The effects of antiinflammatory and antiallergic drugs on cytokine release after stimulation of human whole blood by lipopolysaccharide and zymosan A

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Abstract
IL-1β, IL-8, IL-6 and TNFα, derived from infiltrating leukocytes, are important mediators of inflammation in arthritic and allergic diseases. Heparinized human whole blood was evaluated as a model to study the effects of various classes of antiinflammatory drugs on cytokine release/biosynthesis from leukocytes. Whole blood was stimulated with zymosan A (1.5 mg/ml) or LPS (5 µg/ml) for 4h to induce cytokine release. Dexamethasone was the most potent inhibitor of TNFα, IL-1β, IL-6 and IL-8 release from LPS stimulated blood leukocytes (IC50s of 0.19, 0.11 µM, 0.16 and 0.07 respectively). In LPS stimulated blood, SKF-86002, a 5-lipoxygenase/cytooxygenasae inhibitor, and rolipram, a PDE IV inhibitor, also inhibited the release of TNFα (IC50s of 33 and 11µM, respectively), IL-1β (IC50s of 11 and 30µM, respectively), IL-6 (IC50s of 56 and > 30, respectively) and IL-8 (IC50s of 6.7 and 15, respectively), whereas isoproterenol (1 µM) inhibited significantly only TNFα release. Nonsteroidal antiinflammatory drugs, 5-lipoxygenase inhibitors and immuno-suppressive drugs were inactive at 30 µM against LPS and zymosan A stimulation of cytokine release. Using zymosan A as the stimulus, only SKF-86002 (30 µM) showed significant inhibition of IL-1β (−59%). This 4h human blood assay has the potential to identify novel inhibitors and sites of actions (e.g. transcription, post-transcriptional and secretion) of new antiinflammatory drugs.