Figure 2.

Modes of action of IL-1 family cytokines. All cytokines belonging to the IL-1 family, except IL-1 receptor antagonist (IL-1Ra), lack the leading peptides that are required for cell secretion. Furthermore, all full-length cytokines, except IL-1α and IL-33, are biologically inactive unless they receive appropriate posttranslational processing. Even biologically active full-length IL-1α and IL-33 need the appropriate cellular stimuli to be secreted from cells. IL-33 is localized in cellular nuclei, whereas IL-1α is localized in lysosomes and perhaps in nuclei. After receiving stimuli that induce cell death via destruction of the cellular membranes (i.e., pyroptosis and necroptosis), IL-1α and IL-33 are extracellularly liberated. In contrast, precursor- (pro-) IL-1β, pro-IL-18, and pro-IL-37 require cleavage by caspase-1 in the inflammasome, a large multiple-protein complex (shown in Figure 3). Following appropriate stimuli, the inflammasomes are activated. Consequently, biologically active IL-1β, IL-18, and perhaps IL-37 fragments are secreted. Bioactive IL-37 can also be translocated into nuclei. IL-36 subfamily members also require posttranslational processing for activation and excretion. However, they cannot be processed by caspase-1; their processing enzymes remain to be elucidated. pro: precursor.