Cellular stress, in addition to cellular necrosis, may thus turn out to be an important mechanism for IL-33 release in vivo. Proteases have been shown to regulate IL-33 activity (Figure 2). IL-33 contains a consensus site of cleavage for caspase-3 (DGVD178G in human), and cleavage by caspases at this site generates two biologically inactive products [45 and 46]. Inactivation of IL-33 during apoptosis is likely to be important to avoid alerting the immune system unnecessarily

after physiological programmed (apoptotic) cell death, as opposed to pathological (necrotic) cell death [45 and 46]. By contrast to caspases which inactivate IL-33, proteases released during inflammation appear to increase IL-33 biological Bafilomycin A1 order activity [49••]. Neutrophil serine proteases, cathepsin G and elastase, were found to process full length IL-33 into mature forms containing the IL-1-like cytokine domain (IL-3395–270, IL-3399–270 and IL-33109–270), that had greatly increased biological selleckchem activity (∼10 fold) compared to the full length protein [49••]. Both full length and mature endogenous IL-33 were detected in BAL fluids in a model of acute lung injury associated with high levels of neutrophil recruitment in the alveolar wall [49••]. Together, these results suggested that proteolytic processing of IL-33 may be required for the extracellular generation of highly active cytokine in vivo.

IL-33 is an alarmin cytokine from the IL-1 family, which plays a crucial role in the initiation of type-2 immune responses following infection with parasites or viruses, or exposure to allergens. IL-33 appears to act by activating ILC2s for production of large amounts of type-2 cytokines IL-5 and IL-13. The potent activity of IL-33 on ILC2s and

the crucial role of these cells in the initiation of allergic airway inflammation are likely to explain the dominant role of the IL-33/ST2 pathway in genetic susceptibility to human asthma. Despite these important advances, many questions remain to be answered. For instance, the potential Tolmetin redundancy or synergy of IL-33 with other activators of ILC2s, that have been recently identified (Prostaglandin D2, Leukotriene D4, IL-9, etc.), needs to be studied. Although the functions of IL-33 in the activation of ILC2s and the initiation of allergic inflammation in the lungs have been well established, its roles in allergic and non-allergic inflammation in other tissues, exhibiting high expression levels of the endogenous protein, remain to be fully explored. A better understanding of IL-33 release, mode of action and regulation will be crucial for the development of therapeutics that target the IL-33/ST2 pathway to treat asthma and other inflammatory diseases. Papers of particular interest, published within the period of review, have been highlighted as: • of special interest We thank members of the Girard lab for fruitful discussions.