The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Discovery
Discovery of these cytokines began with studies on the pathogenesis of fever. The studies were performed by Eli Menkin and Paul Beeson in 1943–1948 on the fever-producing properties of proteins released from rabbit peritoneal exudate cells. These studies were followed by contributions of several investigators, who were primarily interested in the link between fever and infection/inflammation. The basis for the term "interleukin" was to streamline the growing number of biological properties attributed to soluble factors from macrophages and lymphocytes. IL-1 was the name given to the macrophage product, whereas IL-2 was used to define the lymphocyte product. At the time of the assignment of these names, there was no amino acid sequence analysis known and the terms were used to define biological properties.
In 1985 two distinct, but distantly related complementary DNAs encoding proteins sharing human IL-1 activity were reported to be isolated from a macrophage cDNA library, thus defining two individual members of the IL-1 family – IL-1α and IL-1β.
The Interleukin-1 superfamily IL-1 family is a group of 11 cytokines, which induces a complex network of proinflammatory cytokines and via expression of integrins on leukocytes and endothelial cells, regulates and initiates inflammatory responses.
IL-1α and IL-1β are the most studied members because they were discovered first and because they possess strong proinflammatory effects. They have a natural antagonist IL-1Ra (IL-1 receptor antagonist). All three of them include a beta trefoil fold and bind IL-1 receptor (IL-1R) and activate signaling via MyD88 adaptor, which is described in the Signaling section of this page. IL-1Ra regulates IL-1α and IL-1β proinflammatory activity by competing with them for binding sites of the receptor.
Nine IL-1 superfamily members occur in a single cluster on human chromosome two; sequence and chromosomal anatomy evidence suggest these formed through a series of gene duplications of a proto-IL-1β ligand. In this way, IL-1β, IL-1α, IL-36α, IL-36β, IL-36γ, IL-36RA, IL-37, IL-38, and IL-1RA are very likely ancestral family members sharing a common lineage. However, IL-18 and IL-33 are on different chromosomes and there is insufficient sequence or chromosomal anatomy evidence to suggest they share common ancestry with the other IL-1 superfamily members. IL-33 and IL-18 have been included into the IL-1 superfamily due to structural similarities, overlap in function and the receptors involved in their signalling.
Synthesis All of the members of IL-1 family, except IL-1Ra, are first synthesized as a precursor protein, which means it is synthesized as a long form of a protein which has to be proteolytically cleaved to a shorter, active molecule, which is generally called a mature protein. IL-1 family precursors do not have a clear signal peptide for processing and secretion and none of them are found in the Golgi; they belong to so-called leaderless secretory protein group. In research, fluorescent reporters can be used to analyze the intracellular cleavage of the protein into its active form. The similar feature of IL-1α and IL-33 is that their precursor forms can bind to their respective receptor and can activate signal transduction. But this is not a common feature for all IL-1 family members, since IL-1β and IL-18 precursor forms do not bind their receptors and require proteolytic cleavage by either intracellular caspase-1 or extracellular neutrophilic proteases.
Nomenclature The interleukin-1 superfamily has 11 members, which have similar gene structure, although originally it contained only four members IL-1α, IL-1β, IL-1Ra and IL-18. After discovery of another 5 members the updated nomenclature was generally accepted which included all members of IL-1 cytokine family. The old IL-1 members were renamed to IL-1F1, IL-1F2, IL-1F3 and IL-1F4.
But according to new trends in nomenclature, the old names of IL-1 family returned. In 2010, laboratories all around the world agreed that IL-1α, IL-1β, IL-1Ra and IL-18 are more familiar to the general scientific knowledge. According to that, they suggested that IL-1F6, IL-1F8 and IL-1F9 should get new names IL-36α, IL-36β and IL-36γ, even though they are encoded by distinct genes, they use the same receptor complex IL-1Rrp2 and coreceptor IL-1RAcP and deliver almost identical signals. The nomenclature also proposes that IL-1F5 should be renamed to IL-36Ra, because it works as an antagonist to IL-36α, IL-36β and IL-36γ similar to how IL-1Ra works for IL-1α and IL-1β. Another revision was the renaming of IL-1F7 to IL-37 because this suppressing cytokine has many splicing variants, they should be called IL-37a, IL-37b and so on. For IL-1F10 there is a reserved name, IL-38.
Name Family name Receptor Coreceptor Property Chromosomal locationIL-1α IL-1F1 IL-1RI IL-1RAcP Proinflammatory 2q14.1IL-1β IL-1F2 IL-1RI IL-1RAcP Proinflammatory 2q14.1IL-1Ra IL-1F3 IL-1RI NA Antagonist for IL-1α, IL-1β 2q14.1IL-18 IL-1F4 IL-18Rα IL-18Rβ Proinflammatory11q23.1IL-36Ra IL-1F5 IL-1Rrp2 NA Antagonist for IL-36α, IL-36β, IL-36γ2q14.1 IL-36α IL-1F6 IL-1Rrp2 IL-1RAcP Proinflammatory 2q14.1IL-37 IL-1F7 Unknown UnknownAnti-inflammatory2q14.1IL-36β IL-1F8 IL-1Rrp2 IL-1RAcP Proinflammatory2q14.1IL-36γ IL-1F9 IL-1Rrp2 IL-1RAcP Proinflammatory 2q14.1IL-38 IL-1F10 IL-1Rrp2 Unknown Anti-inflammatory2q14.1IL-33 IL-1F11 ST2 IL-1RAcP Th2 responses, proinflammatory 9p24.1
Signaling IL-1α and IL-1β bind to the same receptor molecule, which is called type I IL-1 receptor (IL-1RI). There is a third ligand of this receptor – the Interleukin 1 receptor antagonist (IL-1Ra), which does not activate downstream signaling, so it acts as an inhibitor of IL-1α and IL-1β signaling by competing with them for binding sites of the receptor.
IL-1α or IL-1β bind first to the first extracellular chain of IL-1RI, that recruits the IL-1 receptor accessory protein (IL-1RAcP), which serves as a coreceptor and is necessary for signal transduction and it is also needed for activation of IL-1RI by IL-18 and IL-33.
After the formation of receptor heterodimeric complex which is assembled by IL-1α or IL-1β, IL-1RI and IL-1RAcP, two intracellular adaptor proteins are assembled by conserved cytosolic regions called Toll- and IL-1R-like (TIR) domains. They are called the myeloid differentiation primary response gene 88 (MYD88) and interleukin-1 receptor-activated protein kinase (IRAK) 4. Phosphorylation of IRAK4 is followed by phosphorylation of IRAK1, IRAK2 and tumor necrosis factor receptor-associated factor (TRAF) 6. TRAF6 is a ubiquitin E3 ligase, that in association with ubiquitin-conjugating enzyme (ubiquitin E2 ligase) complex attaches K63-linked polyubiquitin chains to some of IL-1signaling intermediates, for instance TGF-β-activated protein kinase (TAK-1). That facilitates the association of TAK-1 with TRAF6 and with MEKK3. These signaling pathways lead to activation of many transcription factors, such as NF-κB, AP-1, c-Jun N-terminal kinase (JNK) and p38 MAPK.1. Simi A, Tsakiri N, Wang P, Rothwell NJ. Interleukin-1 and inflammatory neurodegeneration. Biochemical Society Transactions. 2007 Oct 1;35(5):1122–6.
IL-1α precursor and mature IL-1β lack a signal peptide which should direct them into the endoplasmic/Golgi-dependent secretion pathway and they are secreted by an unconventional protein secretion pathway, of which the mechanism and regulation are not known.
Biological activity IL-1 is intensely produced by tissue macrophages, monocytes, fibroblasts, and dendritic cells, but is also expressed by B lymphocytes, NK cells, microglia, and epithelial cells. They form an important part of the inflammatory response of the body against infection. These cytokines increase the expression of adhesion factors on endothelial cells to enable transmigration (also called diapedesis) of immunocompetent cells, such as phagocytes, lymphocytes and others, to sites of infection. They also affect the activity of the hypothalamus, the thermoregulatory center, which leads to a rise in body temperature (fever). That is why IL-1 is called an endogenous pyrogen. Besides fever, IL-1 also causes hyperalgesia (increased pain sensitivity), vasodilation and hypotension.
IL-1α IL-1α is a "dual-function cytokine", which means it plays a role in the nucleus by affecting transcription, as well as its extracellular receptor-mediated effects as a classical cytokine. IL-33 also belongs in this group.
IL-1α is synthesized as a precursor protein and it is constitutively stored in the cytoplasm of cells of mesenchymal origin and in epithelial cells. In contrast, monocytes and macrophages do not contain preformed IL-1α precursors, but instead rely on de novo synthesis. The IL-1α precursor is processed to its mature 17-kDa form by a Ca2+-activated protease, calpain. Processing liberates the 16-kDa N-terminal propiece cleavage product (ppIL-1α), which contains a nuclear localization sequence (NLS), and translocates to the nucleus, functioning as a transcription factor. The precursor form of IL-1α, which has both the N-terminal and C-terminal receptor interacting domains, acts as a damage-associated molecular pattern (DAMP) molecule. DAMPs, also known as alarmins, are recognized by innate immunity cells by pattern recognition receptors (PRRs) and function as danger signals for the immune system. In short, DAMPs are released from stressed cells, which undergo necrosis or pyroptosis and their intracellular components are released into extracellular space. Because of misfolding and other oxidative changes of these molecules in the context of altered pH, they are recognized by the innate immune system as molecules that should not be in extracellular space. Cell stress could be due to infection, injury, ischemia, hypoxia, acidosis and complement lysis. The IL-33 precursor molecule acts in a similar way as a DAMP molecule.
Inflammatory responses in the absence of infection (such as ischemia) are only dependent on IL-1α signaling via the Interleukin-1 receptor (IL-1R), rather than TLRs signaling. IL-1α also stimulates transcription and secretion of IL-1β from monocytes, so the initiator of immune responses is likely IL-1α precursor by induction of neutrophil infiltration. IL-1β seems to be an amplifier of inflammation by recruitment of macrophages in the context of sterile inflammation.
IL-1β IL-1β is synthesized as a precursor form protein only after stimulation, in contrast to IL-1α. Its expression is induced by transcription factor NF-κB after exposure of innate immune cells to alarmins. This occurs, for instance, after exposure of macrophages and dendritic cells to lipopolysaccharide (LPS), which binds to TLR4 and acts as pathogen-associated molecular pattern, which is another group of alarmins.
The synthesis of IL-1β precursor (and IL-18) is induced by stimulation of innate immune cells by Toll-like receptors (TLRs) or RIG-like receptors (RLRs), but to gain the ability to bind to IL-1 receptor, the IL-1β precursor has to be cleaved by a cysteine protease called caspase-1. Caspase-1 needs to be activated by a formation called the inflammasome which is mediated by cytoplasmic pattern recognition receptor signaling. So, the secretion of IL-1β needs these two steps and activation of different receptors to be activated. Under special circumstances IL-1β can be processed also by other proteases, like during high neutrophilic inflammation.
IL-18 is also synthesized as a precursor which is cleaved by caspase-1.