LIPOPOLYSACCHARIDE INDUCES EXPRESSION OF TUMOR-NECROSIS-FACTOR-ALPHA IN RAT-BRAIN - INHIBITION BY METHYLPREDNISOLONE AND BY ROLIPRAM

1 We have investigated the effects of the phosphodiesterase (PDE) type TV inhibitor rolipram and of the glucocorticoid methylprednisolone on the induction of tumour necrosis factor alpha (TNF-alpha) mRNA and pr otein in brains of rats after peripheral administration of lipopolysac charide (LPS). 2 After intravenous administration of LPS, a similar ti me-dependent induction of both TNF-alpha mRNA and protein was observed in rat brain. Peak mRNA and protein levels were found 7 h after admin istration of LPS. 3 In situ hybridization experiments with a specific antisense TNF-alpha riboprobe suggested that the cells responsible for TNF-alpha production in the brain were microglia. 4 Intraperitoneal a dministration of methylprednisolone inhibited the induction of TNF-alp ha protein in a dose-dependent manner. A maximal inhibition of TNF-alp ha protein production by 42.9+/-10.2% was observed at a dose regimen c onsisting of two injections of each 30 mg kg(-1) methylprednisolone. 5 Intraperitoneal administration of rolipram also inhibited the inducti on of TNF-alpha protein in a dose-dependent manner. The maximal inhibi tion of TNF-alpha protein production was 96.1+/-12.2% and was observed at a dose regimen of three separate injections of each 3 mg kg(-1) ro lipram. 6 In situ hybridization experiments showed that the level of T NF-alpha mRNA induced in rat brain by LPS challenge was reduced by int raperitoneal administration of methylprednisolone (2 x 15 mg kg(-1)) a nd of rolipram (3 x 3 mg kg(-1)). 7 We suggest that peripheral adminis tration of LPS induces a time-dependent expression of TNF-alpha in rat brain, presumably in microglial cells, and that methylprednisolone an d rolipram inhibit LPS-induced expression of TNF-alpha in these cells via a decrease of TNF-alpha mRNA stability and/or TNF-alpha gene trans cription.