IL-1 Cytokine and Family Members

IL-1 Cytokine and Family Members

The IL-1 Cytokine

The cytokine, IL-1, has been the subject of copious research since it was first identified. This pro-inflammatory cytokine is known to play a dichotomous role in disease by inducing pathogenesis of auto-inflammatory disorders, while simultaneously defending against invading pathogens [1]. IL-1 is implicated in the development of numerous inflammatory diseases including ulcerative colitis. This has resulted in the mechanism behind IL-1 signalling becoming the subject of much interest. Likewise, novel members of both the IL-1 family of cytokines and the IL-1 receptor (IL-1R) family are also the focus of intense research in order to determine their involvement in the host response to disease. I will now discuss these cytokines and receptors in more detail, focusing specifically on the IL-33/ST2 and IL-36/ IL-36R pathways as these are the subject of this thesis.

IL-1 and IL-1R Family Members

The IL-1R/ toll-like receptor (TLR) superfamily consists of two subgroups: the IL-1R family whose members contain three extracellular immunoglobulin domains (Ig) and the Toll-like receptor subgroup whose members contain extracellular leucine-rich repeats. All family members share a similar intracellular Toll-IL1R (TIR) domain, which is required for binding of adaptor proteins. The IL-1 family is divided into three subfamilies based on the length of the N-terminal domain (Table 1). The IL-1 subfamily consists of IL-1αIL-1β, IL-1Ra and IL-33. The IL-18 subfamily is composed of IL-18 and IL-37, and finally the IL-36 subfamily contains IL-36αIL-36βIL-36γ, IL-36RN and IL-38.

The IL-1R family members are as follows; the type I IL-1 receptor (IL-1R1) [2], which binds IL-1α and IL-1β and was the first member of the family to be identified, the type II IL-1 receptor (IL-1R2) which is a decoy receptor, ST2 (IL-1RL1) which binds IL-33, and the IL-1Rrp2 (IL-36R), which binds three agonistic ligands, IL-36α, IL-36β and IL-36γ . Other IL-1R family members include the IL-1 receptor accessory protein (IL-1RAcP), which acts as a co-receptor for IL-1R, ST2 and IL-36R, the IL-18 receptor (IL-18Rα) [3] and its accessory protein (IL-18Rβ), and TIGIRR-2 (IL-1 receptor accessory protein like) and the three Ig domain-containing IL-1 receptor-related (TIGIRR-1) [4] . Single Ig-domain containing Il-1 receptor related (SIGIRR) is also a family member although it only possesses one Ig-domain extracellularly, similar to the IL-18BP. SIGIRR is considered an orphan receptor, and it also has regulatory activity.The IL-1 family of cytokines share a core tetrahedron-like structure composed of 12 β-strands [5]. This family consists of 11 members, of which seven are agonistic (i.e. IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ) and four are antagonistic (IL1Ra, IL-36Ra, IL-37 and IL-38). The genes encoding the IL-1 family cytokines cluster on human chromosome 2, with the exception of IL-33 and IL-18, which are located on chromosome 9 and 11, respectively. IL-1 family members form heterodimeric transmembrane receptor complexes and trigger signalling pathways that include the adaptor molecule MYD88IRAK kinase family members and the ubiquitin ligase TRAF6.

IL-1R Family Signalling

The receptor complex for each IL-1 family cytokine is a heterodimer with a specific receptor and a common subunit, usually the IL-1RAcP. Once the complex is formed, following interaction with its cognate ligand, the TIR domain of each receptor chain come together and recruit MyD88, followed by phosphorylation of IL-1R–associated kinases (IRAKs) and activation of TRAF6 (Figure 1). This pathway diverges to activate mitogen activated protein kinases (MAPKs) such as ERKJNK and p38 or to activate TAK1, which subsequently results in the translocation of NF-κB to the nucleus. However, not all IL-1 family receptors activate these pathways; e.g. SIGIRR is an inhibitory receptor, inhibiting IL-1, IL-18 and IL-33 signalling [6].

New Column New Column New Column New Column New Column New Column
Previously

called

Name
Receptor/

coreceptor

Property
Synthesized as precursor
Processing required for activity
IL-1F1
IL-1R1/

IL-1RAcP

Proinflammatory
Yes
No
IL-1F2
IL-1R1/

IL-1RAcP

Proinflammatory
Yes
Yes
IL-1F3
IL-1R1
Antagonist for IL-1α,β
No
No
IL-1F4
IL-18α/

IL-18β

Proinflammatory
Yes
Yes
IL-1F5
IL-1Rrp2
Antagonist for IL-36
Yes
Yes
IL-1F6
IL-1Rrp2/

IL-1RAcP

Proinflammatory
Yes
Yes
IL-1F7
IL-18Rα,IL-18BP
Anti-inflammatory
Yes
Yes
IL-1F8
IL-1Rrp2/

IL-1RAcP

Proinflammatory
Yes
Yes
IL-1F9
IL-1Rrp2/

IL-1RAcP

Proinflammatory
Yes
Yes
IL-1F10
IL-1Rrp2

Antagonist

Yes
No
IL-1F11
ST2/IL-1RAcP
Proinflammatory
Yes
No

Table 1: IL-1 family ligands and receptors The IL-1 family is divided into three subfamilies based on the length of the N-terminal pro-pieces. The IL-1 subfamily shown in green consists of IL-1α, IL-1β, IL-1Ra and IL-33. The IL-18 subfamily is composed of IL-18 and IL-37 shown in blue, and finally the IL-36 subfamily contains IL-36α, IL-36β, IL-36γ, IL-36Ra and IL-38 (purple). The TIR domain of each receptor chain comes together and recruits MyD88. IL-36Ra binds to IL-1Rrp2 but fails to form a complex with IL-1RAcP. Thus, IL-36Ra prevents the binding of IL-36α, IL-36β, or IL-36γ to IL-1Rrp2, and thus is the natural IL-36R antagonist.

Figure 1: IL-1R family signalling activates MAPK and NF-κB. The IL-1 subfamily consists of IL-1α, IL-β, IL-1Ra, and IL-33. The IL-18 subfamily is composed of IL-18 and IL-37. While IL-36α, IL-36β, IL-36γ, IL-36Ra and IL-38 all belong to the IL-36 subfamily. The receptor for each IL-1 family cytokine is a heterodimer composed of a specific receptor and a common co-receptor. The TIR domain of each receptor chain align and recruit MyD88, followed by phosphorylation of IL-1R–associated kinases (IRAKs), activation of TRAF6, and this pathway activates mitogen activated protein kinases (MAPKs). TAK1 can also be activated this results in the translocation of NF-κB to the nucleus. However, not all IL-1R family members activate these pathways. SIGIRR contains an altered TIR domain and inhibits IL-18 signalling.

IL-1α, IL-1β and the IL-1R Complex

The IL-1R1 is the best characterised receptor in the IL-1R superfamily. This 80kDa glycoprotein binds the agonists IL-1α and IL-1β, which have similar biological properties. However, there are some differences between these cytokines. The IL-1α precursor is fully active and found in epithelial layers throughout the gastrointestinal tract. It is released upon necrotic cell death to function as a cellular “alarmin” [7,]. IL-1α also contains a nuclear localization signal and localizes to the nucleus. In contrast, IL-1β is produced by haematopoietic cells such as macrophages and must be cleaved by caspase 1 to become active. Moreover, it has never been observed in the nucleus. In tumorigenesis another variation between IL-1α and IL-1β has been observed. IL-1β-deficient mice develop fewer tumours compared to IL-1α-deficient mice. IL-1β has also been shown to induce angiogenesis and enhance metastatic spread [8]. The IL1R antagonist (IL-1Ra) functions to block both IL-1α and IL-1β activity. The type II IL-1 R contains a truncated cytoplasmic domain lacking the TIR domain and therefore is unable to transduce a signal upon IL-1 ligation. It functions as a decoy receptor to negatively regulate IL-1 signalling [9].

The IL-18 Subfamily

The cytokine IL-18 was first recognised in 1995 as a potent inducer of IFN-γ. The receptor for this cytokine, the IL-18R, was identified as a member of the IL-1R family due to its homology to the IL-1R1, IL-1RAcP and ST2. The IL-18R shares the common conserved sequences found in all members of the IL-1R family. Similar to IL-1β, IL-18 is synthesized as an inactive precursor and requires activation by caspase-1 cleavage. The IL-18 precursor is constitutively expressed in most human and murine cells [10]. Once activated, IL-18 binds to the IL-18 α-chain (IL-18Rα) forming a signalling complex. The accessory protein IL-18R β-chain (IL-18Rβ) then associates to form a heterodimeric complex. The IL-18 binding protein (IL-18BP) is located in the extracellular compartment and regulates IL-18 activity by binding to mature IL-18 and preventing it from activating the IL-18R. IL-37 is also a member of the IL-18 family. The IL-18 precursor is structurally similar to the IL-37 precursor and IL-37 also binds to the IL-18R to inhibit signalling. IL-37 is an anti-inflammatory cytokines, similar to IL-10. IL-37 suppresses innate inflammation and immune responses in a number of ways, including by inhibiting DC activation at the cellular level.


References

  1. Sims, J.E., et al., cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily. Science, 1988. 241(4865): p. 585-9.
  2. Parnet, P., et al., IL-1Rrp is a novel receptor-like molecule similar to the type I interleukin-1 receptor and its homologues T1/ST2 and IL-1R AcP. J Biol Chem, 1996. 271(8): p. 3967-70.
  3. Born, T.L., et al., Identification and characterization of two members of a novel class of the interleukin-1 receptor (IL-1R) family. Delineation of a new class of IL-1R-related proteins based on signaling. J Biol Chem, 2000. 275(39): p. 29946-54.
  4. Lingel, A., et al., Structure of IL-33 and Its Interaction with the ST2 and IL-1RAcP Receptors—Insight into Heterotrimeric IL-1 Signaling Complexes. Structure, 2009. 17(10): p. 1398-1410.
  5. Qin, J., et al., SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated signaling through different mechanisms. J Biol Chem, 2005. 280(26): p. 25233-41.
  6. Chen, C.J., et al., Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med, 2007. 13(7): p. 851-6.
  7. Carmi, Y., et al., The role of IL-1beta in the early tumor cell-induced angiogenic response. J Immunol, 2013. 190(7): p. 3500-9.
  8. Colotta, F., et al., Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science, 1993. 261(5120): p. 472-5
  9. Puren, A.J., G. Fantuzzi, and C.A. Dinarello, Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1beta are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc Natl Acad Sci U S A, 1999. 96(5): p. 2256-61.

Cytokines and Growth Factors

6th Jul 2020 Charlotte O'Donnell PhD

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