Spontaneously hypertensive rat: cholera toxin converts suppression to immunity through a Th2 cell-IL-4 pathway

The spontaneously hypertensive rat (SHR) exhibits a number of T cell dysfunctions that develop concurrently with elevated blood pressure. Studies have shown a mitogen-induced lymphocyte suppression mediated in part by the production of interferon-γ (IFN-γ), which stimulated NO production by macrophages. To assess whether this immune suppression is reversible, SHR were immunized with diphtheria toxoid (DT) with or without cholera toxin (CT) as adjuvant. SHR immunized with DT only displayed weak serum immunoglobulin G (IgG) anti-DT titers, tenfold less than similarly treated normotensive Wistar-Kyoto rats (WKYR). SHR CD4+T cells failed to proliferate upon in vitro stimulation with DT. In contrast, SHR coimmunized with DT and CT showed serum IgG antibody titers similar to WKYR and Brown Norway rats. Coimmunization with CT rescued SHR CD4+T cells from suppression and supported DT- or B subunit of CT-specific proliferative responses, and these cells produced more interleukin-4 (IL-4) than IFN-γ, and anti-IFN-γ antibody treatment enhanced IL-4 production. Exogenous IL-4 increased the proliferation of antigen-specific CD4+T cells, whereas IFN-γ was inhibitory. This study shows that the adjuvant CT induces T helper 2-type responses, reversing the T cell dysfunction in the SHR.

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Antihypertensive effect of piperitenone oxide on spontaneously hypertensive rat by regulating calcium balance and reducing endothelin-1 secretion

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v12i3.32413 ◽

2017 ◽

Vol 12 (3) ◽

pp. 341 ◽

Cited By ~ 2

Author(s):

Wei Lan ◽

Hong Ping Zhang ◽

Ying Wang ◽

Min Jiang ◽

Qian Li ◽

...

Keyword(s):

Spontaneously Hypertensive Rat ◽

Video Clip ◽

No Production ◽

Calcium Balance ◽

Aortic Endothelial Cells ◽

Spontaneously Hypertensive ◽

Vasorelaxant Effect ◽

Hypertensive Rat ◽

Intracellular Ca ◽

Full Screen

The purpose of this study was to investigate the antihypertensive mecha-nisms of piperitenone oxide in spontaneously hypertensive rat (SHR). Compared to control SHR, piperitenone oxide reduced the systolic blood pressure and serum endothelium-1 (ET-1). The nitric oxide (NO) production and ET-1 secretion were significantly inhibited in the noradrenaline-exposed bovine aortic endothelial cells. Piperitenone oxide showed endothelium-independent but concentration-dependent relaxation of the artery rings. The responsible mechanisms appear to be related to the modulation of ET-1 and NO levels. The vasorelaxant effect of piperitenone oxide is independent of endothelium-derived mediators, which is associated with interfering intracellular calcium homeostasis by blocking Ca2+ influx, as well as intracellular Ca2+ release.Video Clip of Methodology:2 min 58 sec: <a href="https://www.youtube.com/v/nLfvvzXpLKs">Full Screen</a> <a href="https://www.youtube.com/watch?v=nLfvvzXpLKs">Alternate</a>

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Abnormal activation and loss of suppressor T cells in the spontaneously hypertensive rat

Cellular Immunology ◽

10.1016/0008-8749(92)90318-j ◽

1992 ◽

Vol 145 (1) ◽

pp. 130-145 ◽

Cited By ~ 8

Author(s):

William Ofosu-Appiah ◽

Christine Ruggiero

Keyword(s):

T Cells ◽

Spontaneously Hypertensive Rat ◽

Suppressor T Cells ◽

Spontaneously Hypertensive ◽

Hypertensive Rat

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Immunization of Mice with a TolA-Like Surface Protein of Trypanosoma cruzi Generates CD4+T-Cell-Dependent Parasiticidal Activity

Infection and Immunity ◽

10.1128/iai.67.9.4603-4612.1999 ◽

1999 ◽

Vol 67 (9) ◽

pp. 4603-4612 ◽

Cited By ~ 26

Author(s):

Natalie M. Quanquin ◽

Charles Galaviz ◽

David L. Fouts ◽

Ruth A. Wrightsman ◽

Jerry E. Manning

Keyword(s):

T Cells ◽

T Cell ◽

Trypanosoma Cruzi ◽

Gene Family ◽

Expression System ◽

Interleukin 2 ◽

No Production ◽

Sequence Identity ◽

Flagellar Proteins ◽

Ifn Γ

ABSTRACT The gene family encoding a trypomastigote-specific protein restricted to the part of the flagellum in contact with the cell body of the trypomastigote form of Trypanosoma cruzi has been isolated, characterized, and expressed in a baculovirus expression system. The gene family contains three tandemly repeated members that have 97 to 100% sequence identity. The predicted protein encoded by the gene family has both significant amino acid sequence identity and other physical and biological features in common with the TolA proteins of Escherichia coli and Pseudomonas aeruginosa. Based on these similarities, we have designated this gene family tolT. Immunization of mice with recombinant TolT generates a population of CD4+ T lymphocytes that recognize T. cruzi-infected macrophages, resulting in the production of gamma interferon (IFN-γ), which leads to NO production and a 50 to 60% reduction in parasite numbers compared to that seen with infected macrophages incubated with naive T cells. This population of T cells also produces both IFN-γ and interleukin 2 (IL-2) but not IL-4 or IL-5 when incubated with spleen cells stimulated with TolT antigen, indicating that they are of the T-helper 1 type. T cells from mice chronically infected with T. cruzi also produce significant levels of IFN-γ when cocultured with macrophages and either TolT protein or paraflagellar rod protein, indicating that both of these flagellar proteins produce positive T-cell responses in mice chronically infected with T. cruzi.

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Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat

Physiological Genomics ◽

10.1152/physiolgenomics.00210.2010 ◽

2011 ◽

Vol 43 (21) ◽

pp. 1207-1218 ◽

Cited By ~ 21

Author(s):

Catherine Morrissey ◽

Ian C. Grieve ◽

Matthias Heinig ◽

Santosh Atanur ◽

Enrico Petretto ◽

...

Keyword(s):

Quantitative Trait ◽

Protein Function ◽

Genomic Sequence ◽

Spontaneously Hypertensive Rat ◽

Transcript Abundance ◽

Brown Norway ◽

Nucleotide Polymorphisms ◽

Susceptibility Loci ◽

Spontaneously Hypertensive ◽

Hypertensive Rat

The spontaneously hypertensive rat (SHR) is a widely used rodent model of hypertension and metabolic syndrome. Previously we identified thousands of cis-regulated expression quantitative trait loci (eQTLs) across multiple tissues using a panel of rat recombinant inbred (RI) strains derived from Brown Norway and SHR progenitors. These cis-eQTLs represent potential susceptibility loci underlying physiological and pathophysiological traits manifested in SHR. We have prioritized 60 cis-eQTLs and confirmed differential expression between the parental strains by quantitative PCR in 43 (72%) of the eQTL transcripts. Quantitative trait transcript (QTT) analysis in the RI strains showed highly significant correlation between cis-eQTL transcript abundance and clinically relevant traits such as systolic blood pressure and blood glucose, with the physical location of a subset of the cis-eQTLs colocalizing with “physiological” QTLs (pQTLs) for these same traits. These colocalizing correlated cis-eQTLs (c3-eQTLs) are highly attractive as primary susceptibility loci for the colocalizing pQTLs. Furthermore, sequence analysis of the c3-eQTL genes identified single nucleotide polymorphisms (SNPs) that are predicted to affect transcription factor binding affinity, splicing and protein function. These SNPs, which potentially alter transcript abundance and stability, represent strong candidate factors underlying not just eQTL expression phenotypes, but also the correlated metabolic and physiological traits. In conclusion, by integration of genomic sequence, eQTL and QTT datasets we have identified several genes that are strong positional candidates for pathophysiological traits observed in the SHR strain. These findings provide a basis for the functional testing and ultimate elucidation of the molecular basis of these metabolic and cardiovascular phenotypes.

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Y‐chromosome lineage determines cardiovascular organ T‐cell infiltration in the stroke‐prone spontaneously hypertensive rat

The FASEB Journal ◽

10.1096/fj.201700933rr ◽

2018 ◽

Vol 32 (5) ◽

pp. 2747-2756 ◽

Cited By ~ 2

Author(s):

Shanzana I. Khan ◽

Karen L. Andrews ◽

Kristy L. Jackson ◽

Basimah Memon ◽

Ann‐Maree Jefferis ◽

...

Keyword(s):

T Cell ◽

Y Chromosome ◽

Spontaneously Hypertensive Rat ◽

Cell Infiltration ◽

Spontaneously Hypertensive ◽

T Cell Infiltration ◽

Hypertensive Rat

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Hyaluronidase and IFN-γ from Activated T-Cells Are Key Mediators To Induce Immunosuppressive Activity of Mesenchymal Stem Cells.

Blood ◽

10.1182/blood.v110.11.3246.3246 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3246-3246

Author(s):

Kazuya Sato ◽

Ozaki Katsutoshi ◽

Iekuni Oh ◽

Haruko Matsu ◽

Raine Tatara ◽

...

Keyword(s):

Molecular Weight ◽

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Inos Expression ◽

T Cell Proliferation ◽

No Production ◽

Immunosuppressive Activity ◽

Activated T Cells ◽

Ifn Γ

Abstract Mesenchymal stem cells (MSC) have been shown to suppress T-cell proliferation in vitro and are being clinically applied to treatment for steroid-refractory graft-versus-host disease (GVHD). However, the molecular mechanisms of immunosuppressive activity of MSC have not been fully understood. We have recently reported that nitric oxide (NO) is one of the key molecules for T-cell suppression by MSC (Blood, 2007;228–34). Inducible NO synthase (iNOS) expression in MSC and NO production were exclusively detected upon interaction with activated T-cells. An inhibitor of NOS restored the proliferation of T-cells. We have also shown that both IFN-γ and NF-κB mediate NO production by MSC (BBRC, 2007;80–90), however the factor(s) from T-cells that induce immunosuppressive activity of MSC have not been elucidated. In the present study, we focused on hyaluronic acid (HA), a major extracellular matrix component, because low molecular weight (LMW) HA is known to play an essential role in regulation of inflammation and infection, HA induces NOS in macrophages through a NF-κB-dependent mechanism, and T-cells are reported to express hyaluronidase-2 mRNA after activation. A series of such information suggests that activated T-cells regulate immunosuppressive activity of MSC through HA signaling. We investigated the molecular events in the interaction between MSC and activated T-cells, and demonstrated that HA may play an important role in the scenario. First, ELISA showed that MSC produce a large amount of HA. RT-PCR revealed that among three hyaluronic acid synthase (HAS), mRNA for HAS-1 but neither HAS-2 nor HAS-3 is constitutively expressed by MSC. Flow cytometric analysis also showed that MSC express CD44, one of the receptors for HA. In macrophages, either IFN-γ or LMW HA is known to induce NO production. Therefore, we investigated whether IFN-γ or LMW HA can induce NO production via NF-κB signaling in MSC. As a result, only in the presence of IFN-γ, LMW HA but not high molecular weight (HMW) HA induced expression of iNOS in MSC, followed by NO production from MSC. We found that prostaglandin E2 (PGE2), which was previously reported as another immunosuppressive factor of MSC, is also induced by the combination of IFN-γ and LMW HA. Since hyaluronidase activity in activated T-cells has already been reported, these data support a novel hypothesis that HMW HA produced by MSC is digested by hyaluronidase from activated T-cells, and that resultant LMW HA cooperates with IFN-γ from activated T-cells in inducing iNOS expression in MSC. Locally produced NO through the above mechanisms may suppress activated T-cell proliferation. These findings would be important to further potentiate and regulate the immunomodulatory activity of MSC in a variety of applications.

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Renal renin activity is associated with alterations of the renin gene in recombinant inbred rat strains

Clinical Science ◽

10.1042/cs0840129 ◽

1993 ◽

Vol 84 (2) ◽

pp. 129-132 ◽

Cited By ~ 3

Author(s):

Irena Pohlová ◽

Josef Zicha ◽

Vladimir Křen ◽

Jaroslav Kuneš ◽

Michal Pravenec

Keyword(s):

Blood Pressure ◽

Recombinant Inbred ◽

Spontaneously Hypertensive Rat ◽

Inbred Strains ◽

Renin Activity ◽

Recombinant Inbred Strains ◽

Brown Norway ◽

Spontaneously Hypertensive ◽

Hypertensive Rat ◽

Renin Gene

1. A structural alteration within the first intron of the renin gene in spontaneously hypertensive rats was demonstrated to co-segregate with blood pressure in some sets of F2 hybrids or recombinant inbred strains. There is no evidence as to whether restriction fragment length polymorphism of the renin gene is associated with any of the changes in the renin tissue level. For this reason we have determined renal renin activity in spontaneously hypertensive, Wistar-Kyoto and Brown Norway rats as well as in 22 recombinant inbred strains derived from F2 hybrids of spontaneously hypertensive and Brown Norway rats. 2. At the age of 4 months significantly lower renal renin activity was observed in spontaneously hypertensive rats than in both normotensive rat strains, Wistar-Kyoto and Brown Norway. The presence of the spontaneously hypertensive rat allele in recombinant inbred strains was associated with a substantially lower renal renin activity as compared with recombinant inbred strains bearing the Brown Norway rat allele. There was no relationship between renal renin activity and the polymorphism in either the angiotensinogen gene or the angiotensin-converting enzyme gene. 3. There was a borderline correlation between blood pressure and renal renin activity in recombinant inbred strains. Nevertheless, additional comparisons within recombinant inbred strains bearing the spontaneously hypertensive rat allele of the renin gene failed to reveal any significant relationship between blood pressure level and renal renin activity. 4. Our data suggest that the restriction fragment length polymorphism marking the renin gene of the spontaneously hypertensive rat is accompanied by an alteration in the renin-angiotensin system at the renal level. The mechanisms by which structural abnormalities of the renin gene might influence the renin level in the kidney remain to be investigated.

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