IL-1 Receptor Signaling Pathway

Overview of the IL-1 Receptor Signaling Pathway

IL-1 is a cytokine produced by activated macrophages which mediates several physiological responses to infections and injuries, including stimulation of thymocyte proliferation, B-lymphocyte maturation and proliferation, induction of acute-phase protein synthesis by hepatocytes and induction of fever. In addition to macrophages, fibroblast keratinocytes, comeal cell astrocytes, and EBV-transformed B-lymphocytes are also capable of producing IL-1. Monocyte cell lines produce IL-1 after treatment with agents such as TPA and LPS.

There are 11 members of the IL-1 family (IL-1F) of ligands including IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), etc. The main function of IL-1-type cytokines is to control proinflammatory reactions in response to tissue injury by pathogen-associated molecular patterns (PAMPs, such as bacterial or viral products) or damage- or danger-associated molecular patterns released from damaged cells (DAMPs, such as uric acid crystals or adenosine 5´-triphosphate). Thus, they are major mediators of innate immune reactions, and their actions are tightly balanced. The occurrence of severe multiorgan inflammation in patients with homozygous mutations or deletions of the gene encoding interleukin-1 receptor antagonist (IL-1RA) and the successful blockade of inflammatory reactions in humans by application of recombinant IL-1RA or antibodies to IL-1β have demonstrated a central role of IL-1α or IL-1β in a number of auto-inflammatory diseases. This pathway summarizes signaling of the founding members, IL-1α and IL-1β, which share only 24% amino acid sequence identity but have largely identical biological function.

Sentinel cells of the innate immune system (macrophages and monocytes) are a major source of IL-1α and IL-1β, but many other cell types, including epithelial cells, endothelial cells, and fibroblasts, can also produce IL-1α and IL-β. IL-1α is primarily membrane anchored and signals through autocrine or juxtracrine mechanisms, whereas IL-1β is secreted by an unconventional protein secretion pathway and can act in a paracrine manner or systemically. There are three major levels of control to restrict the potent proinflammatory activities of IL-1α and IL-β: (i) control of synthesis and release by the NALP3-inflammasome, a multiprotein complex that controls activation of the IL-1β–processing protease caspase-1, which was initially called interleukin-1β–converting enzyme (ICE); (ii) control of the membrane receptors; (iii) regulation of the signal transduction downstream of the activated receptors.

IL-1 Receptor Type Ⅰ

Studies have suggested that IL-1RI undergoes a conformational change when binding IL-1β and allows the IL-1RAcP to form the heterodimer. The cytoplasmic domain of IL-1RI is unique in that it contains homology to the Drosophila Toll protein, termed the TIR domain. The TIR domain is also found in the cytoplasmic domains of each TLR. The TIR domains of IL-1RI and also of the coreceptor IL-1RAcP are necessary for signal transduction. Although most cells express IL-1RI constitutively, expression of IL-1RAcP is not constitutive in some cells. A small synthetic peptide (RYTVELA) derived from the sequence of the third domain of the IL-1RAcP was tested for blocking IL-1 activity. This peptide, known as 101.10, blocks the functions of the IL-1RI in human, mouse, ..., and rat cells and has no effect in mice deficient in IL-1RI. This property of allosteric antagonism has been observed for the leukocyte function–associated antigen-1 (LFA-1) integrin where a peptide binds to an allosteric site and inhibits only some of the properties of LFA-1.

Specifically speaking, IL-1β binding to the IL-1RI recruits the IL-1RAcP to form a heterodimeric receptor. The cytoplasmic Toll domains on each receptor chain approximate. MyD88 and Tollip are recruited. MyD88 binding to the cytoplasmic domains triggers the phosphorylations of the IL-1 receptor–associated kinases IRAK-4, IRAK-2, and IRAK-1. TRAF-6 is recruited. Phosphorylated IRAK-1 and TRAF-6 migrate to the membrane and associate with TAK1 (TGF-β-activated kinase1), TAK1-binding protein TAB1, and TAB2. The complex of TAK1, TAB1, TAB2, and TRAF-6 migrates to the cytosol, where TAK1 is phosphorylated following the ubiquitination of TRAF-6. Phosphorylated TAK1 activates IKKβ, and phosphorylated IKKβ phosphorylates IκB. Phosphorylated IκB degrades, releasing NF-κB, which enters the nucleus. In addition to the phosphorylation of IKKβ, TAK1 also activates mitogen-activated protein kinase (MAPK) p38 and JNK. On the surface of the cell, IL-1RII, a decoy receptor, may also bind IL-1β, but this complex does not recruit IL-1RAcP, and there is no signal. In the extracellular space, the extracellular domains (soluble or sIL-1RII) of the IL-1RII bind IL-1β and neutralize its activity. sIL-1RII can also bind IL-1β and form a complex with soluble IL-1RAcP or cell-bound IL-1RAcP. In the latter two complexes, IL-1β is not available to bind to IL-1RI and therefore cannot transmit a signal. (Fig 1)

Fig1. The IL-1 receptor signaling pathway

IL-1 Receptor Type Ⅱ

IL-1RII is a decoy receptor which captures IL-1without signaling. Intracellularly, the IL-1RII associates with the IL-1α precursor. Genes in the pox family of viruses encode for a protein with a high homology to the extracellular (soluble) domains of the receptor (sIL-1RII). In humans, sIL-1RII is released from the cell surface by a protease; sIL-1RII has a particularly high affinity for mature IL-1β and therefore functions as a naturally occurring neutralization mechanism for IL-1β.

IL-1β binding to the sIL-1RII is nearly irreversible. The IL-1β precursor also preferentially binds to sIL-1RII. A more efficient function of the type II receptor is to form a trimeric complex of the IL-1β with sIL-1RII and the IL-1RAcP chain. This mechanism serves to deprive the cell of both IL-1β as well as a functional receptor accessory chain. SIL-1RAcP forms complexes on the cell surface of IL-1β bound to type II receptors and accounts for the ability of sIL-1RAcP to reduce B lymphocyte activation. SIL-1RAcP inhibits IL-1-induced NF-κB activity in B cells but not in T cells, whereas IL-1Ra inhibited IL-1 in both cell types.

Therapeutic Strategies for IL-1 in Human Diseases

Anakinra is the generic name for the recombinant form of the naturally occurring IL-1Ra (interleukin-1 receptor antagonist) and has been approved in 2001 to treat rheumatoid arthritis and also to treat CAPS (Community acquired pneumonia) later. However, Anakinra has been proved efficacious in a broad spectrum of diseases and is currently in several clinical trials. These include autoimmune hearing loss, hydradenitis suppurativa, stroke, and osteoarthritis of the hand. The responses to anakinra are rapid and sustained and in many conditions, treatment with anakinra allows for a reduction in steroid use, particularly in children with systemic juvenile idiopathic arthritis. Anakinra is also used to treat common diseases such as recurrent gout attacks unresponsive to standards of therapy.

There is a large body of preclinical evidence supporting the rationale for specifically targeting IL-1β with neutralizing antibodies. In autoinflammatory diseases, IL-1β is released from the activated monocyte as a result of dysregulation of caspase-1. Canakinumab is a human monoclonal antibody specifically targeting IL-1β, which is approved for the treatment of CAPS, systemic onset juvenile idiopathic arthritis, and refractory gout. It will be tested in a large trial in cardiovascular pathology. A neutralizing monoclonal anti-IL-1a antibody has been tested in Type 2 diabetes, cancer cachexia, pustular psoriasis, occlusive vascular disease, and scarring acne vulgaris and in each condition, reduced disease severity has been observed in limited trials.

Conclusion

Evidence obtained in the last few years indicates that members of the IL-1 family are key players in the differentiation and function of innate and adaptive lymphoid cells. Thus, in a way, the long overlooked costimulating activity of IL-1 (LAF) has now been vindicated by the discovery of its role in innate and adaptive lymphoid cell differentiation and function. In addition, IL-1 has adjuvant activity and activation of the inflammasome might contribute to the function of adjuvants in current clinical use. The identification of the role of IL-1 family members in lymphoid differentiation raises the issue as to whether this aspect of the function of IL-1 family members can be harnessed for better vaccines. Furthermore, some evidence suggests that negative regulators are key components of resolution of inflammation. It is tempting to speculate that these components of the IL-1 family might represent therapeutic targets in proresolving strategies. Anti-IL-1 strategies have had a tremendous impact in the therapy of autoinflammatory disorders sustained by inflammasome activation and, to a lesser extent, autoimmune diseases. Some studies also suggest that blocking IL-1 might have a broader clinical impact on relatively rare (e.g., Behcet uveitis) and common (e.g., cardiovascular) diseases.

In conclusion, Better understanding of the IL-1 signaling pathway holds promise of innovative therapeutic tools and targets.

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