Structural Basis of IL-1 Family Cytokine Signaling

Abstract

Interleukin-1 (IL-1) family cytokines are key signaling molecules in both the innate and adaptive immune systems, mediating inflammation in response to a wide range of stimuli. The basic mechanism of signal initiation is a stepwise process in which an agonist cytokine binds its cognate receptor. Together, this cytokine-receptor complex recruits an often-common secondary receptor. Intracellularly, the Toll/IL-1 Receptor (TIR) domains of the two receptors are brought into close proximity, initiating an NF-κB signal transduction cascade. Due to the potent inflammatory response invoked by IL-1 family cytokines, several physiological mechanisms exist to inhibit IL-1 family signaling, including antagonist cytokines and decoy receptors. The numerous cytokines and receptors in the IL-1 superfamily are further classified into four subfamilies, dependent on their distinct cognate receptors—the IL-1, IL-33, and IL-36 subfamilies share IL-1RAcP as their secondary receptor, while IL-18 subfamily utilizes a distinct secondary receptor. Here, we describe how structural biology has informed our understanding of IL-1 family cytokine signaling, with a particular focus on molecular mechanisms of signaling complex formation and antagonism at the atomic level, as well as how these findings have advanced therapeutics to treat some chronic inflammatory diseases that are the result of dysregulated IL-1 signaling.

The role of Interleukin 1 receptor antagonist in mesenchymal stem cell‐based tissue repair and regeneration

“…As IL‐1α, IL‐1β, and IL‐1Ra share the same structural motif, all of them engage the same IL‐1RI on target cells. IL‐1Ra represents a typical naturally occurring antagonist that occupies the binding pocket of IL‐1RI without eliciting any downstream signaling . Importantly, binding affinity of IL‐1Ra to IL‐1RI is equal to the affinity of IL‐1α and IL‐1β, enabling IL‐1Ra‐mediated competitive inhibition of IL‐1RI and efficient suppression of IL‐1α/IL‐1β:IL‐1RI‐signaling.…”

“…MyD88 links IL‐1R ternary complex with IL‐1R‐associated kinases (IRAK) and mitogen‐activated protein kinases, resulting in the activation of several transcriptional factors, including NF‐κB and Activator protein 1 . Therefore, activation of IL‐1α/IL‐1β:IL‐1RI signaling pathways results in enhanced release of alarmins from injured cells, increased production of inflammatory mediators, and higher expression of chemokine receptors on immune cells enabling massive influx of circulating leucocytes in injured tissue and consequent development of inflammation …”

“…In similar manner as AECs, lung DCs also capture HDM in TLR‐4‐dependent manner . Activation of TLR‐4 leads to the engagement of intracellular IL‐1α which acts synergistically with TNF‐α to enhance migration of DCs to the regional lymph nodes where DCs activate HDM‐specific naive CD4 + T cells and induce their differentiation in IL‐4‐, IL‐5‐, and IL‐13‐producing, effector Th2 cells . CD4 + Th2 cells, in similar manner as ILC2, induce activation of mast cells, basophils, and eosinophils in the lungs and promote progression of chronic airway inflammation .…”

“…IL-1Ra (IL1-F3) is a member of IL-1 cytokine family that consists of 11 cytokines and 10 receptors. 13 All of IL-1 family members are potent modulators of inflammation and among them, IL-1α and IL-1β are considered as the most important proinflammatory cytokines while IL-1Ra, as naturally occurring antagonist of IL-1α and IL-1β signaling, has crucially important role in alleviation of IL-1α and IL-1β-driven inflammation. 14 IL-1α and IL-1β signaling pathways are initiated by the binding of IL-1α and IL-1β to their cognate receptor IL-1RI.…”

“…15,16 Therefore, activation of IL-1α/IL-1β:IL-1RI signaling pathways results in enhanced release of alarmins from injured cells, increased production of inflammatory mediators, and higher expression of chemokine receptors on immune cells enabling massive influx of circulating leucocytes in injured tissue and consequent development of inflammation. 13 The analysis of X-ray crystal structures of IL-1 family members revealed that many of these cytokines, including IL-1α, IL-1β, and IL-1Ra, have a conserved β-trefoil conformation and a central hydrophobic core composed of 12 βsheets, six of which (β1, β4, β5, β8, β9, and β12) form an antiparallel β-barrel. 13 As IL-1α, IL-1β, and IL-1Ra share the same structural motif, all of them engage the same IL-1RI on target cells.…”