is known about the molecular mechanisms regulating the formation and maintenance of venous valves. However, a team of researchers, led by Taija Makinen, at the Cancer Research UK London Research Institute, United Kingdom, has now identified in mice several signaling pathways regulating venous valve formation. Of particular interest, the cells lining venous valves were found to closely resemble the cells lining valves in lymphatic vessels at the molecular level, suggesting plasticity in the ability of a valve-lining cell to take on a different identity.
TITLE: Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice
MUSCLE BIOLOGY: Endurance protein IL-15R-alpha
The protein IL-15R-alpha is perhaps best known as a component of the protein to which the immune-modulating factor IL-15 binds to mediates its effects. However, recent studies have indicated that this is not the only function of IL-15R-alpha, as some of the characteristics of mice lacking IL-15R-alpha differ from those lacking IL-15. In this context, a team of researchers, led by Tejvir S. Khurana, at the University of Pennsylvania School of Medicine, Philadelphia, has now defined a unique role for IL-15R-alpha in mouse muscle that does not involve IL-15. Specifically, the team found that IL-15R-alpha is important for defining the type of muscle fibers in skeletal muscle. In its absence, the muscles in mice did not tire as easily and the mice could exercise more extensively than normal mice. These data were then shown to be relevant to humans, as the team found that specific variants at a given region of the IL15RA gene occurred with differing frequencies among groups of elite athletes doing different endurance sports.
TITLE: Loss of IL-15 receptor-alpha alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles
Journal of Clinical Investigation