Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tacrolimus (FK-506) and cyclosporin A (CsA) are calcineurin antagonists used widely as T-cell immunosuppressants; however, their relative efficacy on the production of interleukin-18 (IL-18) remains undefined. We have examined the effects of FK-506 and CsA on the cytokine generation of human peripheral blood mononuclear cells (PBMCs) in mixed lymphocyte reaction (MLR) with lipopolysaccharide (LPS). We studied the levels of interleukin-18 (IL-18), IL-12, IL-10, IL-6, IL-2 and interferon-gamma (IFN-gamma) in the supernatant in allo-MLR by ELISA assay. Supernatant levels of IFN-gamma, IL-2, IL-6, IL-10 and IL-12 were detected 12 h after MLR and markedly increased thereafter. In contrast, production of IL-18 was detected at 12 h, reached a near maximum level at 24 h and decreased at 72 h. These results suggested that IFN-gamma production depended on IL-18, IL-12 and IL-2 in the early phase of MLR and depended mainly on IL-12 and IL-2 in the late phase. Both calcineurin antagonists inhibit the generation of IL-18, which plays a large role in allogeneic cell interactions, in macrophages and they also promote an equivalent down-regulation of T helper 1 (Th1) and Th2 responses in a concentration-dependent manner. About 90% of IFN-gamma production induced by MLR was inhibited by an anti-IL-18 antibody, showing that IL-18 can trigger IFN-gamma production in MLR. These results suggest that dual signaling consisting of antigen-driven nuclear factor of activated T cells (NFAT) activation and LPS-mediated NF-kappaB activation is crucial for IL-18 production in macrophages, and that IL-18 can trigger IFN-gamma production in T-cells by MLR.
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PMID:Calcineurin antagonists inhibit interferon-gamma production by downregulation of interleukin-18 in human mixed lymphocyte reactions. 1106 69

We evaluated changes in the signaling potentials and proliferative capacity of single antigen-specific T helper (TH) cells during a primary immune response to a protein antigen. At the peak of cellular expansion in vivo all antigen-specific TH cells exhibited a profound block in CD3- and CD4-mediated mobilization of intracellular calcium together with a more global block in T cell receptor-independent capacitative calcium entry (CCE). The proliferative response of these antigen-specific TH cells to anti-CD3, anti-CD28 and IL-2 was also severely blunted. Cross-linking CD69 on a substantial fraction of CD69+ antigen-specific TH cells relieved this block in CCE and restored proliferative capacity in vitro. The CCE rescue operated through a CD69-coupled G protein and required calcium-bound calmodulin and calcineurin. These data reveal critical changes in the responsiveness of antigen-specific TH cells and provide evidence of new mechanisms for the regulation of antigen-specific TH cell development in vivo.
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PMID:Regulating T helper cell immunity through antigen responsiveness and calcium entry. 1106

To identify intrinsic defects in lupus, we studied short-term, CD4(+) T cell lines that were established from 16 lupus patients (active or inactive) and 15 normal subjects by stimulating once with anti-CD3, anti-CD28, and IL-2. After resting, the pure CD4(+) T cells were exposed to anergy-inducing stimulation with plate-bound anti-CD3 mAb in the absence of APC. Lupus T cells showed prolonged high level expression of CD40 ligand (CD40L, CD154) even in the face of anergy protocol, which shut down CD40L expression in normal T cells. The sustained CD40L expression in lupus T cells did not correlate with memory status or Th deviation, and was relatively independent of IL-2 or other autocrine or paracrine signals via CD28 or CTLA-4. Cyclosporin A could block CD40L expression by lupus T cells when added early during the anti-CD3 stimulation period, but only partially when added later, indicating that another mechanism regulates the prolonged hyperexpression of CD40L besides the Ca(2+) --> calcineurin-dependent NF-AT pathway. When exposed to the anergy protocol, lupus T cells, in marked contrast to normal T cells, did not phosphorylate Cbl/Cbl-b but continued to express strongly phosphorylated extracellular signal-regulated kinase (ERK); U0126, a specific inhibitor of mitogen-activated protein kinase kinase --> ERK, could block both the early and the prolonged hyperexpression of CD40L. Thus, pathways regulating the activities of Cbl and one particular mitogen-activated protein kinase, ERK, are involved in the prolonged hyperexpression of CD40L in lupus T cells.
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PMID:Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. 1108 8

CD58 is the ligand for the CD2 molecule on human T cells and has been shown to provide a co-stimulatory signal for T cell activation. However, its physiological role is still unclear. We studied the effects of co-stimulation by CD58 on the production of T(h)1-type (IL-2- and IFN-gamma) or T(h)2 type (IL-4, IL-5 and IL-10) cytokines in an in vitro culture system of purified human T cells with CD58-transfected P815 cells and with anti-CD3 as the primary stimulus. Co-stimulation of T cells by CD58 potently induced IL-10 and IFN-gamma production (at the protein and at the mRNA level), and transforming growth factor-ss production (at the mRNA level), comparable to what can be found in CD80 co-stimulated T cell cultures. In contrast, we found low to absent IL-2, IL-4, IL-5, IL-13 and tumor necrosis factor-alpha production after CD58 co-stimulation, and this was not due to suppressive effects of endogenously produced IL-10. CD80 co-stimulation strongly induced all these cytokines. Intracellular staining for cytokine expression revealed the existence of a T cell subpopulation induced by CD58 co-stimulation to produce both IFN-gamma and IL-10. We furthermore found that the selective cytokine profile induced by CD58 co-stimulation is further accentuated by rIL-12 and by rIFN-alpha. Using cyclosporin A as an inhibitor of the calcineurin enzyme, we could show that production of all cytokines in this system is calcium dependent. CD58 co-stimulation thus induces a cytokine pattern corresponding to that described for T regulatory (T(r)) 1 cells and to the pattern reported to be induced by the newly identified B7 family member, B7-H1.
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PMID:Effects of co-stimulation by CD58 on human T cell cytokine production: a selective cytokine pattern with induction of high IL-10 production. 1115 51

Interleukin (IL)-10, an immunomodulatory cytokine predominantly produced by monocytes/macrophages and T cells, inhibits several functions of dendritic cells (DC), monocytes and T cells including their cytokine production, but it stimulates B cell immunoglobulin (Ig) production and cytotoxic T lymphocyte (CTL) generation. A precise knowledge of the mechanisms that control the IL-10 production is therefore highly important for understanding the immunoregulation. The IL-10 production was studied in cultures of freshly isolated human T cells. A rise in intracellular calcium as well as the common gamma-chain containing cytokine receptor triggering or CD28 triggering were found to be important signals for IL-10 induction. CD80, CD58, rIL-12 and rIFN-alpha all had efficacious and independent costimulatory activities on the IL-10 production, while PGE2 was inhibitory. Dependence on autocrine IL-2 signalling was shown by the effects of anti-IL-2 and anti-IL-2R monoclonal antibodies (MoAb), but the IL-10 production proceeded partly IL-2-independent when CD80 provided costimulation. Sensitivity to inhibition by CsA was not removed by CD80 or CD58 costimulation and/or by addition of rIL-12 or rIFN-alpha, pointing to the absolute requirement for calcineurin activity. These data reveal important differences in the regulatory pathways between IL-10 (a cytokine-inhibitory interleukin) and IL-2 (a cytokine-inducing interleukin), which can potentially be exploited therapeutically. The fact that CsA blocks the production of IL-10, which itself has important immunosuppressive properties, should be taken into account in defining immunosuppressive treatment schedules which include the use of CsA.
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PMID:Regulation of the IL-10 production by human T cells. 1116 17

We report here on the characterization of the novel immunosuppressant Sanglifehrin A (SFA). SFA is a representative of a class of macrolides produced by actinomycetes that bind to cyclophilin A (CypA), the binding protein of the fungal cyclic peptide cyclosporin A (CsA). SFA interacts with high affinity with the CsA binding side of CypA and inhibits its peptidyl-prolyl isomerase activity. The mode of action of SFA is different from known immunosuppressive drugs. It has no effect on the phosphatase activity of calcineurin, the target of the immunosuppressants CsA and FK506 when complexed to their binding proteins CypA and FK binding protein, respectively. Moreover, its effects are independent of binding of cyclophilin. SFA inhibits alloantigen-stimulated T cell proliferation but acts at a later stage than CsA and FK506. In contrast to these drugs, SFA does not affect IL-2 transcription or secretion. However, it blocks IL-2-dependent proliferation and cytokine production of T cells, in this respect resembling rapamycin. SFA inhibits the proliferation of mitogen-activated B cells, but, unlike rapamycin, it has no effect on CD154/IL-4-induced Ab synthesis. The activity of SFA is also different from that of other known late-acting immunosuppressants, e.g., mycophenolate mofetil or brequinar, as it does not affect de novo purine and pyrimidine biosynthesis. In summary, we have identified a novel immunosuppressant, which represents, in addition to CsA, FK506 and rapamycin, a fourth class of immunophilin-binding metabolites with a new, yet undefined mechanism of action.
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PMID:Sanglifehrin A, a novel cyclophilin-binding compound showing immunosuppressive activity with a new mechanism of action. 1139 Apr 63

The diverse forms of protein phosphatase 1 (PP1) in vivo result from the association of the catalytic subunit with different regulatory subunits. We recently have described that PP1alpha is a Ras-activated Bad phosphatase that regulates IL-2 deprivation-induced apoptosis. With the yeast two-hybrid system, GST fusion proteins, indirect immunofluorescence, and coimmunoprecipitation, we found that Bcl-2 interacts with PP1alpha and Bad. In contrast, Bad did not interact with 14-3-3 protein. Bcl-2 depletion decreased phosphatase activity and association of PP1alpha to Bad. Bcl-2 contains the RIVAF motif, analogous to the well characterized R/KXV/IXF consensus motif shared by most PP1-interacting proteins. This sequence is involved in the binding of Bcl-2 to PP1alpha. Disruption of Bcl-2/PP1alpha association strongly decreased Bcl-2 and Bad-associated phosphatase activity and formation of the trimolecular complex. These results suggest that Bcl-2 targets PP1alpha to Bad.
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PMID:Bcl-2 targets protein phosphatase 1 alpha to Bad. 1139 Apr 85

Calcineurin, a Ca(2+)/calmodulin-dependent Ser/Thr phosphatase (protein phosphatase 2B), plays a critical role in IL-2 production during T cell activation. It has been previously reported that IL-2 release in activated Jurkat T requires caspase-like activity (Posmantur et al. (1998) Exp. Cell. Res. 244, 302-309). We report here that the 60-kDa catalytic subunit of calcineurin A (Cn A) was partially cleaved to a 45-kDa form in phytohemagglutinin A (PHA) or phorbol ester + ionomycin (P + I)-activated Jurkat cells. In parallel, proteolytic activation of upstream caspases (caspase-8 and -9) as well as effector caspase-3 was also observed. Cn A cleavage was caspase mediated, since it was inhibitable by pan-caspase inhibitor Cbz-Asp-CH(2)OC(O)-2,6-dichlorobenzene (Z-D-DCB). Cn A cleavage was also observed when purified calcineurin was digested in vitro with caspase-3. Truncated Cn A was associated with enhanced phosphatase activity and reduced calmodulin sensitivity. Furthermore, in PHA or P + I-activated Jurkat cells, dephosphorylation of calcineurin substrate NFATc (a transcription factor known to be involved in transactivation of the IL-2 gene), was also suppressed by Z-D-DCB. Taken together, our results suggest that caspase-mediated cleavage of Cn A contributes to IL-2 production during T cell activation.
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PMID:Caspase-mediated calcineurin activation contributes to IL-2 release during T cell activation. 1147 81

Cyclosporine is a critical dose drug for which individualisation by therapeutic drug monitoring is indisputable. Current evidence suggests that a single concentration (C2) taken two hours after cyclosporine administration with the microemulsion formulation better predicts exposure and events than the trough concentration (C(0)), which is routinely used for adjusting the dosage of this drug. Studies have shown that the greatest calcineurin inhibition and the maximum inhibition of IL-2 production occur in the first 1 to 2 hours after dosing. These findings support the concept that the C2 level better reflects immunosuppressive efficacy than the trough concentration. Preliminary data from an outcome study in liver transplant recipients have shown that the incidence of biopsy proven moderate to severe acute rejection was significantly lower in patients managed by C2 monitoring compared with those monitored by C(0). The critical importance of achieving adequate cyclosporine exposure during the first 3 to 5 posttransplant days to prevent acute rejection has been documented in prospective studies with de novo renal and liver transplant recipients. Conversion of maintenance liver and heart transplant patients to C2 monitoring resulted in an amelioration of renal function. Time-dependent target values have been proposed for liver and renal transplant recipients. These require further prospective validation. For routine monitoring of C2 levels on-site validated dilution guidelines are necessary for most of the available immunoassays. C2 monitoring necessitates further organizational requirements which may be judged differently between transplant centers. In particular during the early posttransplant period C2 monitoring is a promising new option to make immunosuppressive therapy with the microemulsion formulation of cyclosporine safer and more efficient.
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PMID:Two-hour cyclosporine concentration determination: an appropriate tool to monitor neoral therapy? 1180 21

The novel protein kinase C (PKC) isoform, PKC theta, is selectively expressed in T lymphocytes and is a sine qua non for T cell antigen receptor (TCR)-triggered activation of mature T cells. Productive engagement of T cells by antigen-presenting cells (APCs) results in recruitment of PKC theta to the T cell-APC contact area--the immunological synapse--where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and IL-2 production. The transcription factors NF-kappa B and AP-1 are the primary physiological targets of PKC theta, and efficient activation of these transcription factors by PKC theta requires integration of TCR and CD28 costimulatory signals. PKC theta cooperates with the protein Ser/Thr phosphatase, calcineurin, in transducing signals leading to activation of JNK, NFAT, and the IL-2 gene. PKC theta also promotes T cell cycle progression and regulates programmed T cell death. The exact mode of regulation and immediate downstream substrates of PKC theta are still largely unknown. Identification of these molecules and determination of their mode of operation with respect to the function of PKC theta will provide essential information on the mechanism of T cell activation. The selective expression of PKC theta in T cells and its essential role in mature T cell activation establish it as an attractive drug target for immunosuppression in transplantation and autoimmune diseases.
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PMID:Protein kinase C(theta) in T cell activation. 1186 17


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