Artikel
Immunosuppressive effects of steroids and non-steroidal anti-inflammatory drugs with anti-edema properties
Immunosuppression durch Steroide und nicht-steroidale Antiphlogistika mit antiödematöser Wirkung
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Autoren
Veröffentlicht: | 23. April 2004 |
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Gliederung
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Objective
Immuntherapy represents one approach to tackle infiltrating tumors such as gliomas. A great concern has been edema therapy with steroids which are potent inhibitors of T cell cytotoxicity. We assessed the immunosuppressive effect of steroids (dexamethasone) as well as alternative anti-inflammatory drugs with known anti-edema properties, including cyclooxygenase (COX)-1 (acetylsalicylic acid (ASA) and ibuprofen) and COX-2 prevalent inhibitors (parecoxib) as well as boswellic acids, a 5-lipoxygenase (5-LOX) inhibitor. To assess immunosuppression synthesis of IFN-γ, an important cytokine in T-cell dependent immunoreactivity, was quantified.
Methods
Lymphocytes were isolated from spleens of untreated Balb/c mice and stimulated with ConA (3 µg/ml) in 96-well PVDF-plates for 20 hours. Anti-inflammatory drugs to be tested were added at the same time in doses covering levels which are achieved in serum: dexamethasone 10-1000 ng/ml, acetylsalicylic acid 5-20 mM, ibuprofen 0.05-10 mM, and parecoxib 0.01-10 mM. Boswellic acids isolated in a 70% ethanol fraction from H15 (400 mg tablet/ml) were added to the culture medium in different concentrations (0.01-10.0%). IFN-γ synthesis was quantified by a commercially available ELISPOT assay (Diaclone, France).
Results
Dexamethasone in concentrations of 10, 100, and 1000 ng/ml decreased INF-γ production to 79.9, 43.4, and 18.8%, respectively. IFN-γ synthesis was also suppressed by ASA and ibuprofen: whereas ibuprofen showed complete suppression between 0.5 and 1.0 mM, ASA at 20 mM reduced IFN-γ to only 46.0%. Parecoxib when added at a concentration of 1.0 mM decreased IFN-γ synthesis to 63.2%, and complete suppression was acheived at 5.0 mM. Boswellic acids added at a concentration of ≥0.5% to the culture medium resulted in complete suppression of IFN-γ production. Taking serum levels commonly achieved in patients and the pharmacological properties of these drugs into account their immunosuppressive potency (excluding boswellia acids) in decreasing order is: dexamethasone >> ibuprofen > acetylsalicylic acid > parecoxib.
Conclusions
As expected, dexamethasone showed strong immunosuppressive effects. Nevertheless, immunosuppression was also observed with non-steroidal drugs, including COX-inhibitors as well as the 5-LOX-inhibitor boswellic acids. With respect to future immunotherapeutic trials acetylsalicylic acid and parecoxib which exerted the least immunosuppressive effects should be evaluated further in vivo.