IL-1β and IL-18: inflammatory markers or mediators of hypertension?

Abstract

Chronic inflammation in the kidneys and vascular wall is a major contributor to hypertension. However, the stimuli and cellular mechanisms responsible for such inflammatory responses remain poorly defined. Inflammasomes are crucial initiators of sterile inflammation in other diseases such as rheumatoid arthritis and gout. These pattern recognition receptors detect host-derived danger-associated molecular patterns (DAMPs), such as microcrystals and reactive oxygen species, and respond by inducing activation of caspase-1. Caspase-1 then processes the cytokines pro-IL-1β and pro-IL-18 into their active forms thus triggering inflammation. While IL-1β and IL-18 are known to be elevated in hypertensive patients, no studies have examined whether this occurs downstream of inflammasome activation or whether inhibition of inflammasome and/or IL-1β/IL-18 signalling prevents hypertension. In this review, we will discuss some known actions of IL-1β and IL-18 on leukocyte and vessel wall function that could potentially underlie a prohypertensive role for these cytokines. We will describe the major classes of inflammasome-activating DAMPs and present evidence that at least some of these are elevated in the setting of hypertension. Finally, we will provide information on drugs that are currently used to inhibit inflammasome/IL-1β/IL-18 signalling and how these might ultimately be used as therapeutic agents for the clinical management of hypertension.

Figure 1

Signalling pathway and endogenous antagonists of IL-1β and IL-18. Binding of IL-1β to IL-1R1 and IL-18 to IL-18Rα is facilitated by the accessory proteins IL-1RAcP and IL-18Rβ, respectively, resulting in recruitment of the adapter proteins myeloid differentiation factor 88 (MyD88), IL-1 receptor-associated kinase (IRAK) and TNF receptor-associated factor (TRAF), which then causes NF-κB activation. Endogenous inhibitory molecules also exist for both cytokines. For IL-1β, these include an IL-1R antagonist (IL-1Ra), which competes with the IL-1RI for IL-1β binding, as well as a second IL-1β receptor, IL-1RII. The membrane-bound form of IL-1RII receptor contains a short cytosolic signalling domain whereas the soluble form of IL-1RII contains only the extracellular portion of the receptor. Thus, while they bind IL-1β, they fail to support the activation of intracellular signal transduction pathways. Similarly, the actions of IL-18 are negatively regulated by a binding protein known as IL-18BP.

Figure 2

Actions of IL-1β and/or IL-18 in mediating hypertension. IL-1β and IL-18 are mainly secreted by monocytes, macrophages and neutrophils. These proinflammatory cytokines can act on immune cells such as macrophages, dendritic cells and neutrophils as well as non-immune cell types, including vascular endothelial and smooth muscle cells, to induce inflammation and other prohypertensive effects.

Figure 3

Schematic representation of activators and effectors of the NLRP3 inflammasome. The NLRP3 inflammasome consists of the pattern recognition receptor, NLRP3, the adaptor protein, ASC, and pro-caspase-1. Activation of the NLRP3 inflammasome occurs in two steps. Signal I occurs downstream of Toll-like receptors (TLR) and receptors for cytokines such as TNF, and involves NF-κB-mediated up-regulation of NLRP3, pro-IL-1β and pro-IL-18 gene expression. Signal II occurs when danger-associated molecular patterns (DAMPs) including ATP, microcrystals and ROS, all of which have been shown to be elevated in hypertension, are detected by NLRP3. This leads to oligomerization of NLRP3 subunits and recruitment of ASC and pro-caspase-1. Pro-caspase-1 then undergoes autocleavage into two subunits p10 and p20, which heterodimerize to form the fully active caspase-1. Caspase-1 then processes pro-IL-1β and pro-IL-18 into their active, proinflammatory forms.