Proinflammatory cytokine expression contributes to brain injury provoked by chronic monocyte activation.

Abstract

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.

MATERIALS AND 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.

• Authors: A L Sirén, R McCarron, L Wang, P Garcia-Pinto, C Ruetzler, D Martin, J M Hallenbeck
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 7 Issue 4 Pg. 219-29 (Apr 2001) ISSN: 1076-1551 [Print] England
• PMID: 11471566 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adjuvants, Immunologic
• BCG Vaccine
• Cytokines
• Recombinant Proteins
• Superoxides

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• BCG Vaccine (pharmacology)
• Brain (metabolism, pathology)
• Brain Injuries (metabolism)
• Cell Adhesion
• Cell Movement
• Cerebral Cortex (metabolism)
• Cytokines (biosynthesis)
• Dose-Response Relationship, Drug
• Hippocampus (metabolism)
• Humans
• Immunohistochemistry
• Male
• Monocytes (metabolism)
• Rats
• Rats, Sprague-Dawley
• Recombinant Proteins (metabolism)
• Superoxides (metabolism)
• Thrombosis