• Sanna Rosengren, James L Mueller, Justin P Anderson, Brian L Niehaus, Amirhossein Misaghi, Scott Anderson, David L Boyle, and Hal M Hoffman.
• Division of Rheumatology, Allergy and Immunology, University of California at San Diego School of Medicine, La Jolla, CA 92093-0635, USA.
• J. Allergy Clin. Immunol. 2007 Apr 1; 119 (4): 991-6.

BackgroundFamilial cold autoinflammatory syndrome (FCAS) is characterized by rash, fever, and arthralgia in response to cold exposure. CIAS1, the gene that codes for cryopyrin, is mutated in FCAS. Treatment with anakinra (IL-1 receptor antagonist) prevents symptoms, indicating a crucial role for IL-1 in this disease.ObjectiveTo study cytokine responses to cold exposure in monocytes from subjects with FCAS.MethodsAdherence-enriched monocytes were incubated at 32 degrees C or 37 degrees C. Transcription and release of IL-1beta, IL-6, and TNF-alpha were monitored by quantitative PCR and ELISA.ResultsThe FCAS monocytes but not control cells responded to 4 h incubation at 32 degrees C with significant secretion of IL-1beta. At 16 h, IL-1beta, IL-6, and TNF-alpha were all significantly elevated in FCAS monocytes at 32 degrees C. Increased cytokine transcription was observed in all monocytes at 4 hours, but at 16 hours it was only seen in FCAS monocytes incubated at 32 degrees C. Incubation at 32 degrees C for as little as 1 hour sufficed to induce measurable IL-1beta release. Caspase-1 inhibitors prevented the cold-induced IL-1beta release, whereas a purinergic antagonist did not. Anakinra had no effect on the early IL-1beta release but significantly reduced the late-phase transcription and release of all cytokines.ConclusionFCAS monocytes respond to mild hypothermia with IL-1beta release, which in turn induces autocrine transcription and secretion of IL-6 and TNF-alpha as well as stimulation of further IL-1beta production.Clinical ImplicationsThese results confirm the central role of IL-1beta in FCAS and support the use of IL-1 targeted therapy in these patients.

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