Inflammasome activation and IL-1β target IL-1α for secretion as opposed to surface expression

Interleukin-1 alpha (IL-1 alpha) and -beta both bind to the same IL-1 receptor (IL-1R) and are potent proinflammatory cytokines. Production of proinflammatory (pro)-IL-1 alpha and pro-IL-1 beta is induced by Toll-like receptor (TLR)-mediated NF-kappa B activation. Additional stimulus involving activation of the inflammasome and caspase-1 is required for proteolytic cleavage and secretion of mature IL-1 beta. The regulation of IL-1 alpha maturation and secretion, however, remains elusive. IL-1 alpha exists as a cell surface-associated form and as a mature secreted form. Here we show that both forms of IL-1 alpha, the surface and secreted form, are differentially regulated. Surface IL-1 alpha requires NF-kappa B activation only, whereas secretion of mature IL-1 alpha requires additional activation of the inflammasome and caspase-1. Surprisingly, secretion of IL-1 alpha also required the presence of IL-1 beta, as demonstrated in IL-1 beta-deficient mice. We further demonstrate that IL-1 beta directly binds IL-1 alpha, thus identifying IL-1 beta as a shuttle for another proinflammatory cytokine. These results have direct impact on selective treatment modalities of inflammatory diseases.