Suppression of Interleukin-33 Bioactivity through Proteolysis by Apoptotic Caspases

被引:586
作者
Luethi, Alexander U. [1 ]
Cullen, Sean P. [1 ]
McNeela, Edel A. [2 ]
Duriez, Patrick J. [1 ]
Afonina, Inna S. [1 ]
Sheridan, Clare [1 ]
Brumatti, Gabriela [1 ]
Taylor, Rebecca C. [1 ]
Kersse, Kristof [3 ,4 ]
Vandenabeele, Peter [3 ,4 ]
Lavelle, Ed C. [2 ]
Martin, Seamus J. [1 ]
机构
[1] Trinity Coll Dublin, Smurfit Inst, Dept Genet, Mol Cell Biol Lab, Dublin 2, Ireland
[2] Trinity Coll Dublin, Sch Biochem & Immunol, Adjuvant Res Grp, Dublin 2, Ireland
[3] Univ Ghent VIB, Dept Mol Biomed Res, B-9052 Ghent, Belgium
[4] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium
基金
爱尔兰科学基金会;
关键词
RECEPTOR ACCESSORY PROTEIN; INNATE IMMUNE-SYSTEM; T-CELLS; INFLAMMATORY CASPASES; MAST-CELLS; IL-33; ST2; ACTIVATION; CYTOKINE; EXPRESSION;
D O I
10.1016/j.immuni.2009.05.007
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-1 8, 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-kappa B 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.
引用
收藏
页码:84 / 98
页数:15
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