What Is IL-1 for? The Functions of Interleukin-1 Across Evolution

Abstract

Interleukin-1 is a cytokine with potent inflammatory and immune-amplifying effects, mainly produced by macrophages during defensive reactions. In mammals, IL-1 is a superfamily of eleven structurally similar proteins, all involved in inflammation or its control, which mainly act through binding to specific receptors on the plasma membrane of target cells. IL-1 receptors are also a family of ten structurally similar transmembrane proteins that assemble in heterocomplexes. In addition to their innate immune/inflammatory effects, the physiological role of IL-1 family cytokines seems to be linked to the development of adaptive immunity in vertebrates. We will discuss why IL-1 developed in vertebrates and what is its physiological role, as a basis for understanding when and how it can be involved in the initiation and establishment of pathologies.

Keywords: adaptive immunity; evolution; inflammation; innate immunity; interleukin-1.

Figure 1

IL-1 and IL-1R family molecules in vertebrates. No IL-1-like homologous sequences have been identified in invertebrates, whereas numerous orthologues of IL-1R family genes were identified. This places the appearance of proto-IL-1 genes at the same time as the appearance of the vertebrate subphylum around 420 million years ago (48). The various IL-1R genes are present in all vertebrates, from cartilaginous fish to mammals, except for IL-1RAPL1, which only appeared after separation of bony fish and Tetrapoda clades about 365 million years ago, most likely from duplication of the IL1RAPL2 gene. All vertebrates possess the genes for IL-1β, IL-1Ra and IL-18, whereas all the other IL-1 genes only appeared in mammals; genes encoding IL-1α, the IL-36 group, IL-37 and IL-38 are likely derived from IL-1β gene duplication, while the gene for IL-33 has independently evolved. Please note that the receptor genes were present in evolution long before the appearance of their ligands. Minus and plus signs indicate gene absence or presence.

Figure 2

Inverse agonist hypothesis in the development of IL-1R ligands. Upper panel. Hypothesis on the possible development of IL-1R family molecules and their ligands. The receptor may have developed as a molecule with intrinsic activity, in the absence of interaction with ligands (this is still the case for instance for the orphan receptor IL-1R9). Ligands may have developed as a tool for inhibiting and modulating the receptor activity (inverse agonists, which inhibit rather than activate the receptor), likely by changing the receptor conformation. Consequently, antagonists may have developed as partial ligands, based on modifications of the inverse agonist structure, that bind to the receptor and displace the inverse agonists, while unable to modify the receptor conformation and its activity. Lower panel. Current model of IL-1R and ligand interaction. The receptor is intrinsically inactive (for instance, in the case of IL-1R1). Binding of an agonist (such as IL-1β) changes the receptor conformation thereby enabling the interaction with a second chain (such as IL-1R3) and consequent activation (by approximation of the intracellular domains of the two receptors). Antagonists (such as IL-1Ra) have a similar structure as agonists and are able to partially bind to the receptor, thereby displacing the agonist, but unable to modify the receptor conformation and thus preventing interaction with the second chain and consequent activation. Artwork by W.J. Yang.