Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunomodulatory lectin, Volvariella volvacea lectin (VVL), isolated from the edible mushroom, Volvariella volvacea, has been shown to stimulate the expression of Th1 cytokines and the proliferative activity of mouse splenocytes (She et al. [1998]: Biochem Biophys Res Comm 247:106-111). In order to elucidate the mechanisms underlying these activities, we conducted a kinetic analysis of the early and late activation markers in mouse T lymphocytes: (1) flow cytometric analysis of calcium influx, (2) induction of activation molecules (CD25 and CD69), (3) expression and DNA-binding activity of the nuclear factor of activated T cells (NFAT), NFkappaB, and activation protein-1 (AP-1), (4) translational production of cytokines (interleukin-2 (IL-2) and interferon-gamma (IFNgamma)), and (5) cell proliferation by expression of proliferating cell nuclear antigen (PCNA) and tritiated thymidine incorporation. All results showed that VVL induced a rapid expression of CD69, CD25, NFAT, IL-2, and PCNA in a dose- and time-dependent manner, leading to lymphocyte proliferation. These effects brought about by VVL were more potent than those stimulated by equimolar concentrations of mitogenic lectin, concanavalin A (Con A). Cell activation and proliferation were mediated through a calcium-dependent pathway as demonstrated by a VVL-induced increase of intracellular calcium influx, and a proliferation inhibition by the Ca-dependent phosphatase calcineurin blocker-cyclosporin A (CsA). Taken all data together, VVL is a lectin which activates lymphocyte through successive calcium influx, nuclear localization of NFAT transcription factor, induction of activation markers, CD25 and CD69, intracellular cytokine production, and cell proliferation.
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PMID:Volvariella volvacea lectin activates mouse T lymphocytes by a calcium dependent pathway. 1525 2

We investigated whether certain hydrophobic dipeptides, Leu-Ile, Leu-Pro, and Pro-Ile, which partially resemble the site on FK506 that binds to immunophilin, could stimulate glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) synthesis in cultured neurons and found only Leu-Ile to be an active dipeptide. Leu-Ile protected against the death of mesencephalic neurons from wild-type mice but not from mice lacking the BDNF or GDNF gene. Next, we examined the effects of i.p. or i.c.v. administration of Leu-Ile on BDNF and GDNF contents. Both types of administration increased the contents of BDNF and GDNF in the striatum of mice. Also, peripheral administration of Leu-Ile inhibited dopaminergic (DA) denervation caused by unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of mice. The number of rotations following a methamphetamine challenge was lower in the Leu-Ile-treated group than in the nontreated group. Next, we compared the calcineurin activity and immunosuppressant activity of Leu-Ile with those of FK506. Leu-Ile was not inhibitory toward calcineurin cellular activity in cultured neuronal cells. Furthermore, Leu-Ile did not suppress concanavalin A (ConA)-induced synthesis/secretion of interleukin-2 by cultured spleen cells, suggesting that the immunosuppressant activity of Leu-Ile may be negligible when used as a therapeutic tool for neurodegenerative diseases.
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PMID:Hydrophobic dipeptide Leu-Ile protects against neuronal death by inducing brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis. 1537 10

Transcription factors activated in response to T cell receptor (TCR) signaling include nuclear factor of activated T cells (NFAT) family, which is highly phosphorylated and thereby maintained in the cytoplasm of resting T cells, the nuclear factor NF-kappaB, which is kept in the cytoplasm of resting cells through its association with the inhibitor protein IkappaB, and activating protein-1 (AP-1), which is only transcribed after TCR stimulation. Negative regulators of TCR signaling can be divided into two groups: Class 1 regulators help maintain the quiescent state of unstimulated T cells, whereas class 2 regulators are themselves transcriptionally induced in response to TCR signaling and serve to limit and terminate the activating signal. Class 1 regulators include the autoinhibitory domain of the phosphatase calcineurin; IkappaB and its transcriptional activators Foxj1 and Foxo3a; and various transcriptional coregulators that inhibit interleukin-2 (IL-2) production. Class 2 regulators include the calcipressins, which, like NFATp and NFAT4 are feedback inhibitors of calcineurin-NFAT signaling, IkappaB, and the mitogen-activated protein kinase (MAPK) phosphatases, which inhibit MAPK signaling and thus the nuclear localization of AP-1 components.
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PMID:The yins of T cell activation. 1563 17

Cyclosporin A (CsA) and FK506 suppress T cell activation by inhibiting calcineurin and the calcineurin-dependent transcription factors nuclear factor of activated T cells (NFATc), which are central regulators of T cell function. It was reported that CsA up-regulated the transcription of transforming growth factor-beta1 (TGF-beta1) in lymphocytes and other cells and activated its promoter in A549 lung carcinoma cells, but the mechanisms involved are poorly understood, and it is unclear whether calcineurin plays any role. We have studied the regulation of TGF-beta1 in normal human lymphocytes and cell lines. In Jurkat T cells, the TGF-beta1 promoter was activated by calcineurin and NFATc and inhibited by CsA and FK506. However, the promoter was insensitive to both drugs in A549 cells. In human T cells preactivated with phytohemagglutinin, biosynthesis of TGF-beta1, induced by the T cell receptor (TCR) or the TGF-beta receptor, was not substantially affected by CsA and FK506 concentrations (< or = 1 microM) that effectively inhibited interleukin-2 production. However, pretreatment of fresh lymphocytes with CsA or FK506 during primary TCR stimulation reduced their production of TGF-beta1 during secondary TCR activation. Finally, high concentrations of CsA (10 microM), in the range attained in vivo in experiments in rodents, caused apoptosis in human T cells and the release of preformed, bioactive TGF-beta1. These effects are unlikely to owe to calcineurin inhibition, as they were not observed with FK506. Our results indicate that CsA and FK506 are not general inducers of TGF-beta1 biosynthesis but can cause different effects on TGF-beta1 depending on the cell type and concentrations used.
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PMID:Concentrations of cyclosporin A and FK506 that inhibit IL-2 induction in human T cells do not affect TGF-beta1 biosynthesis, whereas higher doses of cyclosporin A trigger apoptosis and release of preformed TGF-beta1. 1571 27

Recurrence of hepatitis C (HepC) has been a most difficult dilemma in liver transplantation (OLT) because the effects of immunosuppression with steroid, mycophenolate mofetil (MMF) calcineurin antagonists, and anti-interleukin-2 antibody as well as the role of preemptive antiviral therapy are uncertain. In this study, we randomized OLT recipients with HepC into two treatment arms: tacrolimus+daclizumab+MMF (study arm) versus tacrolimus+steroids+MMF (control arm). The study arm only received steroids for the treatment of biopsy-proven rejection episodes. Both arms received preemptive anti-viral therapy with Pegasys and ribavirin. The 39 enrolled patients (among 50 to be enrolled) have median follow-up of 458 days with 23 patients (8 in study arm, 15 in control arm) having reached 1 year. The incidences of rejection episodes within 0 to 3 months, 3 to 6 months, and 6 to 12 months were (study vs control): 0% vs 28%; 0% vs 6%; and 13% vs 20%; respectively (P = NS). The 1-year protocol biopsies showed advanced fibrosis (stage 3 or greater) in 20% (3 of 15) of the control arm, but none (0 of 7) of the study arm (P = NS). We compared anticipated side effects of steroids in the first 3 months (study vs control): hypertension (36% vs 58%, P = NS), PTDM (7% vs 43%, P = .02), and wound infections (14% vs 37%, P = NS). In conclusion, liver transplant recipients with HepC tolerate a steroid-free protocol. There was a trend toward reduced steroid side effects and a lower incidence of advanced fibrosis in 1-year biopsy samples among patients receiving the steroid-free protocol.
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PMID:Steroid-free induction and preemptive antiviral therapy for liver transplant recipients with hepatitis C: a preliminary report from a prospective randomized study. 1584 74

Calcineurin (CN) is thought to play an important role in the immune system by regulating cytokine production, for example, interleukin-2 (IL-2) in T-lymphocytes. We have previously shown that physiological concentrations of Zn2+ inhibit CN activity in vitro [K. Takahashi, E. Akaishi, Y. Abe, R. Ishikawa, S. Tanaka, K. Hosaka, Y. Kubohara, Zinc inhibits calcineurin activity in vitro by competing with nickel, Biochem. Biophys. Res. Commun. 307 (2003) 64-68], in spite of the fact that Zn2+ is an essential element of the CN catalytic domain. In this study, in order to assess whether Zn2+ regulates (suppresses) CN activity in vivo and whether Zn2+ can be used as an anti-inflammatory and/or immunosuppressive drug, we examined the effects of Zn2+ on IL-2 production induced by the mitogen, concanavalin A (ConA), in Jurkat T-cells. Zn2+ at 0.2 mM suppressed ConA-induced IL-2 accumulation in the medium of an in vitro culture of Jurkat cells. Zn2+ at 0.03-0.3 mM dose-dependently suppressed ConA-induced IL-2 mRNA expression in Jurkat cells. Zn2+ also suppressed IL-2 mRNA expression induced by phorbol ester (PMA) and ionomycin. Furthermore, Zn2+ and the immunosuppressant FK506 showed an additive inhibitory effect on ConA-induced IL-2 mRNA expression. These results suggest that exogenously added Zn2+ may disturb (increase) the intracellular Zn2+ concentration and inhibit CN activity, thereby suppressing IL-2 production in Jurkat cells. The present study further indicates that Zn2+ may have therapeutic potential in the treatment of T-cell related inflammation and also that Zn2+ may be utilized as a supplemental drug with FK506.
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PMID:Zinc ions suppress mitogen-activated interleukin-2 production in Jurkat cells. 1605 81

Adapt 78 (DSCR 1/calcipressin/MCIP 1) is a potent natural inhibitor of calcineurin, an important intracellular phosphatase that mediates many cellular responses to calcium. We previously reported two major cytosolic isoforms (1 and 4) of Adapt 78, and that isoform 4 is an oxidative and calcium stress-response protein. Using a higher cell culture density and new antibody, we again observed that both major isoforms localized to the cytosol, but a significant level of isoform 4 (but not isoform 1) was also detected in the nucleus where it was present in the non-soluble region and not associated with RNA. Exposure of cells to hydrogen peroxide led to the significant loss of isoform 4 from the nucleus with a moderate increase in cytosolic localization. The change in isoform 4 phosphorylation state in response to oxidative stress, characterized by a loss of the lesser (hypo) phosphorylated Adapt 78, was not due to accelerated degradation, although general Adapt 78 degradation was proteosome mediated. Finally, stimulation of Jurkat and primary T-lymphocyte signaling led to isoform 4 induction. This induction was BAPTA, diphenylene iodonium, and N-acetylcysteine inhibitable, and accompanied by induction of the classic immune response mediator and calcineurin-pathway-stimulated interleukin-2. These studies reveal new redox-related activities for Adapt 78 isoform 4, which may contribute to its known calcineurin-regulating and cytoprotective activities, and further suggest that Adapt 78 plays a role in basic T-cell response.
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PMID:Redox response of the endogenous calcineurin inhibitor Adapt 78. 1610 2

The major T cell growth factor interleukin-2 (IL-2) is secreted by activated T cells in response to antigenic stimulation. This requires signal transduction via the CD3/TCR complex and the CD28 coreceptor, leading to activation of mitogen-activated protein kinase (MAPK) and calcineurin/NF-AT signaling pathways. We observed that simian immunodeficiency virus derived from African green monkeys (SIVagm3) is a potent activator of IL-2 gene expression. IL-2 promoter studies in A3.01 T cells demonstrated that SIVagm3 induced an up to 38-fold increased transcriptional activation of the IL-2 promoter. Inhibition of MAPK signaling pathways using inhibitors of MEK, JNK or p38 abolished SIVagm3-induced IL-2 activation in a dose-dependent manner. In contrast, the immunosuppressive drug cyclosporin A (CyA), a classical IL-2 inhibitor that blocks calcineurin activity, had no effect. Consistent with this finding, the nuclear factor of activated T cells (NF-AT), which is activated by calcineurin, was not induced by SIVagm3. Analyzing further transcription factor binding sites located on the IL-2 promoter we found that SIVagm3 did mainly promote transcriptional activation of the CD28/AP-1 and NF-kappaB responsive elements. These DNA elements were also induced by the viral transactivator protein (Tat) and expression of Tat was sufficient to activate IL-2 induction in stimulated cells. Our results show that SIVagm3 is capable of stimulating IL-2 gene expression via molecular mechanisms different from those induced during classical T cell activation.
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PMID:IL-2 induction by simian immunodeficiency virus involves MAP kinase signaling but is independent of calcineurin/NF-AT activity. 1612 42

Sirolimus (Rapamycin, Wyeth Pharmaceuticals Australia Pty Ltd, Baulkham Hills, NSW, Australia) (SRL) has received increasing attention as an immunosuppressant in renal and other solid organ transplantation. Sirolimus is the first marketed agent in a new class of drugs with a novel mechanism of action. Sirolimus binds, like tacrolimus, to a member of the FK binding protein (FKBP) family. The SRL/FKBP complex binds to the protein kinase mTOR. Binding to mTOR blocks activation of signal transduction pathways causing arrest of the cell cycle in the G1 phase. It is now known that mTOR is a central regulator of cell growth and proliferation. The immunosuppressive properties of SRL are due primarily to blockade of interleukin-2 (IL-2)-induced proliferation of T cells. There is still much to be learnt about how best to use the drug. The key advantage over the current choice of immunosuppressive agents is the ability to preserve renal function and pathology while producing excellent rejection-free, graft survival rates. Thus, SRL may find its pivotal role as a calcineurin inhibitors replacement in patients whose grafts are affected by chronic allograft nephropathy. A second major driver for use may prove to be the impact of SRL on cancer incidence and prognosis. Studies still need to be performed to evaluate the best timing for commencement of SRL and the optimal dosage to minimize side-effects.
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PMID:Sirolimus: its role in nephrology. 1635 46

This study examined the role of protein phosphatase type-1 (PP1), type-2A (PP2A), and mitogen-activated protein kinase phosphatase-1 (MKP-1) in altered mesenteric lymph node (MLN) T cell function in a two-hit model of alcohol (EtOH) intoxication and burn injury. Male rats (250 g) were gavaged with EtOH to achieve a blood EtOH level of approximately 100 mg/dL prior to burn or sham injury (25% total body surface area). MLN T cells harvested 24 h after injury show a significant decrease in p38 and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation in T cells from rats receiving a combined insult of EtOH intoxication and burn injury compared with rats receiving EtOH intoxication or burn injury alone. Treatment of cells with inhibitors of PP1/PP2A [calyculin A (CA) and okadaic acid (OA)] prevented the suppression in T cells p38 and ERK-1/2 activation. In addition, the suppression in interleukin-2 and interferon-gamma production was attenuated in T cells cultured in the presence of CA and OA. MKP-1 inhibitor triptolide did not prevent the suppression in T cells p38/ERK-1/2 and cytokine production. Furthermore, there was a significant decrease in PP1alpha phosphorylation (Thr320) and an increase in PP2A (Tyr307) phosphorylation in T cells following a combined insult of EtOH intoxication and burn injury. As phosphorylation of PP1 at Thr320 and PP2A at Tyr307 led to an inhibition of their enzymatic activities, the decrease in the PP1alpha phosphorylation correlates with an increase in its enzyme activity. Thus, these results suggest that activation of PP1 is likely to play a predominant role in T cell suppression following a combined insult of EtOH intoxication and burn injury.
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PMID:A role of PP1/PP2A in mesenteric lymph node T cell suppression in a two-hit rodent model of alcohol intoxication and injury. 1638 41


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