Interleukin-1 Superfamily


The Interleukin-1 (IL1) superfamily refers to the larger group of cytokine sub-families including IL 1, IL 18, and IL 33. Unlike other cytokine families, the IL 1 superfamily exerts control over inflammation and immune response at both the receptor and nuclear level while its cytokines and receptors are related by mechanism of origin, receptor structure, and signal transduction.

To date, there exist up to 11 different members in IL 1 superfamily. The details are in the following table. These proteins are divided into three subfamilies, including Interleukin-1 Family, Interleukin-18 Family and Interleukin-33 Family.

 

IL1 Superfamily members

Old Name

New Name

Property

IL1F1

IL1α

Agonist

IL1F2

IL1β

Agonist

IL1F3

IL1Ra

Receptor Antagonist

IL1F4

IL18

Agonist

IL1F5

IL36Ra

Receptor Antagonist

IL1F6

IL36α

Agonist

IL1F7

IL37

Anti-inflammatory

IL1F8

IL36β

Agonist

IL1F9

IL36γ

Agonist

IL1F10

IL38

Receptor Antagonist

IL1F11

IL33

Agonist

 

Interleukin-1 Family

The IL 1 cytokine family consists of two agonists, IL1α and IL1β, a receptor agonist, IL1Ra, and two receptors, IL 1RI and IL 1Racp, which play an important role in host resistance against microorganism and are an important part of the innate immune system. A variety of pro-inflammatory mediators induce the transcription of cytokines of the IL 1 family including pattern-associated molecular patterns (PAMP) such as lipopolysaccharide (LPS) and pro-inflammatory cytokines such as Tumor Necrosis Factors-α (TNFα), Interferon-α (IFNα) and IFNβ. Unlike other cytokines, IL 1 family agonist cytokines do not stimulate the immune response directly but indirectly through other cytokines and effector proteins that are upregulated with increasing levels of these agonists. The role of IL 1 cytokines in autoinflammatory diseases is predominantly caused by either excessive IL 1β production or IL1Ra deficiencies.

 

Interleukin-18 Family

The Interleukin-18 (IL 18) family is involved in both innate and adaptive immune responses and in many ways analogous to the IL1 family. The IL18 family is comprised of an agonist, IL 18, an antagonist, IL18 Binding Protein (IL18BP), and two receptors, IL 18Rα and IL 18Rβ. An additional putative member of the IL18 family, IL1F7B, has been identified through EST screening having putative antagonist activities but the information as to its role in the IL18 family remains unclear. The high level of IL18 in tissues have a pleiotropic effect on immune cells with the sustained production of IFN-γ and increased cytotoxicity of Natural Killer (NK) cells resulting in tissue damage and necrosis.

 

Interleukin-33 Family

The Interleukin-33 (IL 33) family is principally involved in Th2-mediated immune responses such as asthma, allergy-induced inflammation, and parasitic infections. The IL33 family, to date, is only comprised of an agonist, IL33, and one receptor (IL33Rα/ T1/ST2) while using IL1Racp of the IL1 family as a co-receptor to initiate signaling.

 

IL1 family receptors

IL1 family members signal through a group of homologous receptors which are defined by the presence of an intracellular Toll/IL1 receptor (TIR) cytoplasmic domain that is involved in the initiation of the intracellular signaling cascade and an extracellular portion comprised mainly of immunoglobulin domains. The TIR superfamily is a key to host innate defense against infection, inflammation, injury, and stress. The TIR superfamily shares a common intracellular signaling pathway that is found in both invertebrates and vertebrates.

 

IL12 receptors