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.

A properly mounted immune response is indispensable for recognizing and eliminating danger arising from foreign invaders and tissue trauma. However, the 'inflammatory fire' kindled by the host response must be tightly controlled to prevent it from spreading and causing irreparable damage. Accordingly, acute inflammation is self-limiting and is normally attenuated after elimination of noxious stimuli, restoration of homeostasis and initiation of tissue repair. However, unresolved inflammation may lead to the development of chronic autoimmune and degenerative diseases and cancer. Here, we discuss the key molecular mechanisms that contribute to the self-limiting nature of inflammatory signaling, with emphasis on the negative regulation of the NF-κB pathway and the NLRP3 inflammasome. Understanding these negative regulatory mechanisms should facilitate the development of much-needed therapeutic strategies for treatment of inflammatory and autoimmune pathologies.

Members of the extended interleukin-1 (IL-1) cytokine family, such as IL-1, IL-18, IL-33, and IL-36, play a pivotal role in the initiation and amplification of immune responses. However, deregulated production and/or activation of these cytokines can lead to the development of multiple inflammatory disorders. IL-1 family members share a broadly similar domain organization and receptor signaling pathways. Another striking similarity between IL-1 family members is the requirement for proteolytic processing in order to unlock their full biological potential. Although much emphasis has been put on the role of caspase-1, another emerging theme is the involvement of neutrophil- and mast cell-derived proteases in IL-1 family cytokine processing. Elucidating the regulation of IL-1 family members by proteolytic processing is of great interest for understanding inflammation and immunity. Here, we review the identity of the proteases involved in the proteolytic processing of IL-1 family cytokines and the therapeutic implications in inflammatory disease.