Different Strains Of Mice Research Articles

Noncoding variations in Cyp24a1 gene are associated with Klotho-mediated aging phenotypes in different strains of mice.

In mutant mice, reduced levels of Klotho promoted high levels of active vitamin D in the serum. Genetic or dietary manipulations that diminished active vitamin D alleviated aging‐related phenotypes caused by Klotho down‐regulation. The hypomorphic Klotho [kl/kl] allele that decreases Klotho expression in C3H, BALB/c, 129, and C57BL/6 genetic backgrounds substantially increases 1,25(OH)2D3 levels in the sera of susceptible C3H, BALB/c, and 129, but not C57BL/6 mice. This may be attributed to increased basal expression of Cyp24a1 in C57BL/6 mice, which promotes inactivation of 1,25(OH)2D3. Decreased expression of Cyp24a1 in susceptible strains was associated with genetic alterations in noncoding regions of Cyp24a1 gene, which were strongly reminiscent of super‐enhancers that regulate gene expression. These observations suggest that higher basal expression of an enzyme required for catabolizing vitamin D renders B6‐kl/kl mice less susceptible to changes in Klotho expression, providing a plausible explanation for the lack of aging phenotypes on C57BL/6 strain.

Genetic Strain and Sex Differences in a Hyperoxia-Induced Mouse Model of Varying Severity of Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a disease prevalent in preterm babies with a need for supplemental oxygen, resulting in impaired lung development and dysregulated vascularization. Epidemiologic studies have shown that males are more prone to BPD and have a delayed recovery compared with females, for reasons unknown. Herein, we tried to recapitulate mild, moderate, and severe BPD, using two different strains of mice, in males and females: CD1 (outbred) and C57BL/6 (inbred). Aside from higher body weight in the CD1 strain, there were no other gross morphologic differences with respect to alveolar development between the two strains. With respect to lung morphology after oxygen exposure, females had less injury with better preservation of alveolar chord length and decreased alveolar protein leak and inflammatory cells in the bronchoalveolar lavage fluid. In addition, housekeeping genes, which are routinely used as loading controls, were expressed differently in males and females. In the BPD mouse model, gonadotropin-releasing hormone was increased in females compared with males. Specific miRNAs (miR-146 and miR-34a) were expressed differently in the sexes. In the severe BPD mouse model, administering miR-146 mimic to males attenuated lung damage, whereas administering miR-146 inhibitor to females increased pulmonary injury.

Study of tissue inflammatory response in different mice strains infected by dematiaceous fungi Fonsecaea pedrosoi

Background:Diseases caused by melanized fungi include mycetoma, chromoblastomycosis and phaeohyphomycosis. This broad clinical spectrum depends on the dynamic interactions between etiologic agent and host. The immune status of the host influences on the development of the disease, as, an exemple. phaeohyphomicosis is more frequently observed in immunocompromised patients. Objectives:Examine the histological inflammatory response induced by Fonsecaea pedrosoi in several different strains of mice (BALB/c, C57BL/6, Nude and SCID, and reconstituted Nude). Methods:Fonsecaea pedrosoi was cultivated on agar gel and a fragment of this gel was implanted subcutaneously in the abdominal region of female adult mice. After infection has been obtained, tissue fragment was studied histopathologically. Results:There were significant changes across the strains, with the nodular lesion more persistent in Nude and SCID mice, whereas in immunocompetent mice the lesion progressed to ulceration and healing. The histopathological analysis showed a significant acute inflammatory reaction which consisted mainly of neutrophils in the initial phase that was subsequently followed by a tuberculoid type granuloma in immunocompetent mice. Study limitations:There is no a suitable animal model for chromoblastomycosis. Conclusions:The neutrophilic infiltration had an important role in the containment of infection to prevent fungal spreading, including in immunodeficient mice. The fungal elimination was dependent on T lymphocytes. The re-exposure of C57BL/6 mice to Fonsecaea pedrosoi caused a delay in resolving the infection, and appearance of muriform cells, which may indicate that re-exposure to fungi, might lead to chronicity of infection.

Transcriptional profiling of livers from different strain of mice treated with Asparaginase

Transcriptional profiling of livers from different strain of mice treated with Asparaginase

Longitudinal Magnetic Resonance Imaging Analysis and Histological Characterization after Spinal Cord Injury in Two Mouse Strains with Different Functional Recovery: Gliosis as a Key Factor.

Spinal cord injuries (SCI) are disastrous neuropathologies causing permanent disabilities. The availability of different strains of mice is valuable for studying the pathophysiological mechanisms involved in SCI. However, strain differences have a profound effect on spontaneous functional recovery after SCI. CX3CR1+/eGFP and Aldh1l1-EGFP mice that express green fluorescent protein in microglia/monocytes and astrocytes, respectively, are particularly useful to study glial reactivity. Whereas CX3CR1+/eGFP mice have C57BL/6 background, Aldh1l1-EGFP are in Swiss Webster background. We first assessed spontaneous functional recovery in CX3CR1+/eGFP and Aldh1l1-EGFP mice over 6 weeks after lateral spinal cord hemisection. Second, we carried out a longitudinal follow-up of lesion evolution using in vivo T2-weighted magnetic resonance imaging (MRI). Finally, we performed in-depth analysis of the spinal cord tissue using ex vivo T2-weighted MRI as well as detailed histology. We demonstrate that CX3CR1+/eGFP mice have improved functional recovery and reduced anxiety after SCI compared with Aldh1l1-EGFP mice. We also found a strong correlation between in vivo MRI, ex vivo MRI, and histological analyses of the injured spinal cord in both strain of mice. All three modalities revealed no difference in lesion extension and volume between the two strains of mice. Importantly, histopathological analysis identified decreased gliosis and increased serotonergic axons in CX3CR1+/eGFP compared with Aldh1l1-EGFP mice following SCI. These results thus suggest that the strain-dependent improved functional recovery after SCI may be linked with reduced gliosis and increased serotonergic innervation.

Effect of Frataxin Knockout on Mouse Cardiomyocytes Using DsRed.T3 as a Quantifying Marker

Background and Hypothesis: 
 Discosoma Red (DsRed) is a strong fluorescent marker that has many practical uses for scientific studies. We engineered a transgenic mouse expressing DsRed.T3 only in cardiomyocyte nuclei, and then crossed this with a conditional knockout mouse with loss of Frataxin (FXN) in heart. It is known that dysfunction of the Frataxin (FXN) gene can cause Friedrich’s Ataxia (FRDA), a disease associated with ataxia, weakness and dilated cardiomyopathy in humans. The current study aimed to: 1) Determine if DsRed overexpression in cardiomyocyte nuclei would negatively affect cardiac tissue, and 2) Use the DsRed.T3 mouse to determine whether FXN knockout (KO) would cause a loss of cardiomyocytes. 
 
 Experimental Design or Project Methods: 
 The study was done by examining three different strains of mice: wild-type, DsRed.T.3 overexpressing Tg mice, and FXN KO mice with loss of FXN in cardiomyocytes. Mice were analyzed using genotyping, frozen immunofluorescent stains, α-actinin and Hoechst, TPLSM, confocal microscopy, western blotting, H&E, echocardiography, and heart:body weight ratios. 
 Results: 
 Results showed that DsRed.T3 localized to the nucleus of cardiomyocytes and that after 6.5 months there were some significant effects on cardiac function, although not on cardiac tissue. Further analysis is ongoing to determine if there is a loss of cardiomyocytes within the FXN KO group. 
 Conclusion and Potential Impact: 
 This study shows promise for how researchers can study the heart, and more specifically, Friedreich’s Ataxia, while also shedding light on how FXN may ultimately affect the heart in FRDA patients.

From the Literature

From the Literature

Persistence of Gamma-H2AX Foci in Bronchial Cells Correlates with Susceptibility to Radiation Associated Lung Cancer in Mice.

The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in how quickly they repair radiation-induced DNA double-strand breaks (DSBs). We assayed mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA DSBs during protracted irradiation. We measured unrepaired γ-H2AX radiation-induced foci (RIF), which persisted after chronic 24-h gamma irradiation, as a surrogate marker for repair efficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/c founder strain. We observed a very strong correlation (R2 = 79.18%, P < 0.001) between the level of unrepaired RIF and radiogenic lung cancer incidence measured in the same strains. Interestingly, spontaneous levels of foci in nonirradiated mice also showed good correlation with lung cancer incidence when incidence data from male and female mice were combined. These results suggest that genetic differences in DNA repair capacity largely account for differing susceptibilities to radiation-induced lung cancer among CcS/Dem mouse strains, and that high levels of spontaneous DNA damage are also a relatively good marker of cancer predisposition. In a smaller pilot study, we found that the repair capacity measured in peripheral blood leucocytes also correlated well with radiogenic lung cancer susceptibility, raising the possibility that the assay could be used to detect radiogenic lung cancer susceptibility in humans.

Significantly Improved Pharmacokinetics Enhances In Vivo Efficacy of APX001 against Echinocandin- and Multidrug-Resistant Candida Isolates in a Mouse Model of Invasive Candidiasis.

APX001 is a first-in-class, intravenous and orally available, broad-spectrum antifungal agent in clinical development for the treatment of life-threatening invasive fungal infections. The half-life of APX001A, the active moiety of APX001, is significantly shorter in mice than in humans (1.4 to 2.75 h in mice versus 2 to 2.5 days in humans), making the exploration of efficacy in mouse models difficult. After pretreatment with 1-aminobenzotriazole (ABT), a nonspecific cytochrome P450 inhibitor, greatly increased plasma APX001A exposure was observed in mice of different strains and of both genders. As a consequence, 26 mg/kg APX001 plus ABT sterilized kidneys in mice infected with Candida albicans, while APX001 alone at the same dose resulted in a modest burden reduction of only 0.2 log10 CFU/g, relative to the vehicle control. In the presence of ABT, 2 days of once-daily dosing with APX001 at 26 mg/kg also demonstrated significant in vivo efficacy in the treatment of Candida glabrata infections in mice. Potent kidney burden reduction was achieved in mice infected with susceptible, echinocandin-resistant, or multidrug-resistant strains. In contrast, the standard of care (micafungin) was ineffective in treating infections caused by the resistant C. glabrata isolates.

Dopaminergic amacrine cell number, plexus density, and dopamine content in the mouse retina: Strain differences and effects of Bax gene disruption

Many types of retinal neuron modulate the distribution of their processes to ensure a uniform coverage of the retinal surface. Dendritic field area, for instance, is inversely related to the variation in cellular density for many cell types, observed either across retinal eccentricity or between different strains of mice that differ in cell number. Dopaminergic amacrine (DA) cells, by contrast, have dendritic arbors that bear no spatial relationship to the presence of their immediate homotypic neighbors, yet it remains to be determined whether their coverage upon the retina, as a population, is conserved across variation in their total number. The present study assessed the overall density of the dopaminergic plexus in the inner plexiform layer in the presence of large variation in the total number of DA cells, as well as their retinal dopamine content, to determine whether either of these features is conserved. We first compared these traits between two strains of mice (C57BL/6J and A/J) that exhibit a two-fold difference in DA cell number. We subsequently examined these same traits in littermate mice for which the pro-apoptotic Bax gene was either intact or knocked out, yielding a five-fold difference in DA cell number. In both comparisons, we found greater plexus density and DA content in the strain or condition with the greater number of DA cells. The population of DA cells, therefore, does not appear to self-regulate its process coverage to achieve a constant density as the DA mosaic is established during development, nor its functional dopamine content in maturity.

Assessment of mouse strain differences in baseline esterase activities and toxic response to sarin

Genetics likely play a role in various responses to nerve agent (NA) exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses. This study uses different mouse strains to identify if mouse strain differences in sarin exposure exist. In Experiment 1, basal levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CE) were measured in different strains of naïve mice to account for potential pharmacokinetic determinants of individual differences. In Experiment 2, median lethal dose (MLD) levels were estimated in 8 inbred mouse strains following subcutaneous (s.c.) administration of sarin. Few strain or sex differences in esterase activity levels were observed, with the exception of erythrocyte AChE activity in the C57BL/6J strain. Both sex and strain differences in toxicity were observed, with the most resistant strains being the BALB/cByJ and FVB/NJ strains and the most sensitive strain being the DBA/2J strain. These findings can be expanded to explore pathways involved in NA response, which may provide an avenue to develop therapeutics for preventing and treating the damaging effects of NA exposure.

Fetal Growth Restriction Induced by Transient Uterine Ischemia-Reperfusion: Differential Responses in Different Mouse Strains.

We characterized fetal and placental growth and uterine and placental inflammation in pregnant C3H/HeOuJ and C57BL/6J mice (strains with different sensitivities to metabolic and circulatory pathologies), using different uterine ischemia/reperfusion (I/R) protocols, to establish and refine a murine model of I/R-induced fetal growth restriction (FGR). Pregnant C3H/HeOuJ mice on gestation day 15 were subjected to unilateral uterine I/R by (1) total blood flow restriction (TFR) by occlusion of the right ovarian and uterine arteries for 30 minutes, (2) partial flow restriction (PFR) by occlusion of only the right ovarian artery for 30 minutes, or (3) sham surgery. Pregnant C57BL/6J mice were treated the same, but on gestation day 14 and with TFR for only 5 minutes due to high sensitivity of C57BL/6J mice to I/R. Four days post-I/R, the animals were euthanized to determine fetal and placental weight and fetal loss and to assay placental myeloperoxidase (MPO) activity. In C3H/HeOuJ mice, TFR/30 minutes induced significantly ( P < .05) lower fetal and placental weights and higher placental MPO activity, compared to controls. The PFR/30 minutes produced the same effects except placental weights were not reduced. In contrast, in C57BL/6J mice, TFR for only 5 minutes was sufficient to induce FGR and increase fetal loss; while PFR/30 minutes lowered fetal but not placental weights and increased fetal loss but not placental MPO activity. In summary, we present the first published model of I/R-induced FGR in mice. We find that mice of different strains have differing sensitivities to uterine I/R, therefore differing I/R response mechanisms.

Differential Effects of Niacin on High-Fat Diet–Induced Adipose Tissue Inflammation and Nonalcoholic Fatty Liver Disease in C57BL6/J and B6129SF2/J Mice

Pharmacological doses of niacin improve adipose tissue (AT) inflammation and nonalcoholic fatty liver disease (NAFLD) in rodents chronically fed a high-fat diet (HFD). However, recent mouse studies have demonstrated significant metabolic changes in different strains of mice fed a HFD. Therefore, the aim of this study was to assess the effect of niacin on both AT inflammation and liver steatosis in two mouse strains, C57BL6/J (B6) and B6129SF2/J (B6129), under HFD feeding. Thirty-two male B6 and 32 male B6129 mice were randomized into four groups: Chow/Vehicle (CV), Chow/Niacin (CN), HFD/Vehicle (HV), and HFD/Niacin (HN). They were fed either a chow (10% fat) or HFD (60% fat) for 20 weeks. Niacin (360 mg/kg/day) or vehicle was added to the drinking water from week 5 until the end of the study. As expected, HFD-fed mice gained more weight than chow-fed mice in both strains, with no difference in weight gain between strains. Crown-like structure (CLS) number, a hallmark of AT inflammation, was increased in HV mice of both strains compared to CV mice. In addition, HV B6 mice had higher CLS number than HV B6129 mice. In B6129 mice, niacin decreased CLS number in HN compared to HV mice, while this decrease was not observed in B6 mice. Liver weight to body weight (L/B) ratio, liver triglyceride (TG) content and NASH score was increased in HV compared to CV B6 mice. In contrast, in B6129 mice, only NASH score was increased in HV compared to CV controls. Niacin had no impact on L/B ratio, TG content, or NASH score in B6 mice. However, in B6129 mice, niacin increased all three parameters in HN compared to HV mice. In conclusion, there are strain differential effects on AT inflammation and NAFLD induced by HFD feeding. Interestingly, liver steatosis is significantly increased in HFD-fed B6129 mice treated with niacin. This increase is potentially due to methyl deficiency, as niacin is a potent hepatic methyl consumer and 129 mice are more sensitive to methyl deficiency. Disclosure H. Fang: None. E. Graff: None. Z. Li: None. R.L. Judd: None.

How would publication bias distort the estimated effect size of prototypic antidepressants in the forced swim test?

This commentary aims to discuss the impact of publication bias on the estimated effect of prototypic antidepressants in the forced swim test (FST). A systematic review and meta-analysis (SRMA) recently reported by Kara et al. (2018) showed that selected prototypic antidepressants reduced immobility time of mice in the FST across a variety of experimental designs. Despite differences in the procedures for SRMA, these results resemble the interim data collected by our research group according to a protocol deposited in the Systematic Review Facility (http://syrf.org.uk/) and Open Science Framework (osf.io/9kxm4). Both studies detected a high amount of publications reporting statistically significant results and agreement with the primary hypothesis raising the possibility of publication bias in the field of FST. In our preliminary analysis, no evidence for publication bias was observed. However, the present work was limited to the effects of imipramine (doses ranging from 4 to 64 mg/kg) in different strains of mice. Therefore, more comprehensive studies are required to evaluate the risk of publication bias in the field of basic antidepressant research. We see the need to expand the current preliminary studies to evaluate the risk of publication bias within the preclinical research using the FST. Appraisal of the risk of publication bias may avoid misestimated effects of drugs in the FST providing better bases for the discovery of new antidepressants.

The effects of different doses of thymulin in vivo and in vitro on some biological properties of bone marrow-derived multipotent mesenchymal stromal cells in mice of different strains

The effects of different doses of thymulin in vivo and in vitro on some biological properties of bone marrow-derived multipotent mesenchymal stromal cells in mice of different strains

Mouse Strain Affects Behavioral and Neuroendocrine Stress Responses Following Administration of Probiotic Lactobacillus rhamnosus JB-1 or Traditional Antidepressant Fluoxetine.

Currently, there is keen interest in the development of alternative therapies in the treatment of depression. Given the explosion of research focused on the microbiota-gut-brain axis, consideration has turned to the potential of certain probiotics to improve patient outcomes for those suffering from mood disorders. Here we examine the abilities of a known antidepressant, fluoxetine, and the probiotic Lactobacillus rhamnosus JB-1™, to attenuate responses to two established criteria for depressive-like behavior in animal models, the tail suspension test (TST) and the corticosterone response to an acute restraint stressor. We examine two different strains of mice known to differ in the extent to which they express both anxiety-like behavior and measures of despair—BALB/c and Swiss Webster—with respectively high and normal behavioral phenotypes for each. While adult male BALB/c mice responded with increased antidepressive-like behavior to both fluoxetine and L. rhamnosus JB-1 in both the TST and the corticosterone stress response, SW mice did not respond to either treatment as compared to controls. These findings highlight the importance of investigating putative antidepressants in mouse strains known to express face validity for some markers of depression. Clinical studies examining the activity of L. rhamnosus JB-1 in patients suffering from mood disorders are warranted, as well as further pre-clinical work examining how interactions between host genotype and intestinal microbial alterations may impact behavioral responses. This study adds to the literature supporting the possibility that modifying the intestinal microbiota via probiotics represents a promising potential therapeutic breakthrough in the treatment of psychiatric disease.

Color matters: They would choose if they could (see)!

Concerning standardization of laboratory animal husbandry, only exiguous changes of habitat can potentially influence animal physiology or results of behavioral tests. Routinely, mice chow is dyed when different types of diets are dispensed. Given the fact that the dye itself has no effects on food odor or flavor, we wanted to test the hypothesis that the color of chow has an impact on food uptake in mice. Twelve-week-old male mice of different strains (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ; n = 12/strain) were single-housed in PhenoMaster® cages. After acclimatization standard mice chow in different colors was administered. Food intake was monitored as a two-alternative choice test of different color combinations. All animals had an average food intake of 3 g/d and no preferences were observed when a combination of identically colored food was offered. Preference tests yielded significant aversion to blue food and significant attraction to yellow and green food in C57BL/6 and DBA/2J mice. In C3H/HeJ and BALB/cJ mice no color-related pattern occurred. Selected mice strains have known differences concerning functionality of their visual sense. C57BL/6 and DBA/2 mice are considered to be normal sighted at testing age, BALB/c is representative for albino strains and C3H mice carry mutations resulting in retinal alterations. Results suggesting that normal-sighted mice would be selective concerning food color when given the choice. Nevertheless, this does not influence overall quantity of food intake when animals were provided solely with food colored with a single dye. Moreover, visually impaired mice showed no color-related food preferences.

Glycosphingolipid levels and glucocerebrosidase activity are altered in normal aging of the mouse brain.

Aging is the predominant risk factor for both genetic and sporadic Parkinson’s disease (PD). The majority of PD cases are nonfamilial, and the connection between aging and PD-associated genes is not well understood. Haploinsufficiency of the GBA gene, leading to a reduction in glucocerebrosidase (GCase) activity, is one of the most common genetic risk factors for PD. Furthermore, GCase activity is also reduced in brain regions of sporadic PD patients, with a corresponding accumulation of its glycosphingolipid (GSL) substrates. Recent findings in PD patients and aging control cases, and in human PD patient induced pluripotent stem cell neurons, have shown an age-dependent reduction in GCase activity and an elevation of some GSLs. We therefore asked whether aging-induced changes to both lysosomal and nonlysosomal GCase activity and GSL homeostasis in the brain could also be reflected in other nonhuman mammalian systems. Increases in brain polyubiquitin and the lysosomal-associated membrane protein, LAMP2A, were found in 24-month-old wild-type mice compared to 1.5-month-old mice. A lipidomic analysis was performed on brains of wild-type mice of different strains between 1.5 and 24 months of age. Aging created GSL changes that are reminiscent of sporadic PD. Levels of glucosylceramide, glucosylsphingosine, lactosylceramide, and GM1a were elevated in the brain of aged mice, and levels of complex gangliosides, GD1a, GD1b, and GT1b, were reduced with age. Parallel biochemical analyses revealed a change in lipid metabolism probably mediated by lysosomal hydrolases, with reduced GCase and increased neuraminidase activity. Based on these data, we hypothesize that perturbation of GSL metabolism in the aging brain may precede or may be part of abnormal protein handling and may accelerate PD pathophysiological processes in vulnerable neurons in PD and other age-related neurodegenerative disorders.

ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice

The ARID1A gene encodes a protein that is part of the large adenosine triphosphate (ATP)-dependent chromatin remodeling complex SWI/SNF and is frequently mutated in human pancreatic ductal adenocarcinomas (PDACs). We investigated the functions of ARID1A during formation of PDACs in mice. We performed studies with Ptf1a-Cre;KrasG12D mice, which express activated Kras in the pancreas and develop pancreatic intraepithelial neoplasias (PanINs), as well as those with disruption of Aird1a (Ptf1a-Cre;KrasG12D;Arid1af/f mice) or disruption of Brg1 (encodes a catalytic ATPase of the SWI/SNF complex) (Ptf1a-Cre;KrasG12D; Brg1f/fmice). Pancreatic ductal cells (PDCs) were isolated from Arid1af/f mice and from Arid1af/f;SOX9OE mice, which overexpress human SOX9 upon infection with an adenovirus-expressing Cre recombinase. Pancreatic tissues were collected from all mice and analyzed by histology and immunohistochemistry; cells were isolated and grown in 2-dimensional and 3-dimensional cultures. We performed microarray analyses to compare gene expression patterns in intraductal papillary mucinous neoplasms (IPMNs) from the different strains of mice. We obtained 58 samples of IPMNs and 44 samples of PDACs from patients who underwent pancreatectomy in Japan and analyzed them by immunohistochemistry. Ptf1a-Cre;KrasG12D mice developed PanINs, whereas Ptf1a-Cre;KrasG12D;Arid1af/f mice developed IPMNs and PDACs; IPMNs originated from PDCs. ARID1A-deficient IPMNs did not express SOX9. ARID1A-deficient PDCs had reduced expression of SOX9 and dedifferentiated in culture. Overexpression of SOX9 in these cells allowed them to differentiate and prevented dilation of ducts. Among mice with pancreatic expression of activated Kras, those with disruption of Arid1a developed fewer PDACs from IPMNs than mice with disruption of Brg1. ARID1A-deficient IPMNs had reduced activity of the mTOR pathway. Human IPMN and PDAC specimens had reduced levels of ARID1A, SOX9, and phosphorylated S6 (a marker of mTOR pathway activation). Levels of ARID1A correlated with levels of SOX9 and phosphorylated S6. ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.

Induction of Interleukin 10 by Borrelia burgdorferi Is Regulated by the Action of CD14-Dependent p38 Mitogen-Activated Protein Kinase and cAMP-Mediated Chromatin Remodeling.

Host genotype influences the severity of murine Lyme borreliosis, caused by the spirochetal bacterium Borrelia burgdorferi C57BL/6 (B6) mice develop mild Lyme arthritis, whereas C3H/HeN (C3H) mice develop severe Lyme arthritis. Differential expression of interleukin 10 (IL-10) has long been associated with mouse strain differences in Lyme pathogenesis; however, the underlying mechanism(s) of this genotype-specific IL-10 regulation remained elusive. Herein we reveal a cAMP-mediated mechanism of IL-10 regulation in B6 macrophages that is substantially diminished in C3H macrophages. Under cAMP and CD14-p38 mitogen-activated protein kinase (MAPK) signaling, B6 macrophages stimulated with B. burgdorferi produce increased amounts of IL-10 and decreased levels of arthritogenic cytokines, including tumor necrosis factor (TNF). cAMP relaxes chromatin, while p38 increases binding of the transcription factors signal transducer and activator of transcription 3 (STAT3) and specific protein 1 (SP1) to the IL-10 promoter, leading to increased IL-10 production in B6 bone marrow-derived monocytes (BMDMs). Conversely, macrophages derived from arthritis-susceptible C3H mice possess significantly less endogenous cAMP, produce less IL-10, and thus are ill equipped to mitigate the damaging consequences of B. burgdorferi-induced TNF. Intriguingly, an altered balance between anti-inflammatory and proinflammatory cytokines and CD14-dependent regulatory mechanisms also is operative in primary human peripheral blood-derived monocytes, providing potential insight into the clinical spectrum of human Lyme disease. In line with this notion, we have demonstrated that cAMP-enhancing drugs increase IL-10 production in myeloid cells, thus curtailing inflammation associated with murine Lyme borreliosis. Discovery of novel treatments or repurposing of FDA-approved cAMP-modulating medications may be a promising avenue for treatment of patients with adverse clinical outcomes, including certain post-Lyme complications, in whom dysregulated immune responses may play a role.