Effects of Cyclosporin A and Dinactin on T-Cell Proliferation, Interleukin-5 Production, and Murine Pulmonary Inflammation
| Autor: | Manish N. Patel, Himanshu Shah, James Jakway, Charles G. Garlisi, M. Motasim Billah, Robert W. Egan, Shelby P. Umland, Jennifer Shortall, Vinod Hegde, Shad Razac, D. Stelts, Ted T. Kung, Angela Falcone |
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| Rok vydání: | 1999 |
| Předmět: |
CD4-Positive T-Lymphocytes
Pulmonary and Respiratory Medicine CD3 Complex medicine.medical_treatment T cell CD3 Clinical Biochemistry Biology Lymphocyte Activation Mice CD28 Antigens Cyclosporin a Hypersensitivity Respiratory Hypersensitivity medicine Animals Humans RNA Messenger Receptor Molecular Biology Interleukin 5 Dose-Response Relationship Drug CD28 Interleukin Cell Biology Molecular biology Anti-Bacterial Agents Cytokine medicine.anatomical_structure Cyclosporine biology.protein Cytokines Macrolides Interleukin-5 |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 20:481-492 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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