Proinflammatory cytokine expression contributes to brain injury provoked by chronic monocyte activation.
BACKGROUND
We have proposed that an increased interaction between monocyte/macrophages and blood vessel endothelium predisposes subjects to strokes. The effect of chronic monocyte activation on the development of cerebral infarcts was thus studied in rats after provocation of a modified local Swartzman reaction, in brain vasculature.


METHODS
Two weeks after an IV bolus of bacillus Calmette-Guérin (BCG), we studied spontaneous superoxide production, integrin expression, endothelial adhesion of monocytes and the neurological symptoms, brain histology, and cytokine immunoreactivity after a provocative dose of LPS (30-300 microg/rat i.c.v.).


RESULTS
Monocyte migration into the brain was stimulated by BCG priming. The incidence of paralysis and death in response to LPS was markedly increased in BCG-primed rats. Histological evaluation of the brains of neurologically impaired and moribund animals revealed intravascular thrombosis and pale and hemorrhagic infarcts. Infiltrates of leukocytes expressing immunoreactive IL-1:, IL-6, and TNF-alpha were found around blood vessels, cerebral ventricles, and meninges, and were accompanied by a profound microglial expression of IL1P, endothelial expression of IL-6, and expression of TNF-alpha and TNF-R 1 in glia and neurons of cortex and hippocampus. Treatment (2 x 100 microg/10 ,I, i.c.v.) with recombinant human (rh-)TNF 55kDa receptor completely prevented, and treatment with rh-IL- I receptor antagonist significantly decreased the incidence of paralysis and death in response to BCG + LPS. The improvement of neurological symptoms was accompanied by reduced histological damage and supppression of IL-1P/ expression in the brain tissue.


CONCLUSIONS
The data demonstrate that chronic monocyte activation predisposes subjects to thrombosis and hemorrhage via an exaggerated release of proinflammatory cytokines.
Sirén
A L
AL
Department of Neurology, The Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. siren@em.mpg.de
McCarron
R
R
Wang
L
L
Garcia-Pinto
P
P
Ruetzler
C
C
Martin
D
D
Hallenbeck
J M
JM
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001500:BCG Vaccine / Q000494:pharmacology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism*; D002448:Cell Adhesion; D002465:Cell Movement; D002540:Cerebral Cortex / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013927:Thrombosis
D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D016207:Cytokines; D011994:Recombinant Proteins; D013481:Superoxides