Charakterisierung der pyrogenen Wirkung der synthetischen doppelsträngigen RNA Polyinosin-Polycytidylsäure (Poly I:C)
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Beschreibung
The aim of the first part of this thesis was to characterize the properties of polyinosinic : polycytidylic acid (PIPC), a synthetic double stranded RNA and Toll-like receptor 3 agonist, to induce fever and circulating cytokines in guinea pigs. Special emphasis was directed to the route of PIPC administration and on a putative development of tolerance to this pyrogen. Changes in abdominal temperature were recorded in unrestrained animals by use of intra-abdominally implanted radiotransmitters. Circulating concentrations of tumor necrosis factor-a (TNF-) and interleukin-6 (IL-6) were measured by use of specific bioassays. The pyrogenic effect of PIPC at a dose of 500 µg/kg depended on the route of its administration. Intra-arterial (i.a.) or intraperitoneal (i.p.) injections of PIPC induced pronounced fevers and strong elevations of circulating TNF- and IL-6. Intramuscular (i.m.) injections of the synthetic pyrogen caused rather moderate febrile and cytokine responses. Administration of PIPC into artificial subcutaneously (s.c.) implanted Teflon chambers had no pyrogenic and cytokine-inducing effects. I.a. injections of PIPC, repeated five times at intervals of 3 days, resulted in fevers of similar shape and duration and similar cytokine response patterns. However, the strength of fever and cytokine formation was significantly reduced, although not abolished, in response to the repeated injections compared with the first injection, indication a partial development of tolerance to repeated stimulations with PIPC. The modulation of the strength of PIPC-induced fever, dependent on the route of administration, or the state of partial tolerance to this pyrogen, may thus be related to the formation of pyrogenic cytokines.
In the second part of this thesis the effects of i.a. injections of 500 µg/kg PIPC on fever-inducing mechanisms in the brain were investigated. The pronounced fever, which was evoked by this dose of the pyrogen, was completely abolished by treatment with the non-selective cyclooxygenase (COX) inhibitor diclofenac and, in part, attenuated by the administration of the selective COX-2 inhibitor nimesulide (dose: 5 mg/kg for both COX-inhibitors). It was further investigated whether direct activation of brain cells during PIPC-induced fever could be demonstrated. Using radioactive in situ hybridization, it could be demonstrated that treatment with PIPC resulted in an upregulation of COX-2 and IL-1 mRNA in specific areas of the guinea pig brain. Thus, COX-2-specific hybridization signals seemed to be mainly associated with brain blood vessels. I.a. injections of PIPC further induced the pronounced nuclear translocation of the inflammatory transcription factor STAT3 in the endothelium of various fore- and hindbrain areas and in the meninges. In brain structures that lack a tight blood-brain barrier, i.e. the sensory circumventricular organs (area postrema, vascular organ of lamina terminalis, subfornical organ), the astrocyters and a population of still undetermined cellular phenotype also showed marked STAT3 activation in response to PIPC. The Toll-like receptor-3 agonist PIPC therefore caused a similar activation pattern of brain cells as that reported for other experimental models of systemic inflammation.
Autor*in
Thilo Voß
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