Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases

Lüthi, Alexander U., Cullen, Sean P., McNeela, Edel A., Duriez, Patrick J., Afonina, Inna S., Sheridan, Clare, Brumatti, Gabriela, Taylor, Rebecca C., Kersse, Kristof, Vandenabeele, Peter, Lavelle, Ed C. and Martin, Seamus J. (2009) Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity, 31 (1), 84-98. (doi:10.1016/j.immuni.2009.05.007). (PMID:19604486)

Abstract

Interleukin-33 (IL-33) is a member of the IL-1 family and is involved in polarization of T cells toward a T helper 2 (Th2) cell phenotype. IL-33 is thought to be activated via caspase-1-dependent proteolysis, similar to the proinflammatory cytokines IL-1 beta and IL-18, but this remains unproven. Here we showed that IL-33 was processed by caspases activated during apoptosis (caspase-3 and -7) but was not a physiological substrate for caspases associated with inflammation (caspase-1, -4, and -5). Furthermore, caspase-dependent processing of IL-33 was not required for ST2 receptor binding or ST2-dependent activation of the NF-kappaB transcription factor. Indeed, caspase-dependent proteolysis of IL-33 dramatically attenuated IL-33 bioactivity in vitro and in vivo. These data suggest that IL-33 does not require proteolysis for activation, but rather, that IL-33 bioactivity is diminished through caspase-dependent proteolysis within apoptotic cells. Thus, caspase-mediated proteolysis acts as a switch to dampen the proinflammatory properties of IL-33.

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Contributors

Author: Patrick J. Duriez

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