Appearance of cytokine-associated central nervous system myelin damage coincides temporally with serum tumor necrosis factor induction after recombinant interleukin-2 infusion in rats

Abstract

Endogenous tumor necrosis factor (TNF) activity, assessed by L-929 fibroblast bioassay, was determined in serum samples from rats infused intravenously with recombinant interleukin-2 (rIL-2) or rIL-2 vehicle. Parallel studies of cerebral ultrastructure were conducted in additional rats, comparably infused. Rats received rIL-2 or vehicle either one time only or 3 times daily for 3 days. TNF activity was assessed at 2,4, and 8 h after the single or final infusion. Rats employed for ultrastructural studies were sacrificed at 4 h after the single or final infusion. Every rIL-2-infused rat exhibited unusual abnormalities of axonal ultrastructure, identical to those previously described after in vitro TNF application to living spinal cord slices. Serum samples drawn during and after the development of axonal changes revealed significantly elevated circulating TNF activity. Controls exhibited neither TNF activity nor altered axons. These studies demonstrate that, following rIL-2 infusion in rats, endogenous TNF circulates at elevated levels during the development of rIL-2-related central nervous system abnormalities similar to those produced in vitro by recombinant TNF. Whether rIL-2-induced circulating TNF is causally-related to the observed myelin damage remains to be determined but merits further investigation, particularly since blood-brain barrier function has been shown to be compromised following rIL-2 infusion.