Blood Interleukin-6 and Tumor Necrosis Factor-α Elevation after Intracerebroventricular Injection of Escherichia coli Endotoxin in the Rat Is Determined by Two Opposing Factors: Peripheral Induction by LPS Transferred from Brain to Blood and Inhibition of Peripheral Response by a Brain-Mediated Mechanism

Abstract

Following intracerebroventricular injection of LPS in rats, IL-6 and TNF-α appear in peripheral blood. To determine whether these changes are mediated by passage of the injected LPS from the brain to the blood, the time course of appearance in blood of bioactive LPS after intracerebroventricular injection was compared with the time course of appearance of IL-6 and of TNF-α in blood. Bioactive LPS was detected 30 min after intracerebroventricular injection, the first time interval tested. TNF-α appeared in peripheral blood at 30 min, IL-6 at 60 min and both cytokines as well as LPS achieved highest levels at 120 min. To determine pharmacokinetics of LPS transfer from brain to blood more precisely, radioiodinated LPS was injected intracerebroventricularly. ¹²⁵I-LPS was detected in blood as early as 5 min after intracerebroventricular injection, reached peak levels at about 2 h, and was transferred from brain to blood at a rate corresponding to bulk flow (% of brain content per min was 1.40 ± 0.58 and 1.00 ± 0.21% in series 1 and 2, respectively). 70.0% of total injected LPS had entered blood by 4 h. However, when administered intravenously (by a programmed pump) at the same rate that it enters the blood after intracerebroventricular injection LPS induced a much greater cytokine response than when given intracerebroventricularly. This paradoxical response was shown in further studies to be due to the simultaneous central inhibitory effect of LPS; coinjection of intracerebroventricular LPS markedly reduced the peripheral cytokine response to intravenous LPS infusion.