Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases.
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.
Lüthi
Alexander U
AU
Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
Cullen
Sean P
SP
McNeela
Edel A
EA
Duriez
Patrick J
PJ
Afonina
Inna S
IS
Sheridan
Clare
C
Brumatti
Gabriela
G
Taylor
Rebecca C
RC
Kersse
Kristof
K
Vandenabeele
Peter
P
Lavelle
Ed C
EC
Martin
Seamus J
SJ
D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology* / Q000378:metabolism; D053148:Caspase 3 / Q000276:immunology* / Q000378:metabolism; D053179:Caspase 7 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008214:Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D018123:Receptors, Interleukin
C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D008565:Membrane Proteins; D016328:NF-kappa B; D018123:Receptors, Interleukin; D053148:Caspase 3; D053179:Caspase 7; D020170:Caspase 1