STAT3 and COX-2 activation in the guinea-pig brain during fever induced by the Toll-like receptor-3 agonist polyinosinic:polycytidylic acid.
Intra-arterial injections of synthetic double-stranded RNA (polyinosinic:polycytidylic acid, PIPC) at a dose of 500 microg/kg evoked pronounced fever in guinea-pigs. PIPC-induced fever could be antagonized by treatment with the non-selective cyclooxygenase (COX) inhibitor diclofenac and was, in part, attenuated by the administration of the selective COX-2-inhibitor nimesulide (dose: 5 mg/kg for both COX inhibitors). We further investigated whether direct activation of brain cells during PIPC-induced fever could be demonstrated. Using radioactive in situ hybridization, we demonstrated that treatment with PIPC resulted in an upregulation of COX-2 and interleukin-1 beta mRNA in the guinea-pig brain. Thus, COX-2-specific hybridization signals seemed to be mainly associated with brain blood vessels. Intra-arterial injections of PIPC further induced the pronounced nuclear translocation of the transcription factor STAT3 in the endothelium of various fore- and hindbrain areas and in the meninges. In brain structures that lacked a tight blood-brain barrier, i.e. the sensory circumventricular organs (area postrema, vascular organ of laminae terminalis, subfornical organ), the astrocytes 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 of brain cells as that reported for other experimental models of systemic inflammation.
Voss
Thilo
T
Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Frankfurter Strasse 100, 35392, Giessen, Germany.
Barth
Stephan W
SW
Rummel
Christoph
C
Gerstberger
Rüdiger
R
Hübschle
Thomas
T
Roth
Joachim
J
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005334:Fever / Q000139:chemically induced* / Q000378:metabolism; D006168:Guinea Pigs; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D011070:Poly I-C / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014018:Tissue Distribution; D051196:Toll-Like Receptor 3 / Q000819:agonists*
D052246:Cyclooxygenase 2 Inhibitors; D053583:Interleukin-1beta; D050796:STAT3 Transcription Factor; D051196:Toll-Like Receptor 3; D051546:Cyclooxygenase 2; D011070:Poly I-C