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Interleukin-18 and IL-1β, which are cytokines of the IL-1 family, are synthesized as precursor proteins and activated by the inflammasome via proteolytic processing. IL-1β is only induced in response to inflammatory stimuli, but IL-18 is constitutively expressed. However, how IL-18 and IL-1β expression is regulated by different inflammatory signals remains poorly studied. In this study, we found that IL-18 and IL-1β are differentially regulated. Despite being constitutively expressed, IL-18 expression was increased and sustained after stimulation of TLRs. In contrast, IL-1β was induced but not sustained after chronic treatment. Furthermore, type I IFN signaling was essential for induction of IL-18 and macrophages lacking type I IFN signaling were impaired in their ability to promote IL-18 induction. Thus, our findings reveal a fundamental difference in IL-18 and IL-1β regulation and uncover novel mechanisms that are relevant to the inflammatory settings where these proinflammatory cytokines play a critical role.