Interleukin (IL)-1, first described ∼35 years ago as a secreted product of monocytes and neutrophils, refers to IL-1α and IL-1β, two key
cytokines in the activation of innate immunity. These
cytokines were among the first
proteins identified as orchestrators of leukocyte communication, creating the class of secreted products now known as
interleukins. The
IL-1 family comprises a total of 11 members, including the two activating
cytokines IL-1α and IL-1β as well as an inhibitory mediator, the
IL-1 receptor antagonist.
IL-1 is processed and activated by a caspase-1 dependent mechanism in conjunction with
inflammasome assembly, as well as by caspase-1 independent processes that involve neutrophil
proteases. Once activated, IL-1α and IL-1β act as potent proinflammatory
cytokines at the local level, triggering vasodilatation and attracting monocytes and neutrophils to sites of tissue damage and stress. Importantly, these
cytokines are crucial for the induction of matrix
enzymes and serve as potent mediators of tissue damage by altering cartilage and bone homeostasis. Systemically,
IL-1 cytokines foster the hypothalamic
fever response and promote
hyperalgesia. Uncontrolled
IL-1 activation is a central component of some inflammatory diseases, including rare hereditary syndromes with mutations in
inflammasome-associated genes or more frequent diseases such as
gout, characterized by neutrophil infiltration and
IL-1 activation. Apart from these connections to inflammatory diseases, an important role for
IL-1 in inflammatory
atherogenesis is also predicted. To date, four potent inhibitors of
IL-1 are available for clinical use or in late-stage clinical development, which not only constitute efficacious
therapies, but also helped improve our understanding of the role of
IL-1 in human disease.