Sci. Signal., 6 March 2012
Immunology Stressed Cells Secrete Cytokine
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
The cytokine interleukin-33 (IL-33), a member of the IL-1 family, is associated with heterochromatin in the nucleus, where it is thought to repress gene expression. In addition, IL-33 binds to a transmembrane receptor complex of ST-2 and the IL-1 receptor accessory protein to stimulate nuclear factor B (NF-B) activity. Because it lacks both a nuclear export signal and a secretory signal sequence, IL-33 is thought to be released from cells during necrosis. Noting that the abundance of IL-33 is increased in fibroblasts undergoing cellular stretch, Kakkar et al. investigated the regulation of the localization of IL-33 within fibroblasts and its response to mechanical stress. Fluorescence microscopic analysis showed that endogenous IL-33 was located within the nucleus and in the cytoplasm in resting fibroblast cell lines. Analysis of an epitope-tagged IL-33 (TC-IL-33) showed that cytoplasmic IL-33 was found in membrane-bound vesicles. Chase experiments in live cells showed that newly synthesized IL-33 first moved to the nucleus and then was translocated to vesicles. Electron micrographs showed that exit of IL-33 from the nucleus was through nuclear pore complexes. Subjecting fibroblast cell lines and primary human fibroblasts to nonlethal stretching caused the cells to secrete TC-IL-33 in its uncleaved form. Finally, transgenic mice expressing tagged IL-33 exhibited release of IL-33 into the extracellular space when subjected to acute transaortic constriction, which causes mechanical stress in the left ventricle. Together, these data suggest that IL-33 may be released by cells that are subjected to nonlethal stress in addition to being released by necrotic cells under inflammatory conditions.
Citation: J. F. Foley, Stressed Cells Secrete Cytokine. Sci. Signal. 5, ec72 (2012).
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