Effects of the Immunosuppressive Drugs CsA and FK506 on Intracellular Signalling and Gene Regulation

Rühlmann, Andreas; Nordheim, Alfred

doi:10.1016/s0171-2985(97)80040-x

Cited by 84 publications

(60 citation statements)

References 138 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the case of cytokine production, there are reports of enhanced production of IL-6, 3 whereas many other cytokines are inhibited, e.g., IL-1␤, IL-2, IL-4, and IL-8. 2 TNF-␣ production is inhibited in vitro by both cyclosporine and tacrolimus in cells from healthy individuals, although the mode of activation has been shown to influence inhibition. Monocytes in one study were not inhibited by cyclosporine or tacrolimus when activated by LPS, 24 although this has not been a universal finding.…”

Section: Discussionmentioning

confidence: 99%

“…The principal mechanism of their immunosuppressive action is inhibition of interleukin-2 (IL-2) transcription by preventing the activation of nuclear factor of activated T cells. 1 The effect of these drugs on the production of other cytokines is largely inhibitory, 2 although some, such as IL-6, have been shown to be enhanced. 3 Moreover, tacrolimus and cyclosporine have differential effects on the production of some cytokines.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Pretransplantation tumor necrosis factor-α production predicts acute rejection after liver transplantation

et al. 2000

View full text Add to dashboard Cite

Immunosuppressive therapy has many adverse effects in both the short and longer term. Tailoring immunosuppression might be possible if pretransplantation parameters predicted rejection. We investigated production of the proinflammatory cytokine, tumor necrosis factor-␣ (TNF-␣), and the anti-inflammatory cytokine, interleukin-10 (IL-10), pretransplantation to determine whether there is a relation with acute rejection. Peripheral-blood mononuclear cells were obtained from patients with chronic liver disease on the waiting list for orthotopic liver transplantation and healthy controls. Cells (0.5 ؋ 10 6 ) were stimulated with 200 ng of lipopolysaccharide. Preincubation for 30 minutes with tacrolimus, cyclosporine, and dexamethasone at concentrations of 10 and 100 ng was also performed. TNF-␣ and IL-10 levels were measured by enzyme-linked immunosorbent assay. Acute rejection was defined on clinical and histological grounds. Pretransplantation in vitro production of TNF-␣ significantly (P < .05) increased in the group of patients with acute rejection (n ‫؍‬ 9) compared with those who did not develop rejection (n ‫؍‬ 12). Preincubation with dexamethasone significantly (P < .001) reduced TNF-␣ and IL-10 production in both patients and controls (n ‫؍‬ 8). IL-10 production pretransplantation was not different in those who developed acute rejection (n ‫؍‬ 9) compared with those who did not (n ‫؍‬ 9). Preincubation with tacrolimus augmented (P < .05) the production of IL-10 in patients (n ‫؍‬ 18), but not controls (n ‫؍‬ 6). Pretransplantation TNF-␣ production is increased in patients who go on to develop acute rejection posttransplantion. (Liver Transpl 2000;6:721-727.)

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pretransplantation tumor necrosis factor-α production predicts acute rejection after liver transplantation

et al. 2000

View full text Add to dashboard Cite

show abstract

“…Although NFAT proteins represent perhaps the best characterized direct targets of calcineurin (16 -18), several additional signaling mechanisms have been shown to be regulated by calcineurin based on inhibition by CsA and/or FK506. These include signaling pathways involving NF-B, NO, protein kinase A, stress-activated protein kinase/JNK, and p38 (48). In addition, the expression of a fairly wide spectrum of genes has been shown to be inhibited by CsA or FK506, and a role for NFAT proteins in the transcriptional regulation of many of these genes, particularly genes encoding transcription factors, has not been demonstrated (48).…”

Section: Signaling Mechanisms Regulating Nfatl1 Expressionmentioning

confidence: 99%

“…These include signaling pathways involving NF-B, NO, protein kinase A, stress-activated protein kinase/JNK, and p38 (48). In addition, the expression of a fairly wide spectrum of genes has been shown to be inhibited by CsA or FK506, and a role for NFAT proteins in the transcriptional regulation of many of these genes, particularly genes encoding transcription factors, has not been demonstrated (48). Thus NFATL1 represents a member of a larger group of proteins that is regulated by calcineurin through still poorly defined mechanisms that do not involve the calcineurin-mediated activation of NFATc proteins.…”

Section: Signaling Mechanisms Regulating Nfatl1 Expressionmentioning

confidence: 99%

The NFAT-Related Protein NFATL1 (TonEBP/NFAT5) Is Induced Upon T Cell Activation in a Calcineurin-Dependent Manner

Trama

Hawley

et al. 2000

The Journal of Immunology

146

168

View full text Add to dashboard Cite

NFAT DNA binding complexes regulate programs of cellular activation and differentiation by translating receptor-dependent signaling events into specific transcriptional responses. NFAT proteins, originally defined as calcium/calcineurin-dependent regulators of cytokine gene transcription in T lymphocytes, are expressed in many different cell types and represent critical signaling intermediates that mediate an increasingly wide spectrum of biologic responses. Recent studies have identified a novel protein containing a region of similarity to the NFAT DNA binding domain. Here we demonstrate that this protein, designated NFATL1 (also known as tonicity enhancer binding protein and NFAT5) is expressed at high levels in the thymus but is undetectable in mature lymphocytes. However, NFATL1 can be induced in both primary quiescent T lymphocytes and differentiated Th1 and Th2 cell populations upon mitogen- or Ag receptor-dependent activation. The induction of NFATL1 protein, as well as NFATL1-dependent transcription, is inhibited by cyclosporin A and FK506, and expression of constitutively active calcineurin induces NFATL1-dependent transcription. Overexpression of NFATc1 and inhibition of NFATc activity through the use of a dominant negative NFATc1 protein have no affect on NFATL1-dependent transcription, indicating that NFATc proteins do not play a role in the calcineurin-dependent induction of NFATL1. Interestingly, induction of NFATL1 by a hyperosmotic stimulus is not blocked by the inhibition of calcineurin. Moreover, osmotic stress response genes such as aldose reductase are not induced upon T cell activation. Thus inducible expression of NFATL1 represents a mechanism by which receptor-dependent signals as well as osmotic stress signals are translated into transcriptional responses that regulate cell function.

show abstract

“…3 Cyclosporin A (CsA) is one of the most important immunosuppressants used in lung transplantation. [4][5][6] Although the molecular events have not yet been completely defined, some studies indicate that CsA blocks the initial stages of lymphocyte activation, 7,8 inhibiting the production of interleukin-2 and other lymphokins. 9,10 Theoretically, the mechanism of action of CsA includes an influence on cytoplasmatic calcium, which is an essential component for normal cellular function.…”

Section: Introductionmentioning

confidence: 99%

Cyclosporin a Reduces Airway Mucus Secretion and Mucociliary Clearance in Rats

Pazetti

Pêgo‐Fernandes

Ranzani

et al. 2007

Clinics

View full text Add to dashboard Cite

-Filho G, Jatene FB. Cyclosporine A reduces airway mucus secretion and mucociliary clearance in rats. Clinics. 2007:62(3):345-52. PURPOSE:To assay the effects of cyclosporin A on mucus secretion from goblet cells and on mucociliary transport in situ in rats. METHODS: Twenty-one male Wistar rats were assigned to 3 groups: control (n = 5), saline (n = 8), and cyclosporin A (n = 8). After 30 days of drug therapy, the rats were killed, and the lungs were removed from the thoracic cavity. Mucus samples were collected, and the transport rate was evaluated in vitro using a bullfrog palate model. Mucociliary transport was timed in situ by direct view of particles trapped on the mucus moving across the respiratory tract. Finally, the amount of stored mucins in the goblet cells of the respiratory epithelium was measured. RESULTS: Drug dosage measurements showed that cyclosporine blood concentration at the moment the rats were killed was 1246.57 ± 563.88 ng/mL. The in vitro transport rate was significantly lower (P < .001) in the cyclosporin A-treated group. Also, the in-situ mucociliary transport rate was decreased in all cyclosporin A-treated animals when compared to the saline group (P = .02). Mucus quantity measurements showed a significant decrease on both acid (P = .01) and neutral (P = .02) mucus production from goblet cells in the animals submitted to cyclosporin A therapy. The correlation between the percentage of total mucus and in vitro transport rate was positive and significant (r = 0.706, P < .001), as was the correlation between the percentage of total mucus and the in situ mucociliary transport rate (r = 0.688, P = .001). CONCLUSION: This study shows that cyclosporin A plays an important role in the impairment of the mucociliary clearance in rats by reducing both acid and neutral mucus production from goblet cells and causing a decrease in the mucociliary transport velocity.

show abstract

Effects of the Immunosuppressive Drugs CsA and FK506 on Intracellular Signalling and Gene Regulation

Cited by 84 publications

References 138 publications

Pretransplantation tumor necrosis factor-α production predicts acute rejection after liver transplantation

Pretransplantation tumor necrosis factor-α production predicts acute rejection after liver transplantation

The NFAT-Related Protein NFATL1 (TonEBP/NFAT5) Is Induced Upon T Cell Activation in a Calcineurin-Dependent Manner

Cyclosporin a Reduces Airway Mucus Secretion and Mucociliary Clearance in Rats

Contact Info

Product

Resources

About