title: 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.
  
  
  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.affiliation: Department of Neurology, The Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. siren@em.mpg.de
authors.forename: A L
authors.initials: AL
authors.lastname: Sirén
authors.forename: R
authors.initials: R
authors.lastname: McCarron
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Garcia-Pinto
authors.forename: C
authors.initials: C
authors.lastname: Ruetzler
authors.forename: D
authors.initials: D
authors.lastname: Martin
authors.forename: J M
authors.initials: JM
authors.lastname: Hallenbeck
mesh_terms: 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
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D016207:Cytokines; D011994:Recombinant Proteins; D013481:Superoxides