scholarly journals Cytolethal Distending Toxin Is Essential for Helicobacter hepaticus Colonization in Outbred Swiss Webster Mice

2005 ◽  
Vol 73 (6) ◽  
pp. 3559-3567 ◽  
Author(s):  
Zhongming Ge ◽  
Yan Feng ◽  
Mark T. Whary ◽  
Prashant R. Nambiar ◽  
Shilu Xu ◽  
...  
Keyword(s):  
Mrna Level ◽  
Interleukin 10 ◽  
Mouse Strains ◽  
Cytolethal Distending Toxin ◽  
Mrna Levels ◽  
Helicobacter Hepaticus ◽  
Male Mice ◽  
Susceptible Mouse ◽  
Female Mice ◽  
Ifn Γ

ABSTRACT Helicobacter hepaticus, which induces chronic hepatitis and typhlocolitis in susceptible mouse strains, produces a cytolethal distending toxin (CDT) consisting of CdtA, CdtB, and CdtC. A cdtB-deficient H. hepaticus isogenic mutant (HhcdtBm7) was generated and characterized for colonization parameters in four intestinal regions (jejunum, ileum, cecum, and colon) of outbred Swiss Webster (SW) mice. Inactivation of the cdtB gene abolished the ability of HhcdtBm7 to colonize female mice at both 8 and 16 weeks postinfection (wpi), whereas HhcdtBm7 colonized all of four intestinal regions of three of five males at 8 wpi and then was eliminated by 16 wpi. Wild-type (WT) H. hepaticus was detected in the corresponding intestinal regions of both male and female mice at 8 and 16 wpi; however, colonization levels of WT H. hepaticus in the cecum and colon of male mice were approximately 1,000-fold higher than in females (P < 0.0079) at 16 wpi. Infection with WT H. hepaticus, but not HhcdtBm7, at 8 wpi was associated with significantly increased mRNA level of ileal and cecal gamma interferon (IFN-γ) in females (P < 0.016 and 0.031 between WT H. hepaticus-infected and sham-dosed females, respectively). In contrast, the mRNA levels of IFN-γ were significantly higher in the colon (P < 0.0079) and trended to be higher in the cecum (P < 0.15) in the HhcdtBm7-colonized male mice versus the sham-dosed controls at 8 wpi. In addition, mRNA levels of ileal IFN-γ were significantly higher in the control females than males at 8 wpi (P < 0.016). There were significantly higher Th1-associated immunoglobulin G2a (IgG2a), Th2-associated IgG1 and mucosal IgA (P < 0.002, 0.002, 0.002, respectively) responses in the mice infected with WT H. hepaticus when compared to HhcdtBm7 at 16 wpi. Colonic interleukin-10 (IL-10) expressions at 16 wpi were significantly lower in both female and male mice colonized by WT H. hepaticus or in males transiently colonized through 8 wpi by HhcdtBm7 versus control mice (P < 0.0159). These lines of evidence indicate that (i) H. hepaticus CDT plays a crucial role in the persistent colonization of H. hepaticus in SW mice; (ii) SW female mice are more resistant to H. hepaticus colonization than male mice; (iii) there was persistent colonization of WT H. hepaticus in cecum, colon, and jejunum but only transient colonization of H. hepaticus in the ileum of female mice; (iv) H. hepaticus colonization was associated with down-regulation of colonic IL-10 production.

scholarly journals Interleukin 10 deficiency attenuates induction of anti-TSH receptor antibodies and hyperthyroidism in a mouse Graves' model

2011 ◽  
Vol 209 (3) ◽  
pp. 353-357 ◽  
Author(s):  
Ikuko Ueki ◽  
Norio Abiru ◽  
Kentaro Kawagoe ◽  
Yuji Nagayama
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Recombinant Adenovirus ◽  
Interleukin 10 ◽  
T Cell Response ◽  
Tsh Receptor ◽  
Mouse Strains ◽  
Susceptible Mouse ◽  
Ifn Γ

Experimental Graves'-like hyperthyroidism can be induced in susceptible mouse strains by repetitive immunizations with recombinant adenovirus expressing the human full-length TSH receptor (TSHR) or its A-subunit. Previous studies have shown that splenocytes from immunized mice produce interferon (IFN)-γ and interleukin (IL) 10 in response to antigen stimulation in an in vitro T cell recall assay. Although IFN-γ is now well known to be essential for disease induction, the role(s) played by IL10 are unknown. Therefore, this study was conducted to clarify the significance of endogenous IL10 in the pathogenesis of experimental Graves' disease using IL10 deficient (IL10−/−) mice. Our results show that T cell response was augmented when estimated by their antigen-specific secretion of the key cytokine IFN-γ, but B cell function was dampened, that is, anti-TSHR antibody titers were decreased in IL10−/− mice, resulting in a lower incidence of Graves' hyperthyroidism (54% in IL10+/+ vs 25% in IL10−/−). Thus, in addition to IFN-γ, these data clarified the role of IL10 for optimizing anti-TSHR antibody induction and eliciting Graves' hyperthyroidism in our Graves' mouse model.

scholarly journals Helicobacter hepaticus-Induced Colitis in Interleukin-10-Deficient Mice: Cytokine Requirements for the Induction and Maintenance of Intestinal Inflammation

2001 ◽  
Vol 69 (7) ◽  
pp. 4232-4241 ◽  
Author(s):  
Marika C. Kullberg ◽  
Antonio Gigliotti Rothfuchs ◽  
Dragana Jankovic ◽  
Patricia Caspar ◽  
Thomas A. Wynn ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Interleukin 10 ◽  
Inos Mrna ◽  
Th1 Cells ◽  
Mrna Levels ◽  
Helicobacter Hepaticus ◽  
Tnf Α ◽  
Disease Induction ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT We have previously shown that specific-pathogen-free interleukin-10 (IL-10)-deficient (IL-10 KO) mice reconstituted withHelicobacter hepaticus develop severe colitis associated with a Th1-type cytokine response. In the present study, we formally demonstrate that IL-12 is crucial for disease induction, because mice deficient for both IL-10 and IL-12 p40 show no intestinal pathology following H. hepaticus infection. By using monoclonal antibodies (MAbs) to IL-12, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α), we have further analyzed the role of these cytokines in the maintenance of the Th1 response and inflammation in IL-10 KO mice with established H. hepaticus-induced colitis. Treatment of infected colitic IL-10 KO mice with anti-IL-12 p40 resulted in markedly reduced intestinal inflammation, colonic IFN-γ, TNF-α, and inducible nitric oxide synthase (iNOS) mRNA levels, and H. hepaticus-specific IFN-γ secretion by mesenteric lymph node (MLN) cells compared to the findings in control MAb-treated mice. Moreover, the diminished pathology was associated with decreased numbers of colonic CD3+ T cells and significantly reduced frequencies ofHelicobacter-reactive CD4+ Th1 cells in MLN. In contrast, anti-IFN-γ and/or anti-TNF-α had no effect on intestinal inflammation in IL-10 KO mice with established colitis. Using IL-10/IFN-γ double-deficient mice, we further show that IFN-γ is not required for the development of colitis follwing H. hepaticus infection. MLN cells from infected IL-10/IFN-γ KO animals secreted elevated amounts of IL-12 and TNF-α following bacterial antigen stimulation, indicating alternative pathways of disease induction. Taken together, our results demonstrate a crucial role for IL-12 in both inducing and sustaining intestinal inflammation through recruitment and maintenance of a pool of pathogenic Th1 cells.

scholarly journals Regulation of mdr2 P-glycoprotein expression by bile salts

1997 ◽  
Vol 321 (2) ◽  
pp. 389-395 ◽  
Author(s):  
Charles M. G. FRIJTERS ◽  
Roelof OTTENHOFF ◽  
Michel J. A. van WIJLAND ◽  
Carin M. J. van NIEUWKERK ◽  
Albert K. GROEN ◽  
...  
Keyword(s):  
Bile Salt ◽  
Bile Salts ◽  
Control Diet ◽  
Mrna Level ◽  
Northern Blotting ◽  
Mrna Levels ◽  
Male Mice ◽  
Complete Replacement ◽  
P Glycoprotein ◽  
Mrna Content

The phosphatidyl translocating activity of the mdr2 P-glycoprotein (Pgp) in the canalicular membrane of the mouse hepatocyte is a rate-controlling step in the biliary secretion of phospholipid. Since bile salts also regulate the secretion of biliary lipids, we investigated the influence of the type of bile salt in the circulation on mdr2 Pgp expression and activity. Male mice were fed a purified diet to which either 0.1% (w/w) cholate or 0.5% (w/w) ursodeoxycholate was added. This led to a near-complete replacement of the endogenous bile salt pool (mainly tauromuricholate) by taurocholate or tauroursodeoxycholate respectively. The phospholipid secretion capacity was then determined by infusion of increasing amounts of tauroursodeoxycholate. Cholate feeding resulted in a 55% increase in maximal phospholipid secretion compared with that in mice on the control diet. Northern blotting revealed that cholate feeding increased mdr2 Pgp mRNA levels by 42%. Feeding with ursodeoxycholate did not influence the maximum rate of phospholipid output or the mdr2 mRNA content. Female mice had a higher basal mdr2 Pgp mRNA level than male mice, and this was also correlated with a higher phospholipid secretion capacity. This could be explained by the 4-fold higher basal cholate content in the bile of female compared with male mice. Our results suggest that the type of bile salts in the circulation influences the expression of the mdr2 gene.

scholarly journals Gender differences in the response of CD-1 mouse bone to parathyroid hormone: potential role of IGF-I

2006 ◽  
Vol 189 (2) ◽  
pp. 279-287 ◽  
Author(s):  
Yongmei Wang ◽  
Takeshi Sakata ◽  
Hashem Z Elalieh ◽  
Scott J Munson ◽  
Andrew Burghardt ◽  
...  
Keyword(s):  
Gender Differences ◽  
Parathyroid Hormone ◽  
Cortical Bone ◽  
Mineral Apposition Rate ◽  
Mrna Levels ◽  
Male Mice ◽  
Bone Formation Rate ◽  
Male And Female ◽  
Female Mice ◽  
Igf I

Parathyroid hormone (PTH) exerts both catabolic and anabolic actions on bone. Studies on the skeletal effects of PTH have seldom considered the effects of gender. Our study was designed to determine whether the response of mouse bone to PTH differed according to sex. As a first step, we analyzed gender differences with respect to bone mass and structural properties of 4 month old PTH treated (80 μg/kg per day for 2 weeks) male and female CD-1 mice. PTH significantly increased fat free weight/body weight, periosteal bone formation rate, mineral apposition rate, and endosteal single labeling surface, while significantly decreasing medullary area in male mice compared with vehicle treated controls, but induced no significant changes in female mice. We then analyzed the gender differences in bone marrow stromal cells (BMSC) isolated from 4 month old male and female CD-1 mice following treatment with PTH (80 μg/kg per day for 2 weeks). PTH significantly increased the osteogenic colony number and the alkaline phosphatase (ALP) activity (ALP/cell) by day 14 in cultures of BMSCs from male and female mice. PTH also increased the mRNA level of receptor activator of nuclear factor κB ligand in the bone tissue (marrow removed) of both females and males. However, PTH increased the mRNA levels of IGF-I and IGF-IR only in the bones of male mice. Our results indicate that on balance a 2-weeks course of PTH is anabolic on cortical bone in this mouse strain. These effects are more evident in the male mouse. These differences between male and female mice may reflect the greater response to PTH of IGF-I and IGF-IR gene expression in males enhancing the anabolic effect on cortical bone.

scholarly journals Synthetic Nano-selenium Improving Macrophage Immune Responses Treatment of Bladder Tumor Antigens

2021 ◽  
Vol 4 (1) ◽  
pp. 43-52
Author(s):  
Zeinab Agharezaie ◽  
◽  
Setareh Haghighat ◽  
Mohammad Hossein Yazdi ◽  
◽  
...  
Keyword(s):  
Bladder Tumor ◽  
Tumor Antigens ◽  
Mrna Level ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Selenium Nanoparticles ◽  
Maximum Effect ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Tumor Lysate

Background: Synthetic nanoparticles are deemed to improve treatment with the least adverse effects. The effect of Selenium Nanoparticles (SeNPs) was reviewed on various pathogenic disorders. In the present project, the role of SeNPs on macrophage responses was assessed. Materials and Methods: SeNPs were prepared synthetically by ascorbic acid. Macrophages (MQs) were cultured and treated with SeNPs in combination with bladder tumor lysate and Bacillus Calmette Guerin (BCG). Other experimental groups include SeNPs + tumor lysate + MQs, BCG, BCG+MQs, and MQs. The mRNA levels of interferon-γ and interleukin-10 were evaluated using the real-time PCR method. Results: Synthetic selenium nanoparticles combined with the tumor lysate upregulated the mRNA level of interferon-γ after 12 and 24 h treatment. Regarding interleukin-10 expression, there were no remarkable differences in all experimental groups. The maximum effect of synthetic SeNPs was observed after 24 h treatment. Conclusion: The optimum effect of synthetic SeNPs presents in a treatment-dependent manner.

scholarly journals Adipocyte-specific modulation of KLF14 expression in mice leads to sex-dependent impacts in adiposity and lipid metabolism

2021 ◽  
Author(s):  
Qianyi Yang ◽  
Jameson Hinkle ◽  
Jordan N Reed ◽  
Redouane Aherrahrou ◽  
Zhiwen Xu ◽  
...  
Keyword(s):  
Fat Mass ◽  
Risk Allele ◽  
Lipid Storage ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Male Mice ◽  
Adipose Tissues ◽  
Female Mice ◽  
Fat Depots ◽  
Deficient Mice

Genome-wide association studies identified single nucleotide polymorphisms on chromosome 7 upstream of KLF14 to be associated with metabolic syndrome traits and increased risk for Type 2 Diabetes (T2D). The associations were more significant in women than in men. The risk allele carriers expressed lower levels of the transcription factor KLF14 in adipose tissues than non-risk allele carriers. To investigate how adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we characterized high-fat diet fed male and female mice with adipocyte-specific Klf14 deletion or overexpression. Klf14 deletion resulted in increased fat mass in female mice and decreased fat mass in male mice. Female Klf14-deficient mice had overall smaller adipocytes in subcutaneous fat depots but larger adipocytes in parametrial depots, indicating a shift in lipid storage from subcutaneous to visceral fat depots. They had reduced metabolic rates and increased respiratory exchange ratios consistent with increased utilization of carbohydrates as an energy source. Fasting and isoproterenol-induced adipocyte lipolysis was defective in female Klf14-deficient mice and concomitantly adipocyte triglycerides lipase mRNA levels were downregulated. Female Klf14-deficient mice cleared blood triglyceride and NEFA less efficiently than wild type. Finally, adipocyte-specific overexpression of Klf14 resulted in lower total body fat in female but not male mice. Taken together, consistent with human studies, adipocyte KLF14 deficiency in female but not in male mice causes increased adiposity and redistribution of lipid storage from subcutaneous to visceral adipose tissues. Increasing KLF14 abundance in adipocytes of females with obesity and T2D may provide a novel treatment option to alleviate metabolic abnormalities.

scholarly journals The Role of CD40 in Allergic Rhinitis and Airway Remodelling

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Ke-Jia Cheng ◽  
Min-Li Zhou ◽  
Yong-Cai Liu ◽  
Chen Wang ◽  
Ying-Ying Xu
Keyword(s):  
Allergic Rhinitis ◽  
Mrna Level ◽  
Costimulatory Molecule ◽  
Airway Remodelling ◽  
Mrna Levels ◽  
Collagen Deposition ◽  
Tissue Remodelling ◽  
Ifn Γ ◽  
Sirna Therapy

Background. Allergic rhinitis (AR) affects millions of people and is lack of effective treatment. CD40 is an important costimulatory molecule in immunity. However, few studies have focused on the role of CD40 in AR. Methods. In this study, we built mouse model of chronic AR. The mice were divided into the AR, control, intravenous CD40 siRNA, and nasal CD40 siRNA groups ( n = 6 each). We detected OVA-sIgE, IL-4, IL-5, IL-13, IL-10, IFN-γ, and TGF-β levels in serum and supernatant by ELISA, CD40+ splenic DCs, and Foxp3+ Tregs by flow cytometry and CD40 mRNA by RT2-PCR. We also used PAS and MT stains to assess tissue remodelling. Results. (1) The OVA-sIgE, IL-4, IL-5, and IL-13 levels in the serum or supernatant of nasal septal membrane of AR mice were significantly higher than control. After treated with CD40 siRNA, those indicators were significantly decreased. The IFN-γ, IL-10, and TGF-β levels in AR mice were significantly lower than that in control and were increased by administration of CD40 siRNA. (2) AR mice had significantly fewer Foxp3+ Tregs in the spleen than control mice. After treated with CD40 siRNA, AR mice had significantly more Foxp3+ Tregs. (3) AR mice exhibited a significantly higher CD40 mRNA levels than control. Administration of CD40 siRNA significantly reduced the CD40 mRNA level. (4) The AR mice showed significantly greater collagen deposition than the control in MT staining. Applications of CD40 siRNA significantly reduced the collagen deposition in AR mice. Conclusion. CD40 siRNA therapy shows promise for chronic AR as it significantly attenuated allergic symptoms and Th2-related inflammation and upregulated Foxp3+ Tregs. CD40 plays a role in tissue remodelling in AR, which can be inhibited by CD40 siRNA application.

Age and Sex Dependent Regulation of the Factor IX Gene in Mice

1996 ◽  
Vol 76 (06) ◽  
pp. 0965-0969 ◽  
Author(s):  
Sumiko Kurachi ◽  
Eri Hitomi ◽  
Kotoku Kurachi
Keyword(s):  
Reference Group ◽  
Mrna Level ◽  
Factor Ix ◽  
Mouse Strains ◽  
Female Group ◽  
Human Populations ◽  
Activity Levels ◽  
Mrna Levels ◽  
Animal Groups ◽  
Plasma Factor

SummaryPlasma factor IX and liver factor IX mRNA levels in two normal mouse strains (B6D2F1 and BALB/CJNIA) were determined in relation to aging and sex of the animals. With male B6D2F1 mice, mean plasma factor IX activity levels for the 14 and 21-22 month-old animals were found to be 124% and 226%, respectively, of the 5 month-old group. Similarly, liver factor IX mRNA levels for the same age animal groups were 145% and 227%, respectively, of the reference group. Mean plasma factor IX levels for the same age female animals were 132% and 175%, respectively, and were accompanied by similarly elevated liver factor IX mRNA levels, 119 and 175%, respectively, of the 5 month-old female group. Factor IX activity and mRNA levels for the 5,14 and 21-22 month-old female animal groups were lower than those of the corresponding male age groups by 25, 20 and 37%, and 20,36 and 38%, respectively. With BALB/CJNIA mice, similar correlation was observed between the advancing age and substantial elevations in the factor IX mRNA level as well as on the unequal factor IX mRNA levels in females and males.These results indicate that the plasma factor IX level in both male and female mice is greatly elevated with aging, in general agreement with a similar phenomenon observed for human populations, and that this increase is due to a similar elevation in the factor IX mRNA level in the liver. In mice, both factor IX activity and mRNA levels are significantly higher in males than in females, which has not been described for humans.

Abstract 113: Regulatory T Cells Contribute to Sexual Dimorphic Outcomes After Acute Ischemic Brain Injury

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Zeyu Sun ◽  
Wei Su ◽  
Ligen Shi ◽  
Jie Chen ◽  
Xiaoming Hu
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cell ◽  
Infarct Volume ◽  
Young Male ◽  
Young Female ◽  
Male Mice ◽  
Stroke Outcomes ◽  
Female Mice ◽  
Ifn Γ

Introduction: The contribution of CD4 + Foxp3 + regulatory T cells (Treg) to acute stroke outcomes has been controversially reported in young male murine models of stroke, their effects in female stroke mice, however, are not characterized. This study explored the sexual dimorphisms in Treg and its contribution to acute stroke outcomes. Methods: Cerebral ischemia was induced by 60 min tMCAO in male or female (Young: 10-week, aged: 15-month) wild type (WT) mice and DTR mice expressing the diphtheria toxin (DT) receptor under the control of Foxp3 promoter. Tregs depletion was achieved by DT injection in DTR mice for 3 days prior to tMCAO. Infarct volume, sensorimotor functions and peripheral immune cell populations were assessed up to 5d after stroke. For RNA sequencing analysis, Tregs were sorted from blood of male or female DTR mice at 5d after sham or tMCAO surgery. Results: Young Treg competent (WT mice or DTR mice without DT) female mice exhibited significantly reduced infarct volume, as assessed by MRI T2 scanning and MAP2 staining, and greatly improved sensorimotor functions (rotarod test and adhesive removal test) compared to age- and genotype-matched male mice (n=8/group) 5d after tMCAO. Treg depletion deprived the neuroprotection in young female, while showed no significant effect on young male or aged female mice (n=8/group). RNA-seq analysis showed that IFN-γ signaling was downregulated in female Treg while upregulated in male Treg, suggesting a sexual difference in Treg-mediated immune response after stroke. Flow cytometry revealed ameliorated immune cell activation in blood and brain in female vs male mice 5d after stroke. Furthermore, Treg were isolated from young female, young male, aged female or female mice subjected to ovariectomy, and adoptively transferred (1 million cell/animal, iv) to young male mice 1 hour after tMCAO. Only young female Treg significantly reduced the infarct volume and improved sensorimotor functions compared to other treatment groups (n=7-8/group). Conclusion: Treg contribute to the neuroprotection in young female vs male in an age- and hormone-dependent manner. Transcriptomic analysis uncovered sexual differences in an IFN-γ centered regulatory pathways in Tregs, which keep post-stroke immune responses in check.

scholarly journals Adenoviral Delivery of Interleukin-10 Fails To Attenuate Experimental Lyme Disease

2008 ◽  
Vol 76 (12) ◽  
pp. 5500-5507 ◽  
Author(s):  
Charles R. Brown ◽  
Annie Y.-C. Lai ◽  
Steven T. Callen ◽  
Victoria A. Blaho ◽  
Jennifer M. Hughes ◽  
...  
Keyword(s):  
Interleukin 10 ◽  
Lyme Arthritis ◽  
Mouse Strains ◽  
Susceptible Mouse ◽  
Lyme Carditis ◽  
Adenoviral Delivery ◽  
Severity Scores ◽  
C3h Mice

ABSTRACT Production of interleukin-10 (IL-10) by C57BL/6 mice following infection with Borrelia burgdorferi has been proposed as a mechanism whereby resistance to the development of experimental Lyme arthritis is maintained. In the current study, we sought to determine the role of IL-10 during infection of arthritis- and carditis-susceptible C3H mice. Infection of C3H IL-10−/− mice led to increased joint swelling and arthritis severity scores over those of wild-type C3H mice. Measurement of B. burgdorferi numbers in joints or disseminated tissues indicated a more efficient clearance of spirochetes in the absence of IL-10, similar to that reported in C57BL/6 IL-10−/− mice. However, in contrast to previous in vitro work, infection of C3H IL-10−/− mice led to decreased in vivo expression of the cytokines KC, IL-1β, IL-4, and IL-12p70 in the infected joints. Finally, adenoviral expression of IL-10 in the infected joints of C3H mice was unable to modulate the development of severe Lyme arthritis and had no effect on spirochete clearance or Borrelia-specific antibody production. Development of Lyme carditis appeared to be independent of modulation by IL-10. These results suggest that IL-10 limits the development of joint inflammation in both arthritis-resistant and -susceptible mouse strains infected with B. burgdorferi and that increased IL-10 production cannot rescue genetic susceptibility to development of pathology in this model.

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