Direct Inhibition of Human CD8+ Lymphocyte Activation by Cyclosporine A and Rapamune-Sirolimus

Combates, Nicholas J.; Degiannis, D.; Rašková, Jana; Raska, K

doi:10.1006/clin.1995.1147

Cited by 5 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, dexamethasone is more potent than cyclosporine at inhibiting proliferation of human PBMC when stimulated with ConA (Lebrec et al, 1995). Studies evaluating human CD8 + T-lymphocytes stimulated with anti-CD3 antibodies demonstrated that the response was more sensitive to inhibition by rapamycin than to cyclosporine (Combates et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Human lymphocyte activation assay: Anin vitromethod for predictive immunotoxicity testing

Collinge

Cole

Schneider

et al. 2010

Journal of Immunotoxicology

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Human lymphocyte activation assay: Anin vitromethod for predictive immunotoxicity testing

Collinge

Cole

Schneider

et al. 2010

Journal of Immunotoxicology

View full text Add to dashboard Cite

“…The anti-fungal macrolide rapamycin blocks mTORcomplex1 function by forming a gain-of-function inhibitory complex with the immunophilin FK506 binding protein 1A (FKBP12) (Brown et al ., 1994). Rapamycin is a potent immune suppressive agent which inhibits the pro-liferation and the clonal expansion of interleukin-2-stimulated T cells (Combates et al ., 1995). Recent reports show that rapamycin can regulate cycin D3 and Il-3 mRNA levels through their 3'untranslated region (3'UTR) (Banholzer et al ., 1997; Pallet et al ., 2005).…”

Section: Introductionmentioning

confidence: 99%

Destabilization of TNF-α mRNA by Rapamycin

Park¹,

Jeon²,

Lee³

et al. 2012

Biomolecules and Therapeutics

View full text Add to dashboard Cite

Stimulation of mast cells through the high affinity IgE receptor (FcεRI) induces degranulation, lipid mediator release, and cytokine secretion leading to allergic reactions. Although various signaling pathways have been characterized to be involved in the FcεRI-mediated responses, little is known about the precious mechanism for the expression of tumor necrosis factor-α (TNF-α) in mast cells. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR), reduces the expression of TNF-α in rat basophilic leukemia (RBL-2H3) cells. IgE or specific antigen stimulation of RBL-2H3 cells increases the expression of TNF-α and activates various signaling molecules including S6K1, Akt and p38 MAPK. Rapamycin specifically inhibits antigen-induced TNF-α mRNA level, while other kinase inhibitors have no effect on TNF-α mRNA level. These data indicate that mTOR signaling pathway is the main regulation mechanism for antigen-induced TNF-α expression. TNF-α mRNA stability analysis using reporter construct containing TNF-α adenylate/uridylate-rich elements (AREs) shows that rapamycin destabilizes TNF-α mRNA via regulating the AU-rich element of TNF-α mRNA. The antigen-induced activation of S6K1 is inhibited by specific kinase inhibitors including mTOR, PI3K, PKC and Ca2+chelator inhibitor, while TNF-α mRNA level is reduced only by rapamycin treatment. These data suggest that the effects of rapamycin on the expression of TNF-α mRNA are not mediated by S6K1 but regulated by mTOR. Taken together, our results reveal that mTOR signaling pathway is a novel regulation mechanism for antigen-induced TNF-α expression in RBL-2H3 cells.

show abstract

“…We did not identify the source of the DNA but given the high levels of oxidative stress associated with the hypertensive hearts, it most likely represents mtDNA. We were not able to test this directly in vivo as cyclosporin A, which inhibits mitochondrial permeability transition (MPT) pore opening and mtDNA release ( 60 ), also inhibits CD8+ T cell activation ( 61 ). High ROS levels trigger MPT pore opening, resulting in release of mtDNA into the cytosol ( 60 ).…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between cytotoxic CD8+ T cells and stressed cardiomyocytes triggers development of interstitial cardiac fibrosis in hypertensive mouse hearts

et al. 2022

View full text Add to dashboard Cite

AimsCardiac fibrosis is central to heart failure (HF), especially HF with preserved ejection fraction (HFpEF), often caused by hypertension. Despite fibrosis causing diastolic dysfunction and impaired electrical conduction, responsible for arrhythmia-induced sudden cardiac death, the mechanisms are poorly defined and effective therapies are lacking. Here we show that crosstalk between cardiac cytotoxic memory CD8+ T cells and overly stressed cardiomyocytes is essential for development of non-ischemic hypertensive cardiac fibrosis.Methods and resultsCD8 T cell depletion in hypertensive mice, strongly attenuated CF, reduced cardiac apoptosis and improved ventricular relaxation. Interaction between cytotoxic memory CD8+ T cells and overly stressed cardiomyocytes is highly dependent on the CD8+ T cells expressing the innate stress-sensing receptor NKG2D and stressed cardiomyocytes expressing the NKG2D activating ligand RAE-1. The interaction between NKG2D and RAE-1 results in CD8+ T cell activation, release of perforin, cardiomyocyte apoptosis, increased numbers of TGF-β1 expressing macrophages and fibrosis. Deleting NKG2D or perforin from CD8+ T cells greatly attenuates these effects. Activation of the cytoplasmic DNA-STING-TBK1-IRF3 signaling pathway in overly stressed cardiomyocytes is responsible for elevating RAE-1 and MCP-1, a macrophage attracting chemokine. Inhibiting STING activation greatly attenuates cardiomyocyte RAE-1 expression, the cardiomyocyte apoptosis, TGF-β1 and fibrosis.ConclusionOur data highlight a novel pathway by which CD8 T cells contribute to an early triggering mechanism in CF development; preventing CD8+ T cell activation by inhibiting the cardiomyocyte RAE-1-CD8+ T cell-NKG2D axis holds promise for novel therapeutic strategies to limit hypertensive cardiac fibrosis.

show abstract

Direct Inhibition of Human CD8+ Lymphocyte Activation by Cyclosporine A and Rapamune-Sirolimus

Cited by 5 publications

References 0 publications

Human lymphocyte activation assay: Anin vitromethod for predictive immunotoxicity testing

Human lymphocyte activation assay: Anin vitromethod for predictive immunotoxicity testing

Destabilization of TNF-α mRNA by Rapamycin

Crosstalk between cytotoxic CD8+ T cells and stressed cardiomyocytes triggers development of interstitial cardiac fibrosis in hypertensive mouse hearts

Contact Info

Product

Resources

About