Recombinant human adenovirus with rat MIP-2 gene insertion causes prolonged PMN recruitment to the murine brain.
Single injections of recombinant cytokines/chemokines into tissue have provided insights into their possible roles during the inflammatory response. Adenoviral technology may allow us to mimic the in vivo situation more closely, with protein generated in a continuous but transient fashion. Replication-deficient human type 5 adenovirus containing a rat macrophage inflammatory protein-2 (MIP-2) gene insertion and cytomegalovirus promoter was injected into the mouse brain to investigate the inflammatory response to continuous overproduction of MIP-2. Adenovirus with a LacZ gene insertion expressing beta-galactosidase was used as a control. At doses of 10(4) to 10(7) plaque-forming units, a minimal inflammatory response was detected to the LacZ virus, with leukocyte recruitment that was restricted to the injection site. A dose of 10(7) plaque-forming units of both the LacZ and the MIP-2 vector produced extensive transgene product expression that persisted for at least 7 days. Astrocytes, recognized by their morphology, were the predominant cell type expressing MIP-2 and beta-galactosidase. A dose of 10(7) plaque-forming units of MIP-2 vector caused dramatic polymorphonuclear leukocyte (PMN) recruitment to the brain parenchyma after 2 days. PMN recruitment was still observed after 4 and 7 days, but had become more localized to the injection site and was associated with numerous foam-like macrophages. At both 2 and 7 days the blood-brain barrier was breached in the region of leukocyte recruitment. Despite the extent of leukocyte recruitment there were no overt signs of neuronal degeneration or demyelination. Our findings demonstrate that continuous production of MIP-2 in the CNS results in persistent PMN recruitment to the brain parenchyma with no evidence of tachyphylaxis. The lack of PMN recruitment to the brain parenchyma following CNS injury may be a result of deficient production of PMN chemoattractants.
Bell
M D
MD
Department of Pharmacology, University of Oxford, UK.
Taub
D D
DD
Kunkel
S J
SJ
Strieter
R M
RM
Foley
R
R
Gauldie
J
J
Perry
V H
VH
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000098:blood supply*; D054426:Chemokine CXCL2; D002630:Chemotactic Factors / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007249:Inflammation / Q000235:genetics; D007763:Lac Operon; D007958:Leukocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000235:genetics; D009504:Neutrophils / Q000166:cytology*; D051381:Rats; D013997:Time Factors
D054426:Chemokine CXCL2; D002630:Chemotactic Factors; D004274:DNA, Recombinant; D004279:DNA, Viral; D015846:Monokines