News From The Journal Of Clinical Investigation: Dec. 21, 2012

Main Category: GastroIntestinal / Gastroenterology
Also Included In: Cancer / Oncology;  Obesity / Weight Loss / Fitness;  Heart Disease
Article Date: 24 Dec 2012 - 1:00 PST Current ratings for:
News From The Journal Of Clinical Investigation: Dec. 21, 2012

The X-factor in liver metabolism

After you eat, your liver switches from producing glucose to storing it. At the same time, a cellular signaling pathway known as the unfolded protein response (UPR) is transiently activated, but it is not clear how this pathway contributes to the liver's metabolic switch. In this issue of the Journal of Clinical Investigation, researchers led by Phillip Scherer at the University of Texas Southwestern Medical Center report that activation of the UPR triggers the expression of Xbp1s, a protein that regulates genes needed for the metabolic switch. Scherer and colleagues found that they could induce changes in liver metabolism just by increasing expression of Xbps1. These results suggest that Xbps1 could play a role in metabolic disease.

TITLE: The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism

Low iron levels increase the risk of H. pylori-associated gastric cancer

H. pylori frequently causes gastric ulcers and is also one of the greatest risk factors for gastric cancer. H. pylori infection is also associated with another gastric cancer risk factor, iron deficiency. In this issue of the Journal of Clinical Investigation, researchers led by Richard Peek at Vanderbilt University investigated the influence of iron on H. pylori-induced gastric cancer. Peek and colleagues found that low iron accelerated the development of H. pylori-associated cancerous lesions in gerbils. Further, H. pylori strains isolated from a human population at high risk for gastric cancer were more virulent and produced greater inflammation if they came from patients with low iron levels. In an accompanying article, El-Omar Emad of Aberdeen University discusses how iron levels could be used to identify patients that are at a higher risk for gastric cancer after H. pylori infection.

TITLE: Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans

ACCOMPANYING ARTICLE TITLE: Iron deficiency and H. pylori-induced gastric cancer: too little, too bad

A critical genetic regulator of brown fat functionality

Obesity is a direct consequence of prolonged positive energy balance that occurs when energy intake (ie. calories) exceeds energy expenditure. In mammals, brown fat plays a critical role in energy metabolism due to its ability to burn energy by dissipating heat, a process known as thermogenesis. Therapeutics that target brown fat could possibly increase metabolism and correct the imbalance that leads to obesity. In this issue of the Journal of Clinical Investigation, researchers led by Matthias Tschöp identified a protein in mice, p62, that is required for brown fat thermogenesis. Mice that did not express p62 in fat cells became obese and developed glucose intolerance, key features of metabolic syndrome in humans. These findings indicate that p62 is an important regulator of metabolism and energy balance and is could potentially serve as a therapeutic target for the treatment of metabolic syndrome.

TITLE: p62 links beta-adrenergic input with mitochondrial function

Dendritic cells play a protective role in atherosclerosis

Atherosclerosis is characterized by a chronic inflammatory immune response that increases the formation atherosclerotic plaques and lesions that could trigger atherothrombosis. Dendritic cells (DCs) are a type of immune cell that have been shown to play a complex role in atherosclerosis. In this issue of the Journal of Clinical Investigation, researchers led by Ira Tabas and Manikandan Subramanian at Columbia University used atherosclerosis-prone mice to elucidate the role of DCs in atherosclerosis. Tabas, Subramanian, and colleagues found that a protein known as MYD88 is required for the activation of DCs, which in turn activate another group of immune cells that protect against inflammation. These results demonstrate that MYD88-mediated DC activation is protective and could be a useful therapeutic target for the treatment of atherosclerosis.

TITLE: Treg-mediated suppression of atherosclerosis requires MYD88 signaling in dendritic cells

Getting to the heart of thyroid hormone function

Thyroid hormone has profound effects on cardiovascular function and metabolism, regulating heart rate, blood pressure, food intake, and metabolic rate. Originally, thyroid hormone was thought to act directly on the target tissues; however, several recent studies have suggested that thyroid hormones effects are mediated by the central nervous system (CNS). In this issue of the Journal of Clinical Investigation, researchers led by Jens Mittag at the Karolinska Institute in Stockholm, Sweden identified a population of neurons in the hypothalamus that are required for thyroid hormone regulation of blood pressure and heart rate. Loss of these neurons in mice resulted in elevated blood pressure and heart rate. These findings demonstrate an important role for the hypothalamus in the regulation of cardiovascular function and indicate a connection between thyroid disease and cardiovascular disorders. In an accompanying commentary, Jürgen Wess of the National Institute of Diabetes and Digestive and Kidney Diseases discusses the link between developmental hypothyroidism and cardiovascular disease.

TITLE: Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

ACCOMPANYING ARTICLE TITLE: A heartfelt response: new thyroid hormone-sensitive neurons in the hypothalamus

Immune system-associated protein regulates metabolism

Hyperglycemia results from impaired insulin activity and is a hallmark of diabetes. In this issue of the Journal of Clinical Investigation, researchers led by Chih-Hao Li at Harvard University identified IL-13, a protein more commonly associated with the immune system, as a regulator of blood glucose levels. Mice lacking IL-13 had higher blood sugar and lipid levels compared with normal mice, and exhibited glucose intolerance and insulin resistance. Treatment with recombinant IL-13 reversed these effects. Li and colleagues found that IL-13 repressed glucose production in the liver, contributing to lower blood sugar levels. These findings suggest that IL-13 is an important regulator of metabolism and is a potential therapeutic target in the treatment of diabetes. In a companion commentary, Anna Mae Diehl and colleagues discuss how IL-13 connects inflammation and glucose homeostasis.

TITLE: Direct control of hepatic glucose production by interleukin-13

ACCOMPANYING ARTICLE TITLE: The Benefits of Restraint: Pivotal Role for IL13 in Hepatic Glucose Homeostasis

Cyclin D1b is a genetic reprogrammer that drives cancer progression

Cyclin D1b is a protein that is induced during cancer progression; however, it's exact function in cancer is poorly understood. In this issue of the Journal of Clinical Investigation, researchers led by Karen Knudsen at Thomas Jefferson University's Kimmel Cancer Center examined the role of cyclin D1b in prostate cancer. Using a mouse model of the disease, they found that cyclin D1b promoted the expression of genes that allow the cancer to grow and metastasize. Additionally, Knudsen and colleagues demonstrated that cyclin D1b's effects were dependent on androgen receptor signaling. These findings identify cyclin D1b as an important regulator of prostate cancer progression and suggest that this pathway is a potential therapeutic target in the treatment of prostate cancer.

TITLE: Convergence of oncogenic and hormone receptor pathways promotes pro-metastatic phenotypes

A new framework for ovarian cancer

Ovarian cancer is one of the most deadly cancers. It has a five year survival rate below 30% and a high rate of recurrence. It is a variable disease, with many different biological underpinnings that make it difficult to treat. In this issue of the Journal of Clinical Investigation, researchers led by Roel Verhaak at MD Anderson Cancer Center examined gene expression patterns in ovarian cancer tumor samples to identify gene expression signatures that correlated with patient prognosis. Using these data, they developed a model, Classification of Ovarian Cancer (CLOVAR), that could accurately classify ovarian cancer subtypes and predict patient outcomes. This new classification system may be useful in determining which treatments will be most effective for a given patient.

TITLE: Prognostically relevant gene expression signatures of high grade serous ovarian carcinoma

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News From The Journal Of Clinical Investigation

Main Category: Diabetes
Also Included In: Neurology / Neuroscience;  Cancer / Oncology;  Immune System / Vaccines
Article Date: 05 Jun 2012 - 0:00 PDT Current ratings for:
'News From The Journal Of Clinical Investigation'

METABOLISM Improving obesity-induced insulin sensitivity

In recent years, a growing body of evidence has linked inflammation to the development of insulin resistance. In insulin resistance, the hormone insulin is less effective in promoting glucose uptake from the bloodstream into other tissues. Obesity is a major factor that contributes to insulin resistance, which can eventually lead to type 2 diabetes. Previous studies have shown that proinflammatory molecules found in fat tissue decreases sensitivity of tissues to insulin.

To identify drug targets that will improve insulin sensitivity, Dr. Olivia Osborn and her colleagues from the University of California in San Diego investigated the role of G protein-coupled receptor 21 (GPR21) in insulin resistance and energy homeostasis. The group compared mice without the gene encoding GPR21 to healthy control mice under normal and high-fat diet conditions. They discovered that mice lacking GPR21 had enhanced insulin sensitivity and increased energy expenditure independent of diet. This result was attributed to the reduced migration of inflammatory cells to the liver and fat tissue in the absence GPR21. Under normal diet, absence of GPR21 in the hypothalamus caused a modest decrease in body weight. This is the first study to demonstrate the negative impact of GPR21 on inflammation and insulin sensitivity. Their findings suggest that GPR21 inhibition may improve insulin resistance and enhance energy expenditure, making GPR21 inhibitors promising treatments for diabetes.

TITLE: G protein-coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice

View this article at: http://www.jci.org/articles/view/61953?key=dbc390c7fd2397640830

METABOLISM Keep metabolism in mind

Metabolic regulation requires activity in the brain that controls glucose balance and food uptake. The hormones insulin, which controls glucose uptake, and leptin, which regulates energy intake and energy expenditure, are critical for mediating energy balance and influence a number of activities in the brain. Dr. Joel Elmquist and colleagues at the University of Texas in Houston wanted to specifically determine which neurons in the brain are required for regulating energy balance. The research team knew that a transcription factor called FOXO1 controlled expression of many genes in response to insulin and leptin signaling. Using genetically modified mice that lack FOXO1 in a specific area of the brain called the ventral medial nucleus of the hypothalamus, they showed that these mice are lean because of increased energy expenditure. Further, these mice had higher sensitivity to insulin in muscle, and were unable to decrease energy expenditure in response to fasting. Their data shows that the action of FOXO1 in the ventral medial nucleus of the hypothalamus is critical for appropriate regulation of energy expenditure and normal glucose balance.

TITLE: FOXO1 in the ventromedial hypothalamus regulates energy balance

View this article at: http://www.jci.org/articles/view/62848?key=9c93a1c72137e21a5364

NEUROLOGICAL DISEASE Finding new treatment options in inflammatory brain diseases

A team of scientist, led by Dr. Azeb Tadesse Argaw from the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, have identified a promising avenue for treating inflammatory brain diseases like multiple sclerosis. When the barrier that protects the brain, known as the blood brain barrier (BBB), becomes weak and permeable, it can lead to brain inflammation, edema and neurotoxicity. In a previous study, the group discovered that inflammatory mediators involved in brain lesion development induced angiogenic proteins in the astrocytes. This finding led them to investigate the impact of a protein that stimulates angiogenesis, vascular endothelial growth factor-A (VEGF-A), on brain permeability and inflammation. In this study, the team generated mice that have inactivated VEGF-A proteins in the astrocytes. This mouse model showed reduced BBB breakdown, decreased inflammatory cell infiltration, and increased mobility following administration of a paralytic agent. Next, the group evaluated the efficacy of a few agents in diminishing the negative effects of VEGF-A on the BBB. They discovered that systemic inhibition of endothelial nitric oxide synthase (eNOS) abolished the effects of VEGF-A on BBB breakdown. Additionally, they found that treatment with a selective eNOS inhibitor reduced drug-induced paralysis in mice. These exciting results indicate that blocking VEGF-A is an effective strategy for treating inflammatory brain diseases. Importantly, eNOS inhibitors can be given peripherally to reduce the harmful effects of VEGF-A on the brain.

TITLE: Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease

View this article at: http://www.jci.org/articles/view/60842?key=f54bc2cb8432c10cbd88

ONCOLOGY Tumor growth and chemoresistance are promoted by ribosomal associated protein RACK

In cells, ribosomes are responsible for translating genetic information, in the form of messenger RNA, to proteins. Coordinated translation initiation is coupled with cell cycle progression and cell growth, but excessive ribosome synthesis and translation initiation can promote cancer. Hepatocellular carcinoma is among the most common and aggressive cancers worldwide and generally displays inherently high resistance to chemotherapeutic drugs. Dr. Jianxin Gu and colleagues at Fudan University in Shanghai, China found that RACK1, the receptor for activated C-kinase 1, was highly expressed in normal liver and frequently upregulated in hepatocellular carcinoma. Aberrant expression of RACK1 contributed to chemoresistance as well as to tumor growth of hepatocellular carcinoma, effects that depended on ribosome localization of RACK1. The group went on to show that ribosomal RACK1 promoted preferential translation of the potent factors involved in growth and survival. Their results imply that RACK1 may function as an internal factor involved in the growth and survival of hepatocellular carcinoma and suggest that targeting RACK1 may be an efficacious strategy for hepatocellular carcinoma treatment.

TITLE: Ribosomal RACK1 promotes chemoresistance and growth in human hepatocellular carcinoma

View this article at: http://www.jci.org/articles/view/58488?key=b32b824a1904ce6fbd34

IMMUNOLOGY Glucocorticoids regulate immunologic fitness

Glucocorticoids (GCs) are commonly used to treat autoimmunity, but their normal roles in the immune system are not well known. Noting that GCs are naturally made in the thymus, the site where immune cells called T cells originate, Dr. Jonathan Ashwell and his group at the National Cancer Institute studied the role of GCs in T cell development and activation. They designed a mouse line in which the gene encoding the GC receptor (GR) is deleted in immature T cells. They found that the GR-deficient T cells could not respond appropriately to antigen-induced signaling. T cells generate a diverse repertoire of TCR to respond to foreign antigens in the body. Mittelstadt's group concluded that the defects were due to a shift in the TCR repertoire because they found that GR-deficient T cells responded normally when they forced to express a TCR with a fixed specificity. They demonstrated alterations in the TCR repertoire genetically, reporting a difference in the usage of particular TCR-encoding gene segments between GR-deficient and wild-type cells. The TCR repertoire is selected in the thymus where immature T cells that recognize the body's own proteins are selected against and killed. In the GR-deficient thymus, the numbers of T cells late in the maturation pathway were reduced, suggesting unusually high numbers of T cells were previously eliminated. The group concluded that the GCs in the thymus prevent inappropriate killing of T cells during development, thus providing a sufficient and diverse TCR repertoire.

TITLE: Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness

View this article at: http://www.jci.org/articles/view/63067?key=24fae67ed3776d86f2e0

NEUROLOGICAL DISEASE Breathing abnormalities uncovered in mouse model of Leigh Syndrome

Leigh syndrome is a progressive neurodegenerative disorder affecting 1 in 40,000 live births. In up to 75% of cases, patient death is caused by respiratory arrest, but the molecular mechanisms behind breathing abnormalities are unclear.

Mutations in Leigh syndrome patients have been reported to occur in components of the mitochondrial complex I, which plays a vital role in cellular energy production, though how these mutations contribute to the development of disease is unknown. Researchers from the Howard Hughes Medical Institute at University of Washington, led by Dr. Richard Palmiter, have developed a mouse model with the hallmarks of Leigh syndrome, including progressive neurodegeneration, behavioral changes, and respiratory apnea. The researchers found that loss of murine Ndufs4, which encodes NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, resulted in compromised activity of mitochondrial complex 1 and causes a fatal progressive encephalopathy. Using magnetic resonance imaging and immunohistochemistry, the researchers located signs of neuroinflammation in a specialized region of the brain known as the dorsal brainstem vestibular nucleus (VN). Selective inactivation of Ndufs4 in the VN resulted in breathing abnormalities and premature death in mice. Restoration of Ndufs4 using gene therapy in the VN corrected breathing deficits and prolonged the lifespan of knockout mice. This genetic murine model of Leigh syndrome provides new insights into the disease, indicating that compromised mitochondrial function within the VN of the brain contributes to respiration abnormalities.

TITLE: Fatal breathing dysfunction in a mouse model of Leigh Syndrome

View this article at: http://www.jci.org/articles/view/62923?key=69fce563f91f65906283

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News From The Journal Of Clinical Investigation: April 2, 2012

Main Category: Obesity / Weight Loss / Fitness
Also Included In: Cholesterol;  Colorectal Cancer;  Immune System / Vaccines
Article Date: 04 Apr 2012 - 0:00 PDT Current ratings for:
'News From The Journal Of Clinical Investigation: April 2, 2012'

METABOLISM

Linking obesity and high cholesterol

Obese patients are at increased risk for cardiovascular disease and a hardening of blood vessel walls called atherosclerosis. One factor that drives atherosclerosis development in obesity is abnormal blood cholesterol levels. ApoB is the major lipid-binding protein that transports low density lipoprotein (LDL cholesterol) and very low density lipoprotein (VLDL cholesterol) from the liver to blood. Alan Tall of Columbia University and colleagues wanted to better understand the genes that are associated with altered levels of LDL and VLDL cholesterol in an obese mouse model system. The research team discovered that a gene call sortilin-1 was inhibited in obese mice. This inhibition caused an increase in apoB secretion and high cholesterol. Accordingly, restoring sortilin-1 levels in the obese mouse model reduced apoB levels. They went on to show that sortillin-1 levels are controlled by activity of the mTOR signaling pathway, and that rapamycin, a well-known drug that inhibits mTOR, caused an increase in liver levels of sortilin-1 and decreased apoB secretion. Their results link obesity and mTOR signaling, and demonstrate how cholesterol secretion is altered due to obesity.

TITLE: Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice

View this article at: http://www.jci.org/articles/view/61248?key=7c1665cd52d43320f206

ONCOLOGY

Insights into the progression of colon carcinogenesis

The WNT signaling pathway is critical for the control of cell proliferation and differentiation. Altered WNT signaling is frequently associated with colon cancer development. Activation of WNT signaling is dependent upon transcriptional activation mediated by ß-catenin. Researchers at the National Taiwan University College of Medicine sought to better understand how ß-catenin activates transcription and mediates aberrant cell division in colon cancer. Led by Dr. Tzuu-Shuh Jou, the team uncovered a role for a ß-catenin-associated protein known as EBP50 in the initiation of uncontrolled cell growth. Dr. Jou and colleagues found that EBP50 protein is localizes to the nucleus of cells from colorectal carcinoma specimens, but not in normal cells. This nuclear EBP50 enhanced the WNT/ß-catenin signaling events, which led to the transcription of downstream growth promoting genes such as c-MYC and cyclin D1. Moreover, depletion of EBP50 in colonic cancer cells significantly reduced cell divisions and tumorigenesis in mice. This demonstrates the importance of EBP50 in conferring a growth advantage to colon cancer cells through WNT signaling and presents EBP50 as an attractive target to halt the progression of colon carcinogenesis

TITLE: Aberrant nuclear localization of EBP50 promotes colorectal carcinogenesis in xenotransplanted mice by modulating TCF-1 and ß-catenin interactions

View this article at: http://www.jci.org/articles/view/45661?key=1acc81fc56e1cb0c96bb

Also in this issue

IMMUNOLOGY

Critical Function of MyD88 in Immune Tolerance Breakdown in Murine Foxp3 Deficiency

The breakdown of peripheral tolerance upon Regulatory T (TR) cell deficiency due to mutations in Foxp3 precipitates a multi-system autoimmune inflammatory disease. The role of the microbial signals in disease pathogenesis was examined in Foxp3 mutant mice that had concurrent deficiencies in Toll-like receptor (TLR) pathways. Deficiency of the common TLR adaptor MyD88, but not more restricted defects, dissociated the disease into a MyD88-dependent component at the environmental boundaries in the skin, lungs and gut, and a MyD88-independent systemic lymphoproliferation. This effect involved the disruption of chemokine gradients that recruit T effector and dendritic cells to target interface tissues. Thus a key role of TR cells is to maintain tolerance at host-microbial interfaces by restraining tonic MyD88-dependent pro-inflammatory signals.

TITLE: MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice

View this article at: http://www.jci.org/articles/view/40591?key=047b407fa466953ed373

IMMUNOLOGY

Mechanism of lipopolysaccharide-induced skin edema formation in the mouse

Prostaglandin E2 (PGE2) regulates many proinflammatory processes, including swelling and pain. Here we show that tissue resident dendritic cells (DCs) are the main source of PGE2 and the main controllers of tissue edema formation in a model of lipopolysaccharide (LPS)-induced inflammation. Mechanistically, PGE2 production by DCs following LPS exposure is controlled by CD14/NFAT pathway, which regulates the expression of the microsomal PGE synthase-1 (mPGES-1), a key enzyme in the PGE2 biosynthesis. Therefore, tissue edema formation induced by LPS is DCs- and CD14/NFAT-dependent. Moreover, by controlling the transudate formation in the presence of LPS, DCs can regulate free antigen arrival to draining lymph nodes.

TITLE: CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice

View this article at: http://www.jci.org/articles/view/60688?key=690bae7dd09d029af162

GASTROENTEROLOGY

Anti-ceramide Antibody Prevents The Radiation GI Syndrome in Mice

The Radiation Gastrointestinal (GI) Syndrome is a major lethal toxicity that might occur after a radiation/nuclear incident. There are no prophylactic countermeasures against Radiation GI Syndrome lethality for first responders, military personnel or remediation workers entering a contaminated area. Pathophysiology of this syndrome requires depletion of stem cell clonogens (SCCs) within the Crypts of Lieberkühn, necessary for post-injury regeneration of gut epithelium. Recent evidence indicates SCC reproductive death is not exclusively a result of DNA damage, but is critically coupled to ceramide-induced endothelial cell apoptosis within the mucosal microvascular network. Here we show that ceramide generated on the surface of endothelium coalesces to form ceramide-rich platforms that transmit an apoptotic signal. We report generation of 2A2 anti-ceramide monoclonal Ab, a countermeasure that binds ceramide to prevent platform formation on the surface of irradiated endothelial cells of the murine GI tract. Consequently, 2A2 protects against endothelial apoptosis in the small intestinal lamina propria and facilitates recovery of crypt SCCs, preventing death of mice from the GI Syndrome at high radiation doses, up to 17 Gy. As such, 2A2 represents a prototype of a new class of anti-ceramide therapeutics and an effective countermeasure against Radiation GI Syndrome mortality.

TITLE: Anti-ceramide Antibody Prevents The Radiation GI Syndrome in Mice

View this article at: http://www.jci.org/articles/view/59920?key=1372fbfe9f90f79d09c5

DERMATOLOGY

Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination

Spontaneous gene repair, also called revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in one individual the mutation can be repaired in various ways. Here we describe a disseminated pattern of revertant mosaicism observed in six patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in the FERMT1 gene encoding kindlin-1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and - deletions. Additionally, in some revertant patches mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.

TITLE: Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination

View this article at: http://www.jci.org/articles/view/61976?key=3b0f274fc1938461dd73

HEPATOLOGY

Hepatocyte-specific mutation of both NF-?B RelA and STAT3 abrogates the acute phase response in mice

The acute phase response is an evolutionarily conserved reaction in which physiological stress triggers the liver to remodel the blood proteome. It is stimulated by diverse cytokines that activate either NF-?B or STAT3, leading us to hypothesize that the acute phase response could be eliminated by interrupting both transcription factors selectively in hepatocytes. The combined mutation of NF-?B p65 (RelA) and STAT3 together, but neither alone, abrogated all acute phase responses measured. This failure to respond was consistent across multiple different infectious, inflammatory, and noxious stimuli. Pneumococcal pneumonia altered the expression of >1100 transcripts in the liver, and this outcome was >96% inhibited by the combined mutation of RelA and STAT3. This interruption of liver responses increased mortality and exacerbated bacterial dissemination during pneumonia, possibly due to an acute humoral enhancement of opsonophagocytosis that was impaired in hepatocyte-mutant mice. Thus, a critical role of the acute phase response is to compartmentalize local infection. We conclude that RelA and STAT3 are essential for stress-induced transcriptional remodeling in the liver, and their hepatocyte-specific mutation reveals functional roles of the acute phase response. TITLE: Hepatocyte-specific mutation of both NF-?B RelA and STAT3 abrogates the acute phase response in mice

View this article at: http://www.jci.org/articles/view/59408?key=d1f1b014af15f850b079

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our obesity / weight loss / fitness section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

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Journal of Clinical Investigation. "News From The Journal Of Clinical Investigation: April 2, 2012." Medical News Today. MediLexicon, Intl., 4 Apr. 2012. Web.
7 Jun. 2012. APA

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'News From The Journal Of Clinical Investigation: April 2, 2012'

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Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here