Stressed Cells Secrete Cytokine

Science Signaling  06 Mar 2012:
Vol. 5, Issue 214, pp. ec72
DOI: 10.1126/scisignal.2003018

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 κB (NF-κB) 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.

R. Kakkar, H. Hei, S. Dobner, R. T. Lee, Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J. Biol. Chem. 287, 6941–6948 (2012). [Abstract] [Full Text]