2. IL-1 Family Cytokines, Receptors and Co-Receptors
The IL-1 family of
cytokines is composed of 11 cytokine members, with seven agonists (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ) and four antagonists (IL-1 receptor antagonist (Ra), IL-36Ra, IL-37, and IL-38)
[1]. According to their structural and functional characteristics, these cytokines are further classified into four subfamilies (IL-1, IL-18, IL-33, and IL-36), each one having a cognate receptor (IL-1R1, IL-18Rα, IL-33R (suppression of tumorigenicity 2 or
ST2), and IL-36R, respectively). Furthermore, IL-1RAcP is an accessory protein shared by all these cytokines, with the exception of IL-18 (IL-18RAcP or IL-18Rβ chain) (
Table 1)
[2].
Table 1. IL-1 family cytokine members.
To produce their pro-inflammatory functions, IL-1 cytokines form complexes with their respective receptor and a co-receptor (
Figure 1). All of them except IL-1Ra are synthesized as precursors and require N-terminal processing in order to acquire their full function
[3][4]. They can be activated both extracellularly by proteolytic cleavage and intracellularly via inflammasome-mediated cleavage
[5]. Binding of cleaved IL-1α/β to the extracellular domain of IL-1R1 leads to recruitment of IL-1RAcP, resulting in the initiation of a signaling cascade with the recruitment of the myeloid differentiation primary response 88 (MyD88) accessory protein and Interleukin 1 receptor-associated kinases (IRAKs). This in turn results in activation of the nuclear factor κB (NF-κB) and
mitogen-activated protein kinases (MAPKs), ultimately resulting in pro-inflammatory gene expression
[6]. Furthermore, IL-1 signaling also induces activation of defense mechanisms (antigen recognition, phagocytosis, degranulation, and nitric oxide production) and activates lymphocyte functions implicated in adaptive immunity, thus acting as a link between innate and adaptive immune responses
[7]. The other IL-1 family cytokines IL-33, IL-18, and IL-36α/β/γ form similar ternary complexes with their respective receptors and co-receptors and also act through Myd88 to induce pro-inflammatory gene expression.
Figure 1. Signaling pathways and regulatory mechanisms involved in the IL-1 family. (A). Upon binding of IL-1α and IL-β to their receptor IL-1R1 altogether with co-receptor IL-1RAcP, induction of signal transduction with recruitment of myeloid differentiation primary response 88 (MyD88) accessory protein and IL-1R associated kinase (IRAK) proteins, ultimately ending in the activation of the transcription factor nuclear factor κB (NF- κB) and the transcription of proinflammatory genes. Regulatory mechanisms include IL-1R2 and IL-1Ra: IL-1R2 can exist as a soluble receptor or membrane bound, acting as a decoy receptor as it is unable to recruit the co-receptor to induce signal transduction. Finally, IL-1Ra acts as a competitive inhibitor by binding to IL-1R1. (B). Likewise, IL-33 binds to the receptor ST2, inducing the recruitment of co-receptor IL-1RAcP and resulting in signal transduction into the nucleus with transcription of proinflammatory genes. In this family, the soluble form of ST2 also acts as a decoy receptor. IL-18 binds to IL-18Rα and recruits the co-receptor IL-18Rβ resulting in pro-inflammatory signaling. IL-18 binds to the soluble protein IL-18BP preventing binding to the receptor. IL-37 is an anti-inflammatory cytokine and upon binding to IL-18Rα induces recruitment of the Single Ig and TIR Domain Containing (SIGIRR or IL-1R8), ultimately producing inhibitory signaling. (C). IL-36 cytokines also induce pro-inflammatory gene transcription by binding to the receptor IL-36R and recruiting co-receptor IL-1RAcP. IL-36Ra is the competitive antagonist of IL-36 cytokines. The anti-inflammatory cytokine IL-38 forms a complex with IL-36R and three immunoglobulin domain-containing IL-1 receptor-related 2 (TIGIRR-2 or IL1RAPL1), also inducing inhibitory signaling to regulate the pro-inflammatory gene activation.
Regulatory mechanisms are necessary to maintain homeostasis; they include decoy receptors, receptor antagonists, and anti-inflammatory cytokines (
Figure 1). IL-1R2 is a cytoplasmic soluble receptor without a functional TIR domain that binds to IL-1α/β precursors, preventing their processing and secretion. Under proinflammatory conditions, IL-1R2 is cleaved by an inflammasome-dependent mechanism
[8][9]. Likewise, the soluble ST2 receptor (sST2) and the soluble protein IL-18 binding protein (IL-18BP) bind to IL-33 and IL-18, respectively, neutralizing their activities
[10][11]. Furthermore, receptor antagonists IL-1Ra, IL-36Ra, and IL-38 compete with IL-1α/β and IL-36α/β/γ
[4]. Lastly, IL-37 binding to IL-18Rα leads to recruitment of the IL-1R8 co-receptor (also called single immunoglobulin IL-1R-related molecule (SIGIRR), with activation of the inhibitory
STAT3 signaling pathway
[12].
2.1. IL-1 Subfamily
IL-1α and IL-β are both
pro-inflammatory cytokines with some distinctive characteristics. IL-1α is constitutively expressed in hematopoietic immune cells and other cell types such as intestinal epithelial cells and cutaneous keratinocytes (KCs)
[13]. Although non-processed full-length IL-1α has some functional activity, cleavage by calpain and extracellular proteases such as
neutrophil elastase, granzyme B, and mast cell chymase enhances its pro-inflammatory activity
[14][15]. Its major role is played locally, since IL-1α is mostly found bound to membranes. It is also expressed intracellularly in the cytosol—acting as an alarmin upon release from necrotic cell death—and in the nucleus—activating transcription of pro-inflammatory genes or tissue homeostasis and repair genes
[16]. In addition, IL-1α expression can be induced by proinflammatory stimuli, leading to IL-1R1 binding and pro-inflammatory gene expression targeting type 1 or type 17 immune responses. In turn, this produces recruitment and activation of T cells, dendritic cells (DCs),
neutrophils, and monocytes/macrophages that will release further pro-inflammatory cytokines and chemokines, leading to an autoinflammatory amplification loop
[17]. On the contrary, IL-1β is the primary circulating form, and its expression is inducible only in monocytes, macrophages, and DCs
[17]. Full-length IL-1β precursor protein (pro-IL-1β) is stored in the cytoplasm and is cleaved by caspase-1 to its active form in response to activation of pattern recognition receptors (PPR) by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) in an inflammasome-dependent process
[18]. In addition, pro-IL-1β can also be activated in the extracellular space by neutrophils and mast cells-derived proteases or by microbial proteases
[19]. The antagonist IL-1Ra exerts its anti-inflammatory properties by binding to the IL-1R1 receptor and competing with IL-1α and IL-β
[20].
2.2. IL-18 Subfamily
IL-18 is also a pro-inflammatory cytokine and is constitutively expressed in its inactive form in several cell types, mainly KCs, epithelial, and endothelial cells
[21]. Its activation can be produced intracellularly by caspase-1-mediated cleavage or extracellularly by neutrophil or cytotoxic cell-derived proteases
[21][22]. IL-18 pro-inflammatory activity is mainly mediated through IFNγ, but it can induce both Th1 and Th2 cellular responses
[23]. In combination with IL-12 and IL-15, IL-18 stimulates Th1 cells and induces NK cell effector function and IFNγ expression
[24][25]; in the absence of these cytokines, IL-18 induces a Th2 response with mast cell and basophil activation, ultimately ending in IL-4 and IL-13 production
[26]. Moreover, when combined with IL-23, IL-18 activates Th17 cells and induces IL-17 production
[27]. IL-18-BP regulates IL-18 pro-inflammatory activity by binding and sequestering the cytokine. IL-18-BP expression is induced by IFNγ, thus creating a negative feedback mechanism and decreasing inflammation
[11].
2.3. IL-33 Subfamily
IL-33 is also constitutively expressed in many organs, mainly by fibroblasts, endothelial cells, and epithelial cells; its expression can also be induced in
mast cells and DCs in the context of inflammation. Similar to IL-1α, IL-33 requires cleavage to increase its activity and has a dual role: intracellular gene expression regulating homeostasis and extracellular recruitment and activation of immune cells upon cell necrosis and inflammation (alarmin function)
[28][29]. Th2 cells, mast cells, and eosinophils express the IL-33 receptor, ST2, or IL1-1RL1
[28]. IL-33 is a promoter of Th2 immunity and allergic responses, inducing production of IL-4, IL-5, and IL-13, polarization of macrophages and degranulation of mast cells, basophils, and eosinophils with cytokine and chemokine release
[30]. Finally, IL-33 also acts on T-reg cells, DCs, and NK cells
[31].
2.4. IL-36 Subfamily
The IL-36 subfamily is a key regulator of the innate immune system and includes three agonists with pro-inflammatory activity (IL-36α, IL-36β, and IL-36γ) and two antagonists (IL-36RN or IL-36Ra and IL-38)
[32]. They are normally expressed in epithelial and immune cells; after binding to receptor complex IL-36R, agonists induce activation of nuclear factor-kB (NF-kB) and mitogen-activated protein kinases, leading to T-cell proliferation, expression of pro-inflammatory cytokines, chemokines, and co-stimulatory molecules by DCs and Th1 lymphocytes, as well as autocrine KCs signaling. The resulting pro-inflammatory milieu is composed of IL-1β, IL-12, IL-23, IL-6,
TNF-α, CCL1, CXCL1, CXCL2, CXCL8, and GM-CSF, among others
[32]. IL-36α and IL-36γ are mainly produced by KCs but also by
dermal fibroblasts, endothelial cells, macrophages, LCs, and DCs. As opposed to other IL-1 family cytokines, IL-36 cytokines are also produced as precursors but do not contain a caspase cleavage site. Following secretion, they are activated by neutrophil-derived proteases present at neutrophil extracellular traps (NETs)—such as elastase, cathepsin G, and proteinase 3—and by cathepsin S, produced by KCs and fibroblasts
[33][34][35]. In addition, KCs secrete the protease inhibitors alpha-1-antitrypsin and alpha-1-antichymotrypsin (encoded by SERPINA1 and SERPINA3 genes), which inhibit processing of IL-36 cytokines by neutrophil proteases and thus regulate the inflammatory loop
[36].
2.5. IL-37 and IL-38: Antagonist Cytokines
IL-37 acts as an anti-inflammatory cytokine and is constitutively expressed mainly in KCs, but can be induced in monocytes/macrophages, T cells, and B cells. It has a dual action, depending on extracellular or intracellular signaling. Extracellularly, IL-37 binds IL-18Rα and recruits IL-1R8 to form the IL-37/IL-1R8/IL-18Rα complex, restricting IL-18R-dependent inflammation and inhibiting innate immunity
[12]. In the cytosol, IL-37 cleaved by caspase-1 translocates to the nucleus to bind Smad
transcription factors, ultimately decreasing pro-inflammatory cytokine production. The precursor exhibits activity, but cleaved IL-37 binds more effectively to its receptor
[37].
IL-38 also acts as an anti-inflammatory cytokine and is expressed in skin and various immune cells, such as B cells. It specifically binds to IL-36R and inhibits human mononuclear cells stimulated with IL-36 in vitro
[38]. IL-38 expression is inhibited by IL-17, IL-22, and IL-36γ
[4]. Furthermore, IL-38 is able to suppress the production of IL-17A by γδ T-cells through IL-1RAcP antagonism
[39].