Interleukin-1β-converting enzyme-deficient mice resist central but not systemic endotoxin-induced anorexia

1998 ◽  
Vol 274 (6) ◽  
pp. R1829-R1833 ◽  
Author(s):  
William Burgess ◽  
Gilles Gheusi ◽  
Jianhua Yao ◽  
Rodney W. Johnson ◽  
Robert Dantzer ◽  
...  
Keyword(s):  
Food Intake ◽  
Critical Role ◽  
Interleukin 1Β ◽  
Converting Enzyme ◽  
Wild Type ◽  
Motivated Behavior ◽  
Infection And Inflammation ◽  
Intracerebroventricular Injections ◽  
Enzyme Deficient ◽  
Deficient Mice

Interleukin-1β (IL-1β) mediates many of the behavioral responses to infection and inflammation, and IL-1β-converting enzyme (ICE) processes intracellular IL-1β, leading to its maturation and secretion. Here we demonstrate that intracerebroventricular injections of lipopolysaccharide (LPS) produced a greater reduction in both food intake and food-motivated behavior in wild-type compared with ICE-deficient (ICE −/−) mice. This defect occurred although ICE −/− mice were able to fully respond to intracerebroventricular injections of IL-1β. In contrast, ICE −/− mice remained fully responsive to intraperitoneal injections of LPS. These results indicate that brain, but not peripheral, IL-1β plays a critical role in the depression in food intake that occurs during inflammation.

scholarly journals Activation of CPP32 and Mch3α in wild-type p53-induced apoptosis

1997 ◽  
Vol 322 (1) ◽  
pp. 19-23 ◽  
Author(s):  
Julia M. CHANDLER ◽  
Emad S. ALNEMRI ◽  
Gerald M. COHEN ◽  
Marion MacFARLANE
Keyword(s):  
Critical Role ◽  
Interleukin 1Β ◽  
Temperature Sensitive ◽  
Converting Enzyme ◽  
Wild Type ◽  
Lamin B1 ◽  
Dna Damaging Agents ◽  
Wild Type P53 ◽  
Induced Apoptosis ◽  
Dependent Pathway

DNA-damaging agents induce apoptosis primarily by a p53-dependent pathway. LTR6 cells containing a temperature-sensitive p53 were used to dissect further the mechanisms of p53-induced apoptosis. Apoptosis was accompanied by the processing and activation of CPP32 and Mch3α, together with the cleavage of poly(ADP-ribose) polymerase and lamin B1. These results demonstrate a critical role for the activation of interleukin-1β-converting enzyme-like proteases in p53-induced apoptosis.

scholarly journals Cytosolic Phospholipase A2α–deficient Mice Are Resistant to Collagen-induced Arthritis

2003 ◽  
Vol 197 (10) ◽  
pp. 1297-1302 ◽  
Author(s):  
Martin Hegen ◽  
Linhong Sun ◽  
Naonori Uozumi ◽  
Kazuhiko Kume ◽  
Mary E. Goad ◽  
...  
Keyword(s):  
Critical Role ◽  
Wild Type ◽  
Collagen Induced Arthritis ◽  
Cytosolic Phospholipase ◽  
Severity Scores ◽  
In The Wild ◽  
Cytosolic Phospholipase A2α ◽  
Antibody Levels ◽  
Deficient Mice

Pathogenic mechanisms relevant to rheumatoid arthritis occur in the mouse model of collagen-induced arthritis (CIA). Cytosolic phospholipase A2α (cPLA2α) releases arachidonic acid from cell membranes to initiate the production of prostaglandins and leukotrienes. These inflammatory mediators have been implicated in the development of CIA. To test the hypothesis that cPLA2α plays a key role in the development of CIA, we backcrossed cPLA2α-deficient mice on the DBA/1LacJ background that is susceptible to CIA. The disease severity scores and the incidence of disease were markedly reduced in cPLA2α-deficient mice compared with wild-type littermates. At completion of the study, >90% of the wild-type mice had developed disease whereas none of the cPLA2α-deficient mice had more than one digit inflamed. Furthermore, visual disease scores correlated with severity of disease determined histologically. Pannus formation, articular fibrillation, and ankylosis were all dramatically reduced in the cPLA2α-deficient mice. Although the disease scores differed significantly between cPLA2α mutant and wild-type mice, anti-collagen antibody levels were similar in the wild-type mice and mutant littermates. These data demonstrate the critical role of cPLA2α in the pathogenesis of CIA.

scholarly journals An in vivo inflammatory loop potentiates KRAS blockade

2019 ◽  
Author(s):  
Kristina A.M. Arendt ◽  
Giannoula Ntaliarda ◽  
Vasileios Armenis ◽  
Danai Kati ◽  
Christin Henning ◽  
...  
Keyword(s):  
Interleukin 1Β ◽  
Wild Type ◽  
Poor Survival ◽  
Murine Bone Marrow ◽  
Chemokine Ligand ◽  
Isoprenylcysteine Carboxylmethyltransferase ◽  
Chemokine Ligand 2 ◽  
Deficient Mice

ABSTRACTKRAS inhibitors perform inferior to other targeted drugs. To investigate a possible reason for this, we treated cancer cells with KRAS inhibitors deltarasin (targeting phosphodiesterase-δ), cysmethynil (targeting isoprenylcysteine carboxylmethyltransferase), and AA12 (targeting KRASG12C), and silenced/overexpressed mutant KRAS using custom vectors. We show that KRAS-mutant tumor cells exclusively respond to KRAS blockade in vivo, because the oncogene co-opts host myeloid cells via a C-C-motif chemokine ligand 2/interleukin-1β signaling loop for sustained tumorigenicity. Indeed, KRAS-mutant tumors did not respond to deltarasin in Ccr2 and Il1b gene-deficient mice, but were deltarasin-sensitive in wild-type and Ccr2-deficient mice adoptively transplanted with wild-type murine bone marrow. A KRAS-dependent pro-inflammatory transcriptome was prominent in human cancers with high KRAS mutation prevalence and predicted poor survival. Hence the findings support that in vitro systems are suboptimal for anti-KRAS drug screens, and suggest that interleukin-1β blockade might be specific for KRAS-mutant cancers.

Lessons from angiotensin-converting enzyme-deficient mice

1996 ◽  
Vol 5 (6) ◽  
pp. 463-467 ◽  
Author(s):  
Charles R. Esther ◽  
Tom E. Howard ◽  
Yudong Zhou ◽  
Mario R. Capecchi ◽  
Mario B. Marrero ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Converting Enzyme ◽  
Enzyme Deficient ◽  
Deficient Mice

scholarly journals Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in mice

2018 ◽  
Author(s):  
Vruti Patel ◽  
Guillaume Bidault ◽  
Joseph E. Chambers ◽  
Stefania Carobbio ◽  
Angharad J. T. Everden ◽  
...  
Keyword(s):  
Weight Gain ◽  
Food Intake ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Standard Diet ◽  
Wild Type ◽  
Diet Induced Obesity ◽  
Caloric Excess ◽  
Deficient Mice

AbstractPhosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.

scholarly journals 5-Lipoxygenase Negatively Regulates Th1 Response during Brucella abortus Infection in Mice

2015 ◽  
Vol 83 (3) ◽  
pp. 1210-1216 ◽  
Author(s):  
Júlia Silveira Fahel ◽  
Mariana Bueno de Souza ◽  
Marco Túlio Ribeiro Gomes ◽  
Patricia P. Corsetti ◽  
Natalia B. Carvalho ◽  
...  
Keyword(s):  
Brucella Abortus ◽  
Critical Role ◽  
Lipid Mediators ◽  
Negative Regulator ◽  
Host Responses ◽  
Interleukin 12 ◽  
Dependent Manner ◽  
Wild Type ◽  
Content Type ◽  
Deficient Mice

Brucella abortusis a Gram-negative bacterium that infects humans and cattle, causing a chronic inflammatory disease known as brucellosis. A Th1-mediated immune response plays a critical role in host control of this pathogen. Recent findings indicate contrasting roles for lipid mediators in host responses against infections. 5-Lipoxygenase (5-LO) is an enzyme required for the production of the lipid mediators leukotrienes and lipoxins. To determine the involvement of 5-LO in host responses toB. abortusinfection, we intraperitoneally infected wild-type and 5-LO-deficient mice and evaluated the progression of infection and concomitant expression of immune mediators. Here, we demonstrate thatB. abortusinduced the upregulation of 5-LO mRNA in wild-type mice. Moreover, this pathogen upregulated the production of the lipid mediators leukotriene B4and lipoxin A4in a 5-LO-dependent manner. 5-LO-deficient mice displayed lower bacterial burdens in the spleen and liver and less severe liver pathology, demonstrating an enhanced resistance to infection. Host resistance paralleled an increased expression of the proinflammatory mediators interleukin-12 (IL-12), gamma interferon (IFN-γ), and inducible nitric oxide synthase (iNOS) during the course of infection. Moreover, we demonstrated that 5-LO downregulated the expression of IL-12 in macrophages duringB. abortusinfection. Our results suggest that 5-LO has a major involvement inB. abortusinfection, by functioning as a negative regulator of the protective Th1 immune responses against this pathogen.

scholarly journals Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice

2013 ◽  
Vol 305 (10) ◽  
pp. G667-G677 ◽  
Author(s):  
Claire B. Larmonier ◽  
Daniel Laubitz ◽  
Faihza M. Hill ◽  
Kareem W. Shehab ◽  
Leszek Lipinski ◽  
...  
Keyword(s):  
Critical Role ◽  
Mucosal Injury ◽  
Microbiota Composition ◽  
Wild Type ◽  
Microbial Composition ◽  
Epithelial Barrier Function ◽  
Qpcr Analysis ◽  
Enteric Infections ◽  
Inflammatory Bowel ◽  
Deficient Mice

Chronic inflammation and enteric infections are frequently associated with epithelial Na+/H+exchange (NHE) inhibition. Alterations in electrolyte transport and in mucosal pH associated with inflammation may represent a key mechanism leading to changes in the intestinal microbial composition. NHE3 expression is essential for the maintenance of the epithelial barrier function. NHE3−/−mice develop spontaneous distal chronic colitis and are highly susceptible to dextran sulfate (DSS)-induced mucosal injury. Spontaneous colitis is reduced with broad-spectrum antibiotics treatment, thus highlighting the importance of the microbiota composition in NHE3 deficiency-mediated colitis. We herein characterized the colonic microbiome of wild-type (WT) and NHE3−/−mice housed in a conventional environment using 454 pyrosequencing. We demonstrated a significant decrease in the phylogenetic diversity of the luminal and mucosal microbiota of conventional NHE3−/−mice compared with WT. Rederivation of NHE3−/−mice from conventional to a barrier facility eliminated the signs of colitis and decreased DSS susceptibility. Reintroduction of the conventional microflora into WT and NHE3−/−mice from the barrier facility resulted in the restoration of the symptoms initially described in the conventional environment. Interestingly, qPCR analysis of the microbiota composition in mice kept in the barrier facility compared with reconventionalized mice showed a significant reduction of Clostridia classes IV and XIVa. Therefore, the gut microbiome plays a prominent role in the pathogenesis of colitis in NHE3−/−mice, and, reciprocally, NHE3 also plays a critical role in shaping the gut microbiota. NHE3 deficiency may be a critical contributor to dysbiosis observed in patients with inflammatory bowel disease.

Activation of the Hypothalamic- Pituitary-Adrenal Axis in IL-1β-Converting Enzyme-Deficient Mice

2000 ◽  
Vol 7 (4) ◽  
pp. 189-194 ◽  
Author(s):  
Stéphane Liège ◽  
Elisabeth Moze ◽  
Keith W. Kelley ◽  
Patricia Parnet ◽  
Pierre J. Neveu
Keyword(s):  
Hypothalamic Pituitary Adrenal Axis ◽  
Converting Enzyme ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Enzyme Deficient ◽  
Deficient Mice ◽  
Pituitary Adrenal Axis

scholarly journals IDH2-Deficient Mice Develop Spinal Deformities With Aging

2018 ◽  
pp. 487-494 ◽  
Author(s):  
U. CHAE ◽  
N.-R. PARK ◽  
E. S. KIM ◽  
J.-Y. CHOI ◽  
M. YIM ◽  
...  
Keyword(s):  
Animal Model ◽  
Morphological Analysis ◽  
Histological Analysis ◽  
Critical Role ◽  
Spinal Deformities ◽  
Micro Ct ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 2 ◽  
Deficient Mice

Spinal deformities such as scoliosis and kyphosis are incurable, and can lead to decreased physical function, pain, and reduced quality of life. Despite much effort, no clear therapies for the treatment of these conditions have been found. Therefore, the development of an animal model for spinal deformity would be extremely valuable to our understanding of vertebral diseases. In this study, we demonstrate that mice deficient in the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2) develop spinal deformities with aging. We use morphological analysis as well as radiographic and micro-CT imaging of IDH2-deficient mice to characterize these deformities. Histological analysis showed increased abnormalities in IDH2-deficient mice compared to wild type mice. Taken together, the results suggest that IDH2 plays a critical role in maintaining the spinal structure by affecting the homeostatic balance between osteoclasts and osteoblasts. This indicates that IDH2 might be a potent target for the development of therapies for spinal deformities. Our findings also provide a novel animal model for vertebral disease research.

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