title: Ccl22/MDC, is a prostaglandin dependent pyrogen, acting in the anterior hypothalamus to induce hyperthermia via activation of brown adipose tissue.
abstract: CC Chemokine ligand 22 (Ccl22) is a selective, high affinity ligand at the CC chemokine receptor 4 (Ccr4). We have identified cDNAs encoding both ligand and receptor of the Ccl22-Ccr4 pair in cDNA libraries of the anterior hypothalamus/pre-optic area (AH/POA) by PCR. The AH/POA is the key brain region where endogenous pyrogens have been shown to act on warm sensitive neurons to affect thermogenesis in brown adipose tissue (BAT) and other thermogenically responsive tissues. We show that functional Ccr4 receptors are present in the AH/POA neurons as injection of Ccl22 into the POA but not to other hypothalamic nuclei induces an increase in core body temperature as measured by radiotelemetry. Indomethacin (5 mg/kg s.c) pre-treatment markedly reduced the hyperthermia evoked by POA injection of Ccl22 (10 ng/0.5 ul) and thus suggests that this hyperthermia is mediated through cyclooxygenase activation and thus likely through the formation and action of the pyrogen prostaglandin E2. The temperature elevation involves a decrease in the respiratory exchange ratio and increased activation of the brown adipose tissue as demonstrated by ¹⁸F-FDG-PET imaging. We describe a novel role to the ligand Ccl22 and its receptor Ccr4 in the anterior hypothalamus in temperature regulation that depends on the synthesis of the endogenous pyrogen, prostaglandin E2.
authors.affiliation: The Harold L. Dorris Neurological Research Institute, Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, CA 92037, USA. olivia1@scripps.edu
authors.forename: Olivia
authors.initials: O
authors.lastname: Osborn
authors.forename: Manuel
authors.initials: M
authors.lastname: Sanchez-Alavez
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Dubins
authors.forename: Alejandro Sanchez
authors.initials: AS
authors.lastname: Gonzalez
authors.forename: Brad
authors.initials: B
authors.lastname: Morrison
authors.forename: John R
authors.initials: JR
authors.lastname: Hadcock
authors.forename: Tamas
authors.initials: T
authors.lastname: Bartfai
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D054422:Chemokine CCL22 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D015870:Gene Expression; D007032:Hypothalamus, Anterior / Q000187:drug effects / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography; D011301:Preoptic Area / Q000187:drug effects / Q000378:metabolism; D011749:Pyrogens / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013686:Telemetry; D014057:Tomography, X-Ray Computed
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C515355:Ccr4 protein, mouse; D054422:Chemokine CCL22; D011749:Pyrogens; D054398:Receptors, CCR4; D015232:Dinoprostone; D007213:Indomethacin