Interleukin-1 mediates a rapid inflammatory response after injection of adenoviral vectors into the brain

Adenovirus-mediated gene transfer into the brain is associated with signifi cant inflammation and activation of anti-vector and anti-transgene immune r esponses that curtail the gene delivery of adenoviruses and therapeutic eff icacy. Elucidating the molecular mediators of inflammatory and immune respo nses to adenoviruses injected into the brain should allow us to inhibit the ir inflammatory actions, thereby reducing vector clearance and enhance aden oviral-mediated gene transfer into the CNS. Cytokines are primary mediators of the immune response and are released during inflammation. Here we repor t for the first time that injection of replication-deficient adenovirus vec tors into the cerebral ventricles of rats causes a rapid increase in body t emperature. This fever response precedes any vector-encoded transgene expre ssion and occurs with vectors encoding no transgene, as well as with vector s encoding a therapeutic transgene i.e., HSV1-thymidine kinase. No fever is detected after infection of the striatum, an important brain target in stu dies on neurodegeneration. After infection of the brain ventricles, CSF lev els of immunoreactive tumor necrosis factor (TNF)-alpha and interleukin (IL )-1 beta increase significantly (up to 300-fold). In the hypothalamus, the locus of thermoregulation in the brain, only IL-1 beta and IL-6 are signifi cantly elevated. A neutralizing TNF-alpha antibody has no effect on adenovi rus-induced fever. However, pretreatment with either the IL-1 receptor anta gonist or the cyclooxygenase inhibitor flurbiprofen completely abolishes ad enovirus-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-alpha, is the main mediator of a very early inflammatory response to adenovirus in the brain.