Understanding the mechanism of IL-1β secretion

Abstract

The cytokine interleukin-1β (IL-1β) is a key mediator of the inflammatory response. Essential for the host-response and resistance to pathogens, it also exacerbates damage during chronic disease and acute tissue injury. It is not surprising therefore that there is a huge level of interest in how this protein is produced and exported from cells. However, the mechanism of IL-1β release has proven to be elusive. It does not follow the conventional ER-Golgi route of secretion. A literature full of disparate observations arising from numerous experimental systems, has contributed to a complicated mix of diverse proposals. Here we summarise these observations and propose that secretion of IL-1β occurs on a continuum, dependent upon stimulus strength and the extracellular IL-1β requirement.

Fig. 1

Schematic diagrams showing the components and the formation of the inflammasome, and of the conventional pathway of protein secretion. (A) Following the activation of a primed cell by an appropriate stimulus (see Section 3.1) a series of homotypic interactions take place between an adaptor molecule (ASC), a cytosolic PRR (e.g. a NLR) and pro-caspase-1 to form an inflammasome. This results in the activation of caspase-1 and the secretion of IL-1β. (B) Conventionally secreted proteins are translocated into the ER and traffic through the ER and Golgi before reaching their extracellular destination. The fungal metabolite brefeldin A inhibits the conventional pathway of protein secretion.

Fig. 2

The continuum of IL-1β secretion. The secretion of IL-1β is reported to occur via a number of mechanisms. This figure illustrates these mechanisms as part of a continuum. The mechanism recruited may be dependent upon the strength of the inflammatory stimulus as perceived by the cell. The secretion mechanisms are classified as Rescue and redirect, protected release and terminal release.