DIFFERENTIAL INDUCTION OF C-FOS IMMUNOREACTIVITY IN HYPOTHALAMUS AND BRAIN-STEM NUCLEI FOLLOWING CENTRAL AND PERIPHERAL ADMINISTRATION OF ENDOTOXIN

Lipopolysaccharide (LPS), an endotoxin associated with gram-negative bacteria, is a potent activator of the immune system. We have tested the effects of ICV infusions of LPS (10 ng) or Ringer's solution on the induction of the proto-oncogene protein c-Fos in the brain as well as plasma levels of corticosterone and splenic concentrations of norepinephrine (NE) and VIP. At 3 h post-ICV infusion of LPS, numerous labeled neurons were observed in the paraventricular nucleus (PVN) of the hypothalamus and the nucleus tractus solitarius (A2) region of the brain stem. Also, corticosterone and splenic NE and VIP levels were all elevated post-ICV LPS. Analysis of the time course for the induction of c-Fos protein in the brain following IP injections of LPS indicated that, relative to control injections, increased numbers of c-Fos-positive cells were detected in the PVN 0.5 h following IP injections (100 mug), peaked at 2-3 h postinjection, and then returned to control levels at later intervals. Additional dose-response data for IP LPS indicated a small increase in the number of labeled cells at a dose of 4.0 mug, and the number and staining intensity increased up to a dose of 100 mug. Corticosterone levels followed a similar pattern and were elevated at the 4.0 mug IP dose of LPS and increased to peak levels at 40 mug and higher. In contrast to ICV injections, splenic NE levels were unaltered by IP injections of LPS. An additional difference noted between ICV and IP injections of LPS was the presence of c-Fos-labeled neurons in the supraoptic nucleus, arcuate nucleus, and the ventrolateral (A1) region of the brain stem at IP doses of 40 mug and higher. These results indicate selective and differential effects of central and peripheral LPS on the induction of c-Fos protein in hypothalamic and brain stem nuclei. The concurrent changes in corticosterone and splenic neurotransmitter levels produced by ICV LPS suggest that the endocrine and autonomic nervous systems are primary targets for these activational effects of endotoxin.