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In this study we investigated the effect of immunosuppressive drugs on the interleukin-1 alpha (IL-1 alpha) enhanced tumor necrosis factor alpha (TNF alpha) production by proximal tubular epithelial cells (PTEC). Under basal conditions cultured PTEC produce between 0 to 390 pg/ml/10(5) cells of TNF alpha. Upon stimulation with IL-1 alpha an enhancement of TNF alpha production was seen in each cell line tested, ranging from 230 to 2424 pg/ml/10(5) cells. The presence of cyclosporin A (CsA) during stimulation with IL-1 alpha inhibited the enhanced TNF alpha production in a dose dependent fashion, with a maximal inhibition of 90% at a concentration of 250 ng/ml. Inhibition was at the level of mRNA as could be demonstrated by Northern blot analysis. FK506, corticosteroids and rapamycin also inhibited TNF alpha production in a dose dependent fashion, although not as effectively as CsA. Two corticosteroids were tested for their inhibitory effect on TNF alpha production. It was found that dexamethasone at a concentration of 10 ng/ml inhibited TNF alpha production for almost 40%. A 100-fold higher concentration of hydrocortisone was necessary to yield similar inhibition. The effect of rapamycin on the IL-1 alpha enhanced TNF alpha production differed from the effect of CsA. While CsA induced a maximal inhibition of 90%, rapamycin only induced a maximal inhibition of 37%, and even less inhibition at higher concentrations of the drug. The presence of the various drugs was essential for their inhibitory effect, because removal of the drug from the PTEC by washing immediately resulted in loss of inhibition. Combinations of CsA and FK506 or rapamycin were not additive.(ABSTRACT TRUNCATED AT 250 WORDS)
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B A Yard, and
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