Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

IL-1 Family

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101688

Synonyms

Historical Background

The family of IL-1 cytokines (IL-1F) encompasses eleven proteins that share similar structure and signaling mode (similar receptors, similar signaling pathways) (Dinarello 2013). IL-1F cytokines are involved in initiation as well as regulation of inflammation and are central players of innate immunity.

Studies started in the 1940s with the first identification of factors able to induce fever (pyrexin, endogenous pyrogen, leukocytic pyrogen) and developed until the cloning of the first cytokines of the family (IL-1α and IL-1β) in the 1980s. After that, studies bloomed and at present eleven members of the family have been identified, and the function of several of them clarified.

Several IL-1F cytokines are synthesized as long precursors, of which the C-terminal domain is the active secreted cytokine. Secretion takes place by nonconventional mechanisms that are still partly unknown.

In many cases, the procytokine forms have an intracellular function that differs from that of the mature cytokine. In many cases, alternative splicings generate different forms that may have different functions.

IL-1F cytokines bind to plasma membrane receptors, which all belong to the same group of Ig-like receptors of the TIR superfamily. Signaling occurs upon the formation of a trimeric complex between the cytokine, the ligand-binding receptor chain, and an accessory chain necessary for initiating signal transduction.

A number of the IL-1F cytokines have inflammatory activity, whereas others downregulate IL-1F-related inflammation either as receptor antagonist (inactive ligands) or by providing anti-inflammatory signals.

IL-1F cytokines have been known with different names, in the course of years, until a few years ago a new nomenclature has been proposed that has been readily adopted by the scientific community (Dinarello et al. 2010).

A summary of the information regarding the human cytokines is reported in Table 1.
IL-1 Family, Table 1

IL-1 family members

Name

Other names

Receptor

Accession number

Gene (hu)

Chr. (hu)

Functions

IL-1α

IL-1F1, EP, LAF, FAF, BAF, hematopoietin-1

IL-1R1, accessory chain is IL-1R3

UniProtKB/SwissProt: P01583.1

Extra accessions: Q53QF9, Q7RU02

www.ncbi.nlm.nih.gov/protein/P01583

IL1A

2q14

Proform cleaved by calpain in the cytoplasm unless bound and protected by IL-1R2. Pro-piece translocates to nucleus and binds chromatin and transcription factors. Proform upon myristoylation can insert in the plasma membrane and act as cell bound cytokine. Proform can be released upon cell death. Both proform and mature cytokine are biologically active as inflammatory factors

IL-1β

IL-1F2, EP, LP, MCF, LEM, LAF, FAF, BAF, catabolin

IL-1R1, accessory chain is IL-1R3

UniProtKB/SwissProt: P01584.2

Extra accession: Q53X59, Q53XX2, Q7M4S7, Q7RU01, Q96HE5, Q9UCT6

www.ncbi.nlm.nih.gov/protein/P01584

IL1B

2q14

Proform is inactive, is cleaved by caspase-1 within the inflammasome, and only the C-terminal part is released, by nonconventional secretion, as mature active cytokine. Proform released by dead cells can be cleaved by other enzymes and generate partially active cytokine. Mature cytokine is highly inflammatory. A number of inhibitory mechanisms regulate IL-1-initiated activation (soluble receptors, inhibitory receptors, receptor antagonists). Involved in several inflammatory diseases

IL-1Ra

IL-1F3, IRAP, IL-1ra, Anakinra

IL-1R1, no recruitment IL-1R3

UniProtKB/SwissProt: P18510.1

Extra accession: A8K4G1, Q14628, Q53SC2, Q7RTZ4, Q96GD6, Q9UPC0

www.ncbi.nlm.nih.gov/protein/P18510

IL1RN

2q14.2

Receptor antagonist for IL-1, it binds to IL-1R1 with high affinity and competes with agonist IL-1 molecules. Receptor conformational changes do not allow recruitment of the accessory IL-1R3 thereby preventing receptor-mediated cell activation. Intracellular forms have been described. Anakinra, the recombinant human IL-1Ra, is successfully used in clinic in a number of diseases

IL-18

IL-1F4, IGIF, IL-1γ, Iboctadekin

IL-1R5, accessory chain is IL-1R7

UniProtKB/SwissProt: Q14116.1

Extra accessions: O75599, Q6FGY3, Q6WWJ7

www.ncbi.nlm.nih.gov/protein/Q14116

IL18

11q22.2-q22.3

Cytokine important in the development of Th1 and NK differentiation and activity, in concert with IL-12, potent inducer of IFN-γ. Inflammatory activities have been described, but also a role in maintaining metabolic homeostasis. Iboctadekin, the recombinant human IL-18, is in clinical trial in anticancer combination therapies

IL-33

IL-1F11, NF-HEV, DVS27

IL-1R4, accessory chain is IL-1R3

UniProtKB/SwissProt: O95760.1

Extra accessions: B2R8L1, B4DJ35, B4E1Q9, D3DRI5, E7EAX4, Q2YEJ5

www.ncbi.nlm.nih.gov/protein/O95760

IL33

9p24.1

Proform is nuclear protein regulating gene expression and maintaining barrier functions. It acts as alarmin when released upon cell death. Cleaved extracellularly by different enzymes. Mature form orchestrates healing and repair processes

IL-36α

IL-1F6, FIL1, FILε, FIL1ε, IL-1ε

IL-1R6, accessory chain is IL-1R3

UniProtKB/SwissProt: Q9UHA7.1

Extra accessions: B2RAD9, Q53SR7, Q5BLR4, Q7RTZ8

www.ncbi.nlm.nih.gov/protein/Q9UHA7

IL36A

2q12-q14.1

Nonconventionally secreted protein with inflammatory activity. It binds to the same receptor complex IL-1R6/IL-1R3 as other IL-36 cytokines. Preferential expression in different cells/tissues mainly distinguishes it from the others

IL-36β

IL-1F8, IL-1H2, FIL1H, FILη, FIL1η, IL-1η

IL-1R6, accessory chain is IL-1R3

UniProtKB/SwissProt: Q9NZH7.1

Extra accessions: Q3MIH0, Q53SR6, Q7RTZ7, Q9UHA5

www.ncbi.nlm.nih.gov/protein/Q9NZH7

IL36B

2q14

Nonconventionally secreted protein with inflammatory activity. It binds to the same receptor complex IL-1R6/IL-1R3 as other IL-36 cytokines. Preferential expression in different cells/tissues mainly distinguishes it from the others

IL-36γ

IL-1F9, IL-1RP2, IL-1H1, IL-1E

IL-1R6, accessory chain is IL-1R3

UniProtKB/SwissProt: Q9NZH8.1

Extra accessions: Q56B91, Q6UVX7, Q7RTZ9

www.ncbi.nlm.nih.gov/protein/Q9NZH8

IL36G

2q12-q21

Nonconventionally secreted protein with inflammatory activity. It binds to the same receptor complex IL-1R6/IL-1R3 as other IL-36 cytokines. Preferential expression in different cells/tissues mainly distinguishes it from the others

IL-36Ra

IL-1F5, IL1Hy1, IL-1 L1, IL-1RP3, IL-1H3, FILδ, FIL1δ, IL-1δ, PSORP

IL-1R6, no recruitment IL-1R3, possible involvement IL-1R8

UniProtKB/SwissProt: Q9UBH0.1

Extra accessions: A8K2I4, Q56AT9, Q7RTZ6

www.ncbi.nlm.nih.gov/protein/Q9UBH0

IL36RN

2q14

Nonconventionally secreted protein. It binds to IL-1R6 and acts as receptor antagonist, preventing binding of agonist IL-36 molecules and not allowing recruitment of the accessory chain IL-1R3

IL-37

IL-1F7, IL-1RP1, IL-1H, IL-1H4, FIL1Z, FIL1ζ

IL-1R5, no recruitment IL-1R7, possible recruitment of IL-1R8, binding to soluble IL-18BP

UniProtKB/SwissProt: Q9NZH6.1

Extra accessions: B5BU97, Q56AP9, Q8TD04, Q8TD05, Q9HBF2, Q9HBF3, Q9UHA6

www.ncbi.nlm.nih.gov/protein/Q9NZH6

IL1F7

2q12-q14.1

Anti-inflammatory cytokine, produced as a long form that is cleaved by unknown mechanisms. Four human isoforms described, of which only two have a complete IL-1-like structure and are active. Expression of the four isoforms varies depending on the tissue. It binds to IL-1R5 with low affinity. Anti-inflammatory activity possibly involving IL-1R8

IL-38

IL-1F10, FIL1T, FIL1θ, IL-1θ, IL-1Hy2, FKSG75

IL-1R1, IL-1R6, IL-1R9

UniProtKB/SwissProt: Q8WWZ1.1

Extra accessions: Q53SR9, Q56AT8, Q7RTZ5, Q969H5, Q9BYX1

www.ncbi.nlm.nih.gov/protein/Q8WWZ1

IL1F10

2q13

Proform is processed and released by apoptotic cells. The mature cytokine functions by restricting inflammatory activation, whereas the proform induces it. Mature form binds to IL-1R1 and IL-1R9, proform binds to IL-1R6 and with lower affinity to IL-1R1 and IL-1R9

IL-1α

IL-1α is a prototypical member of the IL-1 family, which displays a dual role as intracellular transcriptional regulator and as extracellular inflammatory cytokine (Rider et al. 2013). In normal conditions, IL-1α is constitutively present in practically all nonhematopoietic cells as a long precursor protein. A nuclear localization sequence in the N-terminal domain mediates translocation of IL-1α to the nucleus and transcriptional control. It has been reported that intracellular IL-1α can increase inflammatory gene expression, but its full role as transcriptional regulator is still unknown. The full-length protein can bind to an intracellular form of the IL-1R2 and is thereby protected from cleavage. Full-length IL-1α can be glycosylated and bind extracellularly to the plasma membrane in a lectin-like manner. This membrane-associated IL-1α is biologically active as an inflammatory cytokine upon binding to IL-1R1 on nearby cells. Full-length IL-1α can be processed by calpain and by several other enzymes (including neutrophil elastase). The need for processing is not clear, because full-length IL-1α is active as extracellular cytokine. However, it has been reported that cleavage can increase the cytokine activity. Secretion of IL-1α takes place by unconventional mechanisms, most probably involving cell necrosis and degradation of the protecting IL-1R. IL-1α acts as an inflammatory cytokine similar with IL-1β, i.e. by binding to IL-1R1 on target cells and recruiting into the receptor complex the accessory chain IL-1R3. IL-1α activity can be inhibited by the IL-1R1 antagonist IL-1Ra and is effectively captured by the soluble form of IL-1R1. Conversely, both membrane and soluble IL-1R2 are less efficient in inhibiting IL-1α than IL-1β.

IL-1β

IL-1β is the major inflammatory and immunostimulatory cytokine of the IL-1 family (Joosten et al. 2013). As the majority of the cytokines of the family, IL-1β is produced as a long inactive precursor protein, which needs cleavage by a specific protease (caspase-1) for maturation and secretion. Secretion is unconventional and not fully clarified, but possibly including secretion or shedding of different types of vesicles. Secretion of IL-1β is often associated with cell death, since the same stimuli that induce IL-1β synthesis and secretion also induce caspase-1-dependent cell death. At variance with IL-1a, IL-1β is not constitutively present in cells and needs to be induced. However, stimuli that induce IL-1b gene expression are distinct from those inducing its maturation and secretion. Thus, the full-length IL-1β can be found in the cytoplasm, associated with microtubules of producing cells (Baldari and Telford 1989), as a “reservoir” of precursor cytokine ready to be cleaved and released.

Mature IL-1β binds to the IL-1R1 on target cells and activates them upon recruitment of the accessory chain IL-1R3. The activity of IL-1β is kept under strict control by a series of inhibitors, the soluble receptor antagonist IL-1Ra, which competes for IL-1R1, the membrane IL-1R2 that captures both IL-1β and IL-1R3 (Lang et al. 1998), the soluble IL-1R1 and IL-1R2, and IL-1R8 that blocks receptor signaling. Several other control mechanisms regulate signal transduction intracellularly. Upon binding, IL-1β is internalized and most likely undergoes degradation. However, a fragment of the cytokine, corresponding to one of the loops involved in receptor binding, was shown to possess receptor-independent immunostimulating activities without displaying inflammatory capacity (Boraschi et al. 1988). This fragment could translocate to the nucleus and associate with chromatin, leading to hypothesizing a postreceptor activation pathway.

Due to its potent inflammatory activity, IL-1β is involved in the pathology of many diseases. Clinical strategies to block IL-1β, in particular with Anakinra (the recombinant IL-1Ra drug), are yielding successful results (Dinarello and van der Meer 2013).

IL-1Ra

The IL-1 receptor antagonist IL-1Ra is the natural inhibitor of IL-1 activity, due to its capacity of binding to the IL-1R1 with high affinity, thereby efficiently competing with agonist IL-1. IL-1Ra has a structure very similar with that of IL-1 proteins, which makes it able to bind to IL-1R1, except for a loop between the fifth and the sixth β-strand, which does not allow binding in a specific position of IL-1R1 and consequently prevents the receptor structural changes necessary for engagement of the accessory chain IL-1R3 (Boraschi and Tagliabue 2013). IL-1Ra has lower affinity for the second IL-1 receptor IL-1R2, which is an inhibitory decoy receptor. Four isoforms of IL-1Ra have been described, one having a classical signal peptide and giving rise to the soluble extracellular IL-1-like molecule, and intracellual forms whose biological role is poorly understood (Arend and Guthridge 2000). A rare genetic condition called DIRA (deficiency of interleukin-1 antagonist) is lethal at early age if untreated and is characterized by massive sterile inflammation of skin, joints, and organs. Treatment with Anakinra, the recombinant IL-1Ra drug, prevents inflammation and the fatal outcome. Anakinra is presently used for a series of inflammatory diseases with excellent results (Dinarello and van der Meer 2013).

IL-18

IL-18 is a major inducer of IFNγ in T and NK cells, and has a central role, together with IL-12 and IL-15, in the activation of Th1 responses (Novick et al. 2013). IL-18 is produced as a biologically inactive full-length precursor that is cleaved by caspase-1 to produce the biologically active mature cytokine. However, the caspase-1-independent production of biologically active IL-18 has been also reported. In addition to its role in immunoregulation, through modulation of adaptive immune responses, IL-18 has been described as an important cytokine in many inflammatory conditions and diseases, from autoimmunity to chronic inflammation, renal failure, and heart disease (Boraschi and Dinarello 2006; Novick et al. 2013). IL-18 also has a protective role, since the lack of IL-18 worsens intestinal diseases, prevents mucosal healing, and induces metabolic syndrome and eye wet macular degeneration, and all these conditions are improved by exogenous supply of IL-18. IL-18 is active by binding to IL-1R5 and upon recruitment of the accessory chain IL-1R7. A soluble form of IL-1R5 possibly acts as inhibitor. The major inhibitor of IL-18 is however the IL-18 binding protein IL-18BP, a soluble protein with some similarities to a domain of receptors of the IL-1R family. Circulating and urinary levels of IL-18 and IL-18BP are generally increased during an ongoing inflammation or disease and with aging.

IL-33

IL-33 is a dual cytokine, with well described and clear roles both as full-length intracellular protein and as cleaved extracellular cytokine (Martin 2013; Martin and Martin 2016). In steady-state conditions, the full-length IL-33 protein is constitutively produced by endothelial and epithelial barrier cells, localizes to the nucleus and associates with chromatin. Full-length IL-33 modulates gene expression by different mechanisms, including modulation of higher-order chromatin structure, binding to a transcriptional repressor, sequestering NFκB, and transcriptionally regulating NFκB p65 expression. In all cases, the activity of full-length IL-33 is of downregulating inflammatory gene expression. During inflammation, the synthesis of IL-33 decreases, thereby allowing inflammatory gene expression. IL-33 lacks a signal peptide and its extracellular release occurs via yet unidentified mechanisms. Full-length IL-33 is biologically active as a cytokine, but its N-terminal cleavage by leukocyte proteases significantly increases its activity. Extracellular IL-33 binds to its specific receptor IL-1R4 and activates target cells upon recruitment of the accessory protein IL-1R3. Soluble IL-1R4 can inhibit IL-33 by capturing it and preventing its binding to the plasma membrane receptor. Extracellular IL-33 activates mast cells, Th2 cells, ILC2 cells, and other cell types that express the receptor, and is therefore involved in Th2-type inflammation and defense against multicellular parasites, and also in allergic reactions. IL-33 was found to be an important factor in maintaining barrier integrity and in tissue repair. Its presence has a protective role in cardiac diseases.

IL-36α, β, and γ

IL-36 cytokines are members of the IL-1 family that are synthesized as inactive proforms, activated upon cleavage of few N-terminal amino acids by still unidentified proteases, and released by unconventional and unknown secretion mechanisms (Towne et al. 2011). The mature forms bind to IL-36R and initiate cell activation upon recruitment of the common accessory chain IL-1R3 (Towne et al. 2004). Studies on the biological effects of IL-36 cytokines have been partially hampered by the fact that for many years only the full length recombinant cytokines have been studies, which had minimal/no effect. More recently, it turned out that the three cytokines have inflammatory activity and are associated with several diseases, from renal inflammation to arthritis, although their precise and mutual role is still a matter of investigation (Gresnigt and van de Veerdonk 2013). IL-36α is preferentially expressed in the skin, but in general all three cytokines have a rather restricted expression (brain, skin, bronchial epithelium, but also monocytes/macrophages and T lymphocytes). In addition to an inflammatory role, IL-36 apparently have the capacity of modulating T cell activation during inflammation in skin and epithelial surfaces.

IL-36Ra

The IL-36 antagonist IL-36Ra binds to IL-1R6 and does not allow recruitment of IL-1R3, thereby antagonizing the receptor-dependent activity of IL-36 cytokines (Towne et al. 2011). IL-36Ra acquires it activity after removal of the N-terminal methionine (Gresnigt and van de Veerdonk 2013). The features of the anti-inflammatory activity of IL-36Ra are not completely clear and seem to be different from those of IL-1Ra. In addition to dampening IL-36R-mediated inflammation, there are reports of IL-36- and IL-36R-independent effects. In the mouse brain, IL-36Ra could downregulate LPS-induced inflammation in a IL-4- and IL-1R8-dependent manner. Also, in glial cells in vitro IL-36Ra could induce IL-4 production (Costelloe et al. 2008).

IL-37

IL-37 was identified in silico by several groups as a member of the IL-1 family, due to its homology with IL-1 (reviewed by Boraschi et al. 2011). Five IL-37 isoforms have been described in humans (a, b, c, d, and e), generated by alternative splicing, of which two have a complete IL-1-like structure (a and b), while the others are truncated and possibly inactive. The two active forms a and b are different only at the N-terminal end, in a sequence that is expected to be cleaved upon maturation. Thus, the mature forms of IL-37a and IL-37b should be identical. Like other members of the family, IL-37 does not possess a signal peptide, and the N-terminus of the mature form has not been univocally identified (Boraschi et al. 2011; Dinarello and Bufler 2013). IL-37 binds to IL-1R5 with low affinity and is therefore unable to antagonize IL-18. Binding of IL-37 to IL-1R5 does not induce IL-18-like activation (e.g. production of IFN-γ), implying its inability to recruit IL-1R7 into an active receptor complex. Also, it has been reported that IL-37 can bind to IL-18BP. IL-37 has anti-inflammatory activity. It appears that its effects are mostly mediated by the C-terminal domain, allegedly generated by caspase-1 cleavage, that translocates to the nucleus and acts as transcriptional regulator, similarly to IL-1α and IL-33. Extracellularly the anti-inflammatory activity of IL-37 activity appears to need the presence of IL-1R8, which may act as accessory chain for the IL-37/IL-1R5 complex (Nold-Petry et al. 2015).

IL-38

IL-38 was identified as a member of the IL-1 family due to its high homology with other cytokines of the family (Lin et al. 2001). Like most of the other members of the family, IL-38 lacks a signal peptide and, unlike IL-1β and IL-18, it also lacks a caspase-1 cleavage site. An N-terminally processed form of IL-38 is released upon apoptosis (Mora et al. 2016). Due to its high homology with IL-1Ra, IL-38 was thought to be an IL-1 receptor antagonist, and indeed both the truncated form and, with lower affinity, the proform could bind to IL-1R1 (Lin et al. 2001; Mora et al. 2016). Also, it was found that the full-length IL-38 could bind IL-1R6 (van de Veerdonk et al. 2012). Binding to IL-1R9 was also described for the truncated form and, with lower affinity, for the full-length cytokine (Mora et al. 2016). IL-38 has anti-inflammatory activity, although this does not seem to depend on its ability to antagonize IL-1 or IL-36. Truncated IL-38 can inhibit the production of inflammatory cytokines induced by IL-1 in an IL-1R9-dependent manner (Mora et al. 2016), while the full-length cytokine could inhibit Th17 cytokines and responses elicited by C. albicans (van de Veerdonk et al. 2012). Conversely, full-length IL-38 was found to enhance the production of inflammatory cytokines induced by IL-1β, again in an IL-1R9-dependent fashion (Mora et al. 2016).

Summary

The IL-1 family includes eleven cytokines that share sequence homology, structure, receptor binding, and signaling mode. IL-1F cytokines are involved in inflammation, some of them as activators of inflammatory reactions, and other with anti-inflammatory or inflammation-inhibiting capacity. Most of the IL-1F cytokines are produced as precursor proteins that need cleavage by proteases and are secreted or released from producing cells by nonconventional mechanisms. The unprocessed full-length proteins can have an intracellular role as transcriptional regulators.

We can summarize the function of the IL-1F proteins as follows.
  • IL-1α in its intracellular full-length form is active as transcriptional regulator with inflammatory activity. In its membrane-bound form and in its soluble form it acts as inflammatory cytokine by binding IL-1R1 on target cells and forming an active receptor complex with IL-1R3.

  • IL-1β is a major inflammatory cytokine. The intracellular precursor is inactive and is cleaved by caspase-1 to give rise to the mature active cytokine, which is secreted. Similar with IL-1α, mature IL-1β activates target cells by binding to IL-1R1 and forming an active receptor complex with IL-1R3.

  • IL-1Ra is the receptor antagonist that blocks activation of IL-1R1 by the agonist ligands IL-1α and IL-1β and prevents engagement of IL-1R3. IL-1Ra has potent anti-inflammatory activity.

  • IL-18 is a cytokine with immunomodulatory, inflammatory, and homeostatic protective activity. It binds to IL-1R5 and engages IL-1R7 into an active receptor complex. It is inhibited by a soluble receptor-like molecule called IL-18BP.

  • IL-33 in its intracellular full-length form acts as a transcriptional regulator in anti-inflammatory direction. The mature form is secreted nonconventionally and binds to IL-1R4, forming an active receptor complex together with IL-1R3. IL-33 activates type 2 inflammatory responses and is involved in allergic reactions, but it also has a protective role in mucosal and other barriers of the body.

  • IL-36α, IL-36β, and IL-36γ are inflammatory cytokines, secreted nonconventionally, involved in a number of inflammatory conditions in skin and other organs. They bind to IL-1R6, and the receptor complex engages the accessory protein IL-1R3.

  • IL-36Ra is the receptor antagonist that binds IL-1R6 and competes with agonist IL-36. Its anti-inflammatory role is however more complex than simple receptor competition, and it could involve IL-1R8.

  • IL-37 is an anti-inflammatory cytokine that intracellularly, after cleavage, can act as transcriptional regulator in anti-inflammatory direction. After nonconventional secretion, extracellular IL-37 binds IL-1R5 but does not engage the accessory protein IL-1R7. IL-37 is not an antagonist of IL-18 and exerts its anti-inflammatory action with the contribution of IL-1R8.

  • IL-38 binds to IL-1R1, IL-1R6, and IL-1R9. It has anti-inflammatory activity, however independent of a possible antagonism with IL-1 or IL-36. The full-length and the truncated forms have different affinity for the different receptors and different activity, including exacerbation of inflammatory responses.

See Also

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Protein BiochemistryNational Research CouncilNaplesItaly