Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and nuclear factor kappa B activity in the brain during endotoxemia

Systemic injection of the endotoxin lipopolysaccharide (LPS) upregulates th e gene encoding CD14 early in the circumventricular organs (CVOs) and later in the brain parenchyma. The present study tested the hypothesis that the parenchymal production of the proinflammatory cytokine tumor necrosis facto r a (TNF-alpha) by microglial cells is responsible for triggering CD14 tran scription in an autocrine/paracrine loop-like manner. In a first set of exp eriments, Sprague Dawley rats were killed 1, 3, 6, and 12 hr after an intra cerebroventricular administration of recombinant rat TNF-alpha or vehicle s olution. Second, anti-rat TNF-alpha-neutralizing antibody or vehicle soluti on was administrated into the lateral ventricle 10 hr before an intraperito neal injection of LPS. Central administration of the cytokine caused a stro ng induction of I kappa B alpha, TNF-alpha, and CD14 mRNA in parenchymal mi croglial cells. The hybridization signal for these transcripts was localize d to the edge of the ventricles and the site of infusion. The time-related expression of each mRNA suggested that TNF-alpha has the ability to trigger its own production followed by the transcription of the LPS receptor; the signal for I kappa B alpha, TNF-alpha, and CD14 peaked at 1, 3, and 6 hr, r espectively. The genes encoding TNF-alpha and mCD14 were also induced in th e CVOs and within microglial cells across the brain parenchyma in response to intraperitoneal LPS administration. This induction in parenchymal cells of the brain was prevented in animals that received the anti-TNF-antisera i ntracerebroventricularly 10 hr before the systemic treatment with the endot oxin. The present data provide the evidence that microglial-derived TNF-alp ha is responsible for the production of the LPS receptor CD14 during endoto xemia. This autocrine/paracrine stimulatory loop may be of great importance in controlling the inflammatory events that take place in the CNS during i nnate immune response as well as under pathological conditions.