Disease relevance of cyclosporin A

• In certain nonhuman primate cells, the CA-CypA interaction is essential for restriction: HIV-1 infectivity is increased >100-fold by cyclosporin A (CsA), a competitive inhibitor of the interaction, or by an HIV-1 CA mutation that disrupts CypA binding [1].
• Furthermore, the fibrosis that occurs in the granuloma is apparently T cell--dependent, since no fibrotic lesions developed in SCW-injected athymic nude rats nor in SCW-injected animals treated with the T cell inhibitor, cyclosporin A (CsA) [2].
• These data provide the first demonstration in vivo that activation of a protein phosphatase can inactivate I kappa B, and suggest one possible explanation for mechanism-based toxicities associated with FK-506 and CsA by demonstrating that these drugs can inhibit the calcineurin-dependent activation of a virtually ubiquitous transcription factor [3].
• Cyclosporin A (CsA) prevents hypertrophy caused by activation of calcineurin [Molkentin, J. D., Lu, J.-R., Antos, C. L., Markham, B., Richardson, J., Robbins, J., Grant, S. R. & Olson, E. N. (1998) Cell 93, 215-228] [4].
• CypA knock-down eliminated the HIV-1 stimulatory effect of cyclosporin A (CsA), a competitive inhibitor of the CypA-CA interaction, or of CA mutants that block binding to CypA but caused no change in titer of retroviruses that don't interact with CypA [5].

Psychiatry related information on cyclosporin A

• Injection of CsA led to enhanced phosphorylation of tau at Ser-262 (12E8 site), Ser-198, Ser-199, and/or Ser-202 (Tau-1 site) and Ser-396 and/or Ser-404 (PHF-1 site), as well as to impaired spatial memory, which are two characteristic features of Alzheimer's disease [6].
• Individual differences in the in vitro response to cyclosporin A (CsA): possible heterogeneity in the involvement of the CD28-B7/BB1 pathway [7].

High impact information on cyclosporin A

• Treatment of Col6a1-/- mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo [8].
• A cyp C fusion protein has peptidyl-prolyl isomerase activity, and CsA inhibits this activity [9].
• We report the cloning and characterization of a new binding protein for the immunosuppressive drug cyclosporin A (CsA) [9].
• We propose that the p77 is involved in cyp C native function and that the p55 is involved in signal transduction events blocked by treatment with immunosuppressive levels of CsA [9].
• In concordant models, this type of rejection is prevented by brief complement inhibition by cobra venom factor (CVF) and sustained T-cell immunosuppression by cyclosporin A (CyA) [10].

Chemical compound and disease context of cyclosporin A

• We show that the immunosuppressant cyclosporin A (CsA) and benzothiophene-2-carboxamide, 5-methoxy-3-(1-methyl ethoxy)-1-oxide (PD 144795) block the induction of p53 and NF-kappaB binding to the HIV-1 long terminal repeat (LTR) by the T cell receptor activator phytohemagglutinin [11].
• However, CsA and FK506 pretreatments markedly increased protein carbonylation in the myocardium despite elevated manganese superoxide dismutase activity during endotoxemia [12].
• The Vcr effect in non-proliferating Vcr-resistant cells from a malignant schwannoma was potentiated by Ver and CsA, which had no effect in cells from a kidney adenocarcinoma [13].
• The objective was to investigate the effects of vitamin E on collagen deposition induced by Cyclosporin A (CsA) administration in rats with caerulein (Cr) pancreatitis [14].
• The aim of the present study was to analyze the effect of the immunomodulator compounds, Complete Freund Adjuvant (CFA) and cyclosporin A (CsA), administered alone or together with citral on the induction and extent of rat prostatic hyperplasia [15].

Biological context of cyclosporin A

• The immunosuppressive drugs cyclosporin A (CsA) and FK506 both interfere with a Ca(2+)-sensitive T-cell signal transduction pathway, thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A) involved in lymphokine gene expression [16].
• Here we report that transfection of a calcineurin catalytic subunit increases the 50% inhibitory concentration (IC50) of the immunosuppressants FK-506 and CsA, and that a mutant subunit acts in synergy with phorbol ester alone to activate the interleukin-2 promoter in a drug-sensitive manner [17].
• The first 38 amino-acid residues of porcine PPIase and of bovine cyclophilin are identical and the two proteins both have a relative molecular mass of about 17,000 (ref. 7). The catalysis of prolyl isomerization in oligopeptides and of protein folding by PPIase are strongly inhibited in the presence of low levels of CsA [18].
• These results show that, like alpha/beta T cells, V gamma 3+ thymocytes differentiate from TCRlow precursors to cells with a mature phenotype and that CsA inhibits this transition [19].
• In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX(3)CR1(-/-) and CX(3)CR1(+/+) recipient mice [20].

Anatomical context of cyclosporin A

• We report here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription [16].
• Mouse hearts that survive indefinitely in rats treated with CVF plus CyA express the anti-inflammatory gene heme oxygenase-1 (HO-1) in their endothelial cells and smooth muscle cells [10].
• Characterization of cells infiltrating the grafts revealed a selective reduction in natural killer cells in the CX(3)CR1(-/-) recipients in the absence of CsA and a reduction in macrophages, natural killer cells, and other leukocytes in the presence of CsA [20].
• Now we report an identical spectrum of activities of FK506, CsA, rapamycin, and 506BD on IgE receptor-mediated signal transduction that results in exocytosis of secretory granules from the rat basophilic leukemia cell line RBL-2H3, a mast cell model [21].
• Calcineurin is also involved in the maintenance of the slow muscle fiber gene program because in the adult soleus muscle, cain causes a switch from MyHC-slow to fast-type MyHC-2X and MyHC-2B gene expression, and the activity of the MyHC-slow promoter is inhibited by CsA and FK506 [22].

Associations of cyclosporin A with other chemical compounds

• Both Dex and CsA inhibited the binding of transcription factors AP-1 and NF-AT, but not of NF-kB and OCT-1/OAF, to their corresponding sites on the IL-2 gene promoter [23].
• Flow cytometric analysis of rhodamine 123 dye efflux indicated a functional P-gp that was efficiently blocked by verapamil or cyclosporin A (CsA) [24].
• Transactivation by recombinant NFAT1 in Jurkat T cells requires dual stimulation with ionomycin and phorbol 12-myristate 13-acetate; this activity is potentiated by coexpression of constitutively active calcineurin and is inhibited by CsA [25].
• No apoptosis was detectable at 0.01 microgram/mL adriamycin, the in vivo steady-state level, with or without CsA [24].
• We have investigated the potential involvement of the immune system in the pathogenesis of EMC-D-induced diabetes using cyclosporin-A (CyA), a potent immunosuppressive drug [26].

Gene context of cyclosporin A

• CD40-mediated induction of bcl-x required neither wild-type BTK nor extracellular Ca2+ and was insensitive to CsA [27].
• When expressed in Jurkat T cells, recombinant NFAT1 is regulated, as expected, by the calmodulin-dependent phosphatase calcineurin, and its function is inhibited by the immunosuppressive agent cyclosporin A (CsA) [25].
• The suppressive effect on IFN-gamma production was also more potent than that of either DEX or CyA [28].
• Cyclophilins comprise a highly conserved family of proteins which are the primary targets of the potent immunosuppressive drug, cyclosporin A (CsA), and which display peptidyl prolyl cis-trans-isomerase (PPIase) activity [29].
• This up-regulation of Cdk4 mRNA and protein was resistant to the immunosuppressant drugs cyclosporin A (CsA) and FK506 [30].

Analytical, diagnostic and therapeutic context of cyclosporin A

• Although NF-AT has not been cloned or purified, there is evidence that it is a major target for immunosuppression by cyclosporin A (CsA) and FK506 (refs 2-7) [31].
• Affinity chromatography with FK506, CsA, and rapamycin matrices indicates that the same set of immunophilins present in RBL-2H3 cells have been found in Jurkat T cells and calf thymus; however, the relative amounts of these proteins differ in the two cell types [21].
• Gel mobility shift assays indicated that the binding activities of the factors specifically interacting with these sequences were detected in activated cells regardless of whether the cells were treated with FK-506 or CsA [32].
• Cyclosporin A (CsA) and FK506 (tacrolimus) are immunosuppresants that are widely used in organ transplantation [33].
• Short-term CsA treatment did not prolong survival of allografts from farm pigs into minipigs.(ABSTRACT TRUNCATED AT 250 WORDS)[34]

References