Systemic injection of the
endotoxin lipopolysaccharide (LPS) upregulates the 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 factor alpha (
TNF-alpha) by microglial cells is responsible for triggering CD14 transcription in an autocrine/paracrine loop-like manner. In a first set of experiments, Sprague Dawley rats were killed 1, 3, 6, and 12 hr after an intracerebroventricular administration of recombinant rat
TNF-alpha or vehicle
solution. Second, anti-rat
TNF-alpha-
neutralizing antibody or vehicle
solution was administrated into the lateral ventricle 10 hr before an
intraperitoneal injection of LPS. Central administration of the
cytokine caused a strong induction of
IkappaBalpha,
TNF-alpha, and CD14
mRNA in parenchymal microglial cells. The hybridization signal for these transcripts was localized 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
IkappaBalpha,
TNF-alpha, and CD14 peaked at 1, 3, and 6 hr, respectively. The genes encoding
TNF-alpha and mCD14 were also induced in the 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 intracerebroventricularly 10 hr before the systemic treatment with the
endotoxin. The present data provide the evidence that microglial-derived
TNF-alpha is responsible for the production of the
LPS receptor CD14 during
endotoxemia. This autocrine/paracrine stimulatory loop may be of great importance in controlling the inflammatory events that take place in the CNS during innate immune response as well as under pathological conditions.