Effects of Cyclosporin A and Dinactin on T-Cell Proliferation, Interleukin-5 Production, and Murine Pulmonary Inflammation

Abstract

We compared the effects of cyclosporin A (CSA) and a macrotetrolide antibiotic, dinactin, on human T-cell proliferation and cytokine production induced by stimulation of the T-cell receptor alone (monoclonal antibody [mAb] directed against CD3) or in combination with costimulatory signals (mAbs directed against CD3 and CD28). These agents were also examined in a murine model of interleukin (IL)-5-mediated pulmonary inflammation. Dinactin inhibited T-cell proliferation induced by IL-2, by mAb to CD3, and by mAbs to CD3 plus alpha-CD28 with identical dose-response curves (IC50 = 10-20 ng/ml). Dinactin inhibited cytokine production with IC50 values of 10 ng/ml for IL-4 and IL-5 and 30 or 60 ng/ml for interferon-gamma or IL-2, respectively. Unlike CSA, exogenous IL-2 did not alter the dinactin-mediated effects on T cells, and nuclear run-on and steady-state messenger RNA (mRNA) analysis showed that dinactin inhibited cytokine production through a post-transcriptional mechanism. CSA selectively blocked T-cell receptor-induced T-cell proliferation and cytokine production (IC50 = 10 ng/ml). Under costimulatory conditions, IL-5 synthesis was only minimally inhibited by high concentrations of CSA, and at CSA concentrations of less than 125 ng/ml, IL-5 was significantly increased above control values. Dinactin and CSA reduced pulmonary eosinophilia when administered within 1 d of airway antigen challenge. Of the cytokine mRNAs examined in the lungs of CSA-pretreated, antigen-challenged mice, IL-5 mRNA levels were the least reduced, paralleling the resistance of IL-5 to CSA observed in vitro and suggesting a role for CD28 in the in vivo induction of IL-5.

Defective T cell development and function incalcineurinAβ-deficient mice

“…Indeed, CsA administration in vivo reduces CD4 and CD8 single-positive cells, reduces cytokine levels, and compromises T cell proliferation (16)(17)(18). Quantitative immunoblotting (8) and the results presented in this report demonstrate that CnA␤ is the predominant isoform of calcineurin expressed in lymphocytes.…”

Co-occurrence of toxic bacterial and fungal secondary metabolites in moisture-damaged indoor environments

“…Valinomycin, monactin and nonactin are known ionophors that disrupt transmembrane ion gradients. Monactin and nonactin are members of the macrotetrolid antibiotics family and have been shown to modulate cytokine production and T-cell proliferation (Mori et al, 2000;Umland et al, 1999). Research on the biological activity of valinomycin proposed mitochondrial swelling, reduced natural killer cell activity and at higher doses apoptosis in peripheral blood lymphocytes (Paananen et al, 2000).…”

Cyclosporin A, apoptosis of BAL T‐cells and expression of Bcl‐2 inasthmatics

“…Functionally, CsA inhibits the transcription of numerous cytokines and immunomodulators involved in T-cell activation and proliferation. It has been shown that CsA inhibits T-cell proliferation, induces apoptosis of CD4-positive T-cells and downregulates cytokine expression in in vitro and animal studies [22][23][24]. In clinical studies in asthma, it has been found that CsA inhibits the LAR, improves lung function, decreases blood and BALF eosinophil numbers, inhibits cytokine/ chemokine expression and reduces the requirement for oral corticosteroid in severe disease [7][8][9][10]25].…”