Mechanisms of interleukin-1beta release

Interleukin-1beta (IL-1beta) is a potent proinflammatory cytokine that initiates and amplifies a wide variety of effects associated with innate immunity and host responses to microbial invasion and tissue injury. Production and release of IL-1beta are stimulated by either pathogen-associated molecular pattern molecules (PAMPs) or damage-associated molecular pattern molecules (DAMPs) and involve several steps. IL-1beta is first synthesized as biologically inactive pro-IL-1beta, then processed into mature, biologically active IL-1beta by caspase-1, and subsequently released into the extracellular milieu. Whereas a large body of recent publications has greatly increased our knowledge of the mechanisms involved in production and processing of IL-1beta, we are only beginning to understand mechanisms of IL-1beta secretion. This review highlights the different models of a non-classical secretory pathway used by monocytes, macrophages and dendritic cells to export the leaderless cytokine IL-1beta. In particular, five different release mechanisms have been suggested, namely (i) exocytosis of IL-1beta-containing secretory lysosomes, (ii) release of IL-1beta from shed plasma membrane microvesicles, (iii) fusion of multivesicular bodies with the plasma membrane and subsequent release of IL-1beta-containing exosomes, (iv) export of IL-1beta through the plasma membrane using specific membrane transporters, and (v) release of IL-1beta upon cell lysis. Reasons for the diversity of IL-1beta secretory pathways remain to be elucidated. A better understanding of IL-1beta release mechanisms is of great therapeutic relevance and may help in the development of strategies aimed at reducing the severity of inflammatory and autoimmune diseases.