Effect of corticosteroids, cyclosporin A, and methotrexate on cytokine release from monocytes and T-cell subsets.
Corticosteroids are the most effective drugs in the management of asthma. However, because of their known side effects and the existence of corticosteroid-resistant patients, there is a need for substitute medications in asthma therapy. Using cell lines, in the present study, the two corticosteroids dexamethasone (Dex), and beclomethasone (Bec), as well as the immunosuppressant cyclosporin A (CsA), and the antimetabolic drug methotrexate (Mtx) were examined in their effect on release of immunoreactive IL-1 beta, IL-2, IL-4, IL-5, and IL-8. THP-1 cells served as a test model for monocytes secreting IL-1 beta and IL-8 upon stimulation by lipopolysaccharide. Jurkat cells were used as a test model for TH1-type T-cells and were stimulated for IL-2 release with a combination of phytohemagglutinin and phorbol myristate acetate. Representing TH2-type T-cells, D10.G4.1 cells challenged by anti-CD3-mAb produced IL-4, and IL-5. Considerable qualitative and quantitative differences in the relative efficacy of the test compounds were found. Following IC50 values (nmol/l) of the test compounds were estimated (IL-1 beta/IL-8/IL-2/IL-4/IL-5): Dex (10.8/35.7/ > 10,000.0/5.1/4.1), Bec (30.9/102.2/8591.4/0.6/0.4), and CsA (318.7/6211.2/2.3/68.2/237.9). Mtx in concentrations up to 10,000.0 nmol/l was completely inactive. It can be concluded that corticosteroids show another inhibition pattern than CsA: corticosteroids affect mainly TH2-type T-cells, while CsA primarily inhibits the TH1-type T-cell response.
Schmidt
J
J
Department of Pharmacology, ASTA Medica AG, Frankfurt/Main, Germany.
Fleissner
S
S
Heimann-Weitschat
I
I
Lindstaedt
R
R
Pomberg
B
B
Werner
U
U
Szelenyi
I
I
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D001507:Beclomethasone / Q000494:pharmacology; D017252:CD3 Complex; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D003907:Dexamethasone; D016572:Cyclosporine; D001507:Beclomethasone; D008727:Methotrexate