Immune-induced fever is mediated by IL-6 receptors on brain endothelial cells coupled to STAT3-dependent induction of brain endothelial prostaglandin synthesis.
The cytokine IL-6, which is released upon peripheral immune challenge, is critical for the febrile response, but the mechanism by which IL-6 is pyrogenic has remained obscure. Here we generated mice with deletion of the membrane bound IL-6 receptor α (IL-6Rα) on neural cells, on peripheral nerves, on fine sensory afferent fibers, and on brain endothelial cells, respectively, and examined its role for the febrile response to peripherally injected lipopolysaccharide. We show that IL-6Rα on neural cells, peripheral nerves, and fine sensory afferents are dispensable for the lipopolysaccharide-induced fever, whereas IL-6Rα in the brain endothelium plays an important role. Hence deletion of IL-6Rα on brain endothelial cells strongly attenuated the febrile response, and also led to reduced induction of the prostaglandin synthesizing enzyme Cox-2 in the hypothalamus, the temperature-regulating center in the brain, as well as reduced expression of SOCS3, suggesting involvement of the STAT signaling pathway. Furthermore, deletion of STAT3 in the brain endothelium also resulted in attenuated fever. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6Rα on brain endothelial cells to induce prostaglandin synthesis in these cells, probably in concerted action with other peripherally released cytokines.
['Eskilsson|Anna|A|', 'Mirrasekhian|Elahe|E|', 'Dufour|Sylvie|S|', 'Schwaninger|Markus|M|http://orcid.org/0000-0002-4510-9718', 'Engblom|David|D|', 'Blomqvist|Anders|A|']
D000818:Animals D001921:Brain D042783:Endothelial Cells D005260:Female D005334:Fever D006801:Humans D007111:Immunity, Cellular D015850:Interleukin-6 D053698:Interleukin-6 Receptor alpha Subunit D008070:Lipopolysaccharides D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D011453:Prostaglandins D050796:STAT3 Transcription Factor
fever prostaglandins STAT3 blood–brain barrier cell-specific gene deletions interleukin-6