Circulating interleukin-6 induces fever through a STAT3-linked activation of COX-2 in the brain.
Interleukin (IL)-6 is an important humoral mediator of fever following infection and inflammation and satisfies a number of criteria for a circulating pyrogen. However, evidence supporting such a role is diminished by the moderate or even absent ability of the recombinant protein to induce fever and activate the cyclooxygenase-2 (COX-2) pathway in the brain, a prerequisite step in the initiation and maintenance of fever. In the present study, we investigated the role of endogenous circulating IL-6 in a rodent model of localized inflammation, by neutralizing its action using a specific antiserum (IL-6AS). Rats were injected with LPS (100 microg/kg) or saline into a preformed air pouch in combination with an intraperitoneal injection of either normal sheep serum or IL-6AS (1.8 ml/rat). LPS induced a febrile response, which was accompanied by a significant rise in plasma IL-6 and nuclear STAT3 translocation in endothelial cells throughout the brain 2 h after treatment, including areas surrounding the sensory circumventricular organs and the median preoptic area (MnPO), important regions in mediating fever. These responses were abolished in the presence of the IL-6AS, which also significantly inhibited the LPS-induced upregulation of mRNA expression or immunoreactivity (IR) of the inducible form of COX, the rate-limiting enzyme for PGE2-synthesis. Interestingly, nuclear signal transducer and activator of transcription (STAT)3-positive cells colocalized with COX-2-IR, signifying that IL-6-activated cells are directly involved in PGE2 production. These observations suggest that IL-6 is an important circulating pyrogen that activates the COX-2-pathway in cerebral microvasculature, most likely through a STAT3-dependent pathway.
Rummel
Christoph
C
Douglas Hospital Research Centre, Dept. of Psychiatry, McGill Univ., 6875 Blvd. LaSalle, Verdun, Montreal, QC, H4H 1R3, Canada.
Sachot
Christelle
C
Poole
Stephen
S
Luheshi
Giamal N
GN
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005334:Fever / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000502:physiology; D007106:Immune Sera / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood* / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011749:Pyrogens / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
D007106:Immune Sera; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011749:Pyrogens; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat