Interleukin-1 mediates a rapid inflammatory response after injection of adenoviral vectors into the brain - PubMed (original) (raw)

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

T Cartmell et al. J Neurosci. 1999.

Abstract

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)-alpha and interleukin (IL)-1beta increase significantly (up to 300-fold). In the hypothalamus, the locus of thermoregulation in the brain, only IL-1beta and IL-6 are significantly elevated. A neutralizing TNF-alpha 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-alpha, is the main mediator of a very early inflammatory response to adenovirus in the brain.

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Figures

Fig. 1.

Fig. 1.

A, A replication-deficient recombinant adenovirus expressing β-galactosidase (RAd35) injected intracerebroventricularly (1.3 × 108 pfu in 2 μl) caused a significant increase in core body temperature that was maximal 7 hr after injection (***p < 0.001 vs vehicle; n = 6). _Dotted line_indicates time of injection (0 hr, 10:00 A.M.). B, Striatal injection of the same recombinant adenovirus vector resulted in no significant change in core body temperature (vs vehicle;n = 5) for the duration of the experiment (48 hr).Dotted line indicates time of injection (0 hr).

Fig. 2.

Fig. 2.

Temperature responses to intracerebroventricular (2 μl) injection of 1.3 × 108 pfu/rat of RAd35 (encoding the marker transgene β-galactosidase), RAd0 (containing no transgene), or RAd128 (encoding HSV1-TK) were significantly different from that of vehicle (ANOVA, ***p < 0.001). The concentration of CsCl, as used in the viral purification gradient, was dialyzed against the purification buffers and injected intracerebroventricularly to control for the possible pyrogenic effect of any remaining CsCl in the viral preparation. Neither the vehicle nor CsCl induced fever. Furthermore, heat treatment of RAd0 (30 min at 90°C) completely eliminated the fever response.

Fig. 3.

Fig. 3.

A, Intracerebroventricular injection of adenovirus elicited a marked increase in the levels of TNF-α (**p < 0.01) and IL-1β (#p < 0.05) in the CSF 1.5 hr after injection, followed at the 3 hr time point by a reduction in the TNF-α levels (by 61%) and a continued increase in IL-1β levels (#p < 0.05) when compared with vehicle-injected controls. IL-6 increased significantly (**p < 0.01 vs vehicle) 3 hr after adenovirus injection. B, Hypothalamic IL-1β increased significantly at the 1.5 hr time point (#p < 0.05 vs vehicle). Both IL-1β (***p < 0.001) and IL-6 (***p< 0.001) levels were significantly elevated 3 hr after adenovirus injection, compared with vehicle-injected controls.

Fig. 4.

Fig. 4.

A, The temperature response to intracerebroventricular injection of adenovirus (0 hr) after pretreatment with vehicle or TNF-α antiserum was only significantly different (ANOVA; ***p < 0.001) from that of vehicle or TNF-α antiserum injected 24 hr earlier plus vehicle injected at 0 hr. B, The increase in core temperature elicited by adenovirus (i.c.v., 0 hr) was abolished by injection of IL-1ra (200 μg/rat, i.c.v.; 0 and 1 hr). The temperature response to adenovirus was significantly different from that of vehicle, IL-1ra, or adenovirus plus IL-1ra (ANOVA; ***p < 0.001).C, Intracerebroventricular injection of adenovirus (0 hr) elicited a marked and sustained increase in core temperature that was totally abolished by intraperitoneal injection of flurbiprofen (1 mg/kg, −0.5 hr). Data for vehicle, flurbiprofen, or adenovirus plus flurbiprofen were all significantly different from the temperature response to adenovirus (ANOVA; ***p < 0.001).

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