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The Journal of Neuroscience, February 15, 1999, 19(4):1517-1523
Interleukin-1 Mediates a Rapid Inflammatory Response After
Injection of Adenoviral Vectors into the Brain
Tammy
Cartmell1,
Tom
Southgate2,
Gwen S.
Rees3,
Maria G.
Castro1, 2,
Pedro R.
Lowenstein2, and
Giamal N.
Luheshi1
1 Division of Neuroscience, School of Biological
Sciences, and 2 Molecular Medicine Unit, Department of
Medicine, University of Manchester, Manchester M13 9PT, United Kingdom,
and 3 Division of Endocrinology, National Institute for
Biological Standards and Control, Herts EN6 3QG, United Kingdom
Adenovirus-mediated gene transfer into the brain is associated with
significant inflammation and activation of anti-vector and
anti-transgene immune responses that curtail the gene delivery of
adenoviruses and therapeutic efficacy. Elucidating the molecular mediators of inflammatory and immune responses to adenoviruses injected
into the brain should allow us to inhibit their inflammatory actions,
thereby reducing vector clearance and enhance adenoviral-mediated gene
transfer into the CNS. Cytokines are primary mediators of the immune
response and are released during inflammation. Here we report for the
first time that injection of replication-deficient adenovirus vectors
into the cerebral ventricles of rats causes a rapid increase in body
temperature. This fever response precedes any vector-encoded transgene
expression and occurs with vectors encoding no transgene, as well as
with vectors encoding a therapeutic transgene i.e., HSV1-thymidine
kinase. No fever is detected after infection of the striatum, an
important brain target in studies on neurodegeneration. After infection
of the brain ventricles, CSF levels of immunoreactive tumor
necrosis factor (TNF)- and interleukin (IL)-1 increase
significantly (up to 300-fold). In the hypothalamus, the locus of
thermoregulation in the brain, only IL-1 and IL-6 are significantly
elevated. A neutralizing TNF- antibody has no effect on
adenovirus-induced fever. However, pretreatment with either the IL-1
receptor antagonist or the cyclooxygenase inhibitor flurbiprofen
completely abolishes adenovirus-induced fever, suggesting that IL-1 and
prostaglandins are direct mediators of this response. These results are
the first to demonstrate that IL-1, but not TNF-, is the main
mediator of a very early inflammatory response to adenovirus in the brain.
Key words:
adenovirus; inflammation; cytokines; brain; rat; fever
Copyright © 1999 Society for Neuroscience 0270-6474/99/1941517-07$05.00/0
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