IL-1 Family Cytokine Regulation of Vascular Permeability and Angiogenesis

Abstract

The IL-1 family of cytokines are well-known for their primary role in initiating inflammatory responses both in response to and acting as danger signals. It has long been established that IL-1 is capable of simultaneously regulating inflammation and angiogenesis, indeed one of IL-1's earliest names was haemopoeitn-1 due to its pro-angiogenic effects. Other IL-1 family cytokines are also known to have roles in mediating angiogenesis, either directly or indirectly via induction of proangiogenic factors such as VEGF. Of note, some of these family members appear to have directly opposing effects in different tissues and pathologies. Here we will review what is known about how the various IL-1 family members regulate vascular permeability and angiogenic function in a range of different tissues, and describe some of the mechanisms employed to achieve these effects.

Keywords: IL-1; IL-18; IL-33; IL-36; angiogensis; vascular permeability.

Figure 1

IL-1F family signaling complexes. The IL-1R family has four signaling complexes; IL-1R1/IL-1RAcP, IL-18R/IL-18RAcP, ST-2/IL-1RAcP, and IL-36R/IL-1RAcP. IL-1α/IL-1β signal through IL-1R1/IL-1RAcP; this pathway can be antagonized by IL-1Ra. IL-18 signaling uses the IL-18R/IL-18RAcP complex. IL-18 ligand can be sequestered and thereby inhibited by IL-18BP. IL-37 also utilizes this complex. ST-2/IL-1RAcP is the receptor complex for the IL-33 cytokine. IL-36α/IL-36β/IL-36γ signal through the IL-36R/IL-1RAcP complex, which can be antagonized by IL-36Ra and IL-38.

Figure 2

Graphical representation of IL-1F cytokine regulation of angiogenesis. IL-1 F cytokines regulate angiogenesis either by promotion of proliferation, migration, and tube formation or by inhibiting these steps. Direct mechanisms are depicted by solid arrows, indirect mechanisms are depicted by broken arrows. Brackets on the right hand side of the figure indicate mechanisms associated with specific angiogenic diseases. Transcription factors are shown in boxes; P, indicates phosphorylation event; Mϕ, macrophage.

Figure 3

Graphical representation of IL-1F cytokine regulation of vascular permeability. IL-1 F cytokines regulate vascular permeability, direct mechanisms are depicted by solid arrows, indirect mechanisms are depicted by broken arrows. EC, endothelial cell; P, indicates phosphorylation event. ↑ indicates upregulation of protein; ↓ indicates down regulation of protein.