Calcineurin deficiency decreases inflammatory lesions in transforming growth factor β1-deficient mice

Bommireddy, Ramireddy; Bueno, Orlando F.; Martin, Jennifer; Ormsby, Ilona; Chen, H.; Gard, Connie; Molkentin, Jeffery D.; Boivin, Gregory P.; Babcock, George F.; Doetschman, Thomas

doi:10.1111/j.1365-2249.2009.04015.x

Cited by 5 publications

(7 citation statements)

References 26 publications

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“…Although CNAα compensates to a certain extent for the loss of CNAβ in mature T cells, CNAβ plays a non-redundant role in T-cell homeostasis and T-cell regulation [16]. The present study is a follow up to our recent study in which we have demonstrated that T cells in Cnab −/− mice are activated and produce increased levels of IL-6 and IFNγ [23]. Since young CNAβ-deficient mice exhibit defective T-cell maturation [16] but they develop splenomegaly, and hepatomegaly we hypothesize that defective T-cell regulation increases inflammatory response resulting in lymphoid hyperplasia.…”

Section: Introductionsupporting

confidence: 56%

“…We found that both naïve and activated T cells in Cnab −/− mice have significantly increased levels of BCL-2 compared to WT controls (Figure 2 D,E), consistent with their increased accumulation. Further, most of these cells also expressed IL-7Rα at relatively high levels (data not shown), and a small percentage of them express CD69 at this time point [23]. However, the increase in BCL-2 levels did not correlate with T-cell accrual as BCL-2 levels were increased to a greater extent in naïve T cells that did not accumulate compared to activated T cells which did accumulate (Figure 2 D, E).…”

Section: Resultsmentioning

confidence: 99%

“…Cells were harvested and stained for surface expression of CD4, CD25 and intracellular FOXP3 as described above. For cytokine measurements, culture supernatants were harvested and assayed for cytokines by ELISA kits from BD Biosciences as described in our recent study [23]. …”

Section: Methodsmentioning

confidence: 99%

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Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis

Doetschman¹,

Sholl²,

Chen³

et al. 2011

Clinical Immunology

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Calcineurin (CN) is a phosphatase that activates nuclear factor of activated T cells (NFAT). While the CN inhibitors cyclosporine A (CsA) and tacrolimus (FK506) can prevent graft rejection, they also cause inflammatory diseases. We investigated the role of calcineurin using mice deficient in the CN catalytic subunit Aβ (CNAβ). Cnab−/− mice exhibit defective thymocyte maturation, splenomegaly and hepatomegaly. Further, as Cnab−/− mice age, they exhibit spontaneous T-cell activation and enhanced production of proinflammatory cytokines (IL-4, IL-6, and IFNγ). FOXP3+ Treg cells were significantly decreased in Cnab−/− mice likely contributing to increased T-cell activation. Interestingly, we found that CNAβ is critical for promotion of BCL-2 expression in FOXP3+ Treg and for permitting TGFβ signaling, as TGFβ induces FOXP3 in control but not in Cnab−/− T-cells. Together, these data suggest that CNAβ is important for the production and maintenance of Treg cells and to ensure mature T-cell quiescence.

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Section: Introductionsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

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Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis

Doetschman¹,

Sholl²,

Chen³

et al. 2011

Clinical Immunology

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“…Although TGF-β 1 appears to be the primary driver of kidney fibrosis, a vast array of additional molecules may have modulating roles [4]. Additionally, TGF-β 1 knock-out (KO) mice develop severe multi-focal autoimmune inflammatory lesions and die within 3 weeks after birth [39], which indicates that TGF-β 1 may not be a good drug target, making it necessary to find additional modulating molecules. Through the proteomic and genomic analysis, we found that the introduction of inflammation and TIF was accompanied by significant reduction in CBS in the UUO model, a rodent model of fibrotic nephropathy resembling human CKD.…”

Section: Discussionmentioning

confidence: 99%

Loss of the Protein Cystathionine β-Synthase During Kidney Injury Promotes Renal Tubulointerstitial Fibrosis

Yuan¹,

Zhang²,

Xie³

et al. 2017

Kidney Blood Press Res

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Background/Aims: Renal tubulointerstitial fibrosis (TIF) is the common pathway of progressive chronic kidney disease. Inflammation has been widely accepted as the major driving force of TIF. Cystathionine β-synthase (CBS) is the first and rate-limiting enzyme in the transsulfuration pathway. CBS is considered to play protective role in liver and pulmonary fibrosis, but its role in TIF remains unknown. The purpose of this study was to investigate the potential role and mechanism of CBS in renal inflammation and TIF. Methods: Renal function, tubulointerstitium damage index score, extracellular matrix (ECM) deposition, and the expressions of collagen I, collagen III, fibronectin, CD3, CD68, IL-1β, TNF-α were measured in sham operation and unilateral ureteral obstruction (UUO) rats. Proteomics and gene array analysis were performed to screen differentially expressed molecules in the development of renal inflammation and TIF in UUO rats. The expression of CBS was detected in patients with obstructive nephropathy and UUO rats. We confirmed the expression of CBS using western blot and real-time PCR in HK-2 cells. Overexpression plasmid and siRNA were transfected specifically to study the possible function of CBS in HK-2 cells. Results: Abundant expression of CBS, localized in renal tubular epithelial cells, was revealed in human and rat renal tissue, which correlated negatively with the progression of fibrotic disease. Expression of CBS was dramatically decreased in the obstructed kidney from UUO rats as compared with the sham group (SHM). In addition, knocking down CBS exacerbated extracellular matrix (ECM) deposition, whereas CBS overexpression attenuated TGF-β1-induced ECM deposition in vitro. Inflammatory and chemotactic factors were also increased in CBS knockdown HK-2 cells stimulated by IL-1β.

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“…For example, NSCs secrete paracrine factors including transforming growth factor (TGF)-β1, prostaglandins (PGE2), nitric oxide (NO) and heme oxygenases (HOs) (54). TGF-β1 maintains immune tolerance, T-cell homeostasis and balances the immunogenicity of NSCs (20,55,56). In addition, HOs alone or in combination with NO production mediate immunosuppressive effects of NSCs (57,58), and growth factors and neurotrophins influence stem cell-immune cell interactions (54).…”

Section: R E S E a R C H A R T I C L Ementioning

confidence: 99%

Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing

Schmitt

Eckardt

Schlegel

et al. 2015

Mol Med

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Parent-of-origin imprints have been implicated in the regulation of neural differentiation and brain development. Previously we have shown that, despite the lack of a paternal genome, human parthenogenetic (PG) embryonic stem cells (hESCs) can form proliferating neural stem cells (NSCs) that are capable of differentiation into physiologically functional neurons while maintaining allele-specific expression of imprinted genes. Since biparental ("normal") hESC-derived NSCs (N NSCs) are targeted by immune cells, we characterized the immunogenicity of PG NSCs. Flow cytometry and immunocytochemistry revealed that both N NSCs and PG NSCs exhibited surface expression of human leukocyte antigen (HLA) class I but not HLA-DR molecules. Functional analyses using an in vitro mixed lymphocyte reaction assay resulted in less proliferation of peripheral blood mononuclear cells (PBMC) with PG compared with N NSCs. In addition, natural killer (NK) cells cytolyzed PG less than N NSCs. At a molecular level, expression analyses of immune regulatory factors revealed higher HLA-G levels in PG compared with N NSCs. In line with this finding, MIR152, which represses HLA-G expression, is less transcribed in PG compared with N cells. Blockage of HLA-G receptors ILT2 and KIR2DL4 on natural killer cell leukemia (NKL) cells increased cytolysis of PG NSCs. Together this indicates that PG NSCs have unique immunological properties due to elevated HLA-G expression.

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Calcineurin deficiency decreases inflammatory lesions in transforming growth factor β1-deficient mice

Abstract: SummaryTransforming growth factor (TGF) b1) is an immunoregulatory cytokine involved in self-tolerance and lymphocyte homeostasis.

Cited by 5 publications

References 26 publications

Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis

Divergent effects of calcineurin Aβ on regulatory and conventional T-cell homeostasis

Loss of the Protein Cystathionine β-Synthase During Kidney Injury Promotes Renal Tubulointerstitial Fibrosis

Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing

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