Ccl22/MDC, is a prostaglandin dependent pyrogen, acting in the anterior hypothalamus to induce hyperthermia via activation of brown adipose tissue

• Published in: Cytokine (Philadelphia, Pa.) Vol. 53; no. 3; pp. 311 - 319
• Main Authors: Osborn, Olivia, Sanchez-Alavez, Manuel, Dubins, Jeffrey S., Gonzalez, Alejandro Sanchez, Morrison, Brad, Hadcock, John R., Bartfai, Tamas
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2011
• Subjects: Adipose Tissue, Brown - drug effects; Adipose Tissue, Brown - metabolism; AH/POA; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Body Temperature - drug effects; Brown adipose tissue; Ccl22; cDNA libraries; Chemokine CCL22 - genetics; Chemokine CCL22 - metabolism; Chemokine CCL22 - pharmacology; chemokines; Dinoprostone - metabolism; Female; fever; Fever - chemically induced; Fever - physiopathology; Fever - prevention & control; Gene Expression; heat production; Hyperthermia; hypothalamus; Hypothalamus, Anterior - drug effects; Hypothalamus, Anterior - metabolism; image analysis; indomethacin; Indomethacin - pharmacology; Male; MDC; Mice; Mice, Inbred C57BL; neurons; Positron-Emission Tomography; Preoptic Area - drug effects; Preoptic Area - metabolism; pretreatment; prostaglandin synthase; prostaglandins; Pyrogens - metabolism; Pyrogens - pharmacology; radio telemetry; Rats; Rats, Sprague-Dawley; receptors; Receptors, CCR4 - genetics; Receptors, CCR4 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Telemetry; Tomography, X-Ray Computed; AH/POA; RPa; IL-1; PGE 2; Brown adipose tissue; 18F-FDG; MDC; CT; Ccl22; Ccr4; Hyperthermia; DMH; PET
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2010.11.017

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.