The name "interleukin" first appeared in the mid-1980s, but scientists had already been studying these molecules well before that. Take IL-1 as an example: before it was officially named, it had been studied under various names such as leukocyte endogenous mediator, hematopoietin 1, endogenous pyrogen, catabolin, and osteoclast-activating factor. These names reflect the diverse biological functions of IL-1.

Over time, more members of the interleukin family were discovered. To date, the IL family is known to have 11 members: IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18, IL-33, and IL-1F5 through IL-1F10. These proteins are likely derived from a common ancestral gene, as their gene structures are highly conserved, including identical positions of certain introns and the retention of key amino acid sequences that allow each protein to fold into a 12-stranded β-barrel structure.

Interestingly, except for IL-18 and IL-33, all the genes encoding IL family members are located within a 400kb region on human chromosome 2. This gene clustering supports the hypothesis that they share a common origin.

Figure 1. Figure 1. Timeline of key IL-1 discoveries, highlighting major findings (A) before and (B) after IL-1 cloning, with key references. (Dinarello CA. et al., 2010)

Structure and Secretion of IL-1 Family Members

While all IL family members are extracellular proteins, only the gene for IL-1Ra (IL1RN) encodes a classical signal peptide that allows it to be secreted via the endoplasmic reticulum and Golgi apparatus. The secretion mechanisms for the other IL family members remain a mystery.

IL-1β and IL-18 have an N-terminal pro-domain that must be cleaved by a protein complex called the inflammasome to generate biologically active forms for secretion. IL-1α also has a pro-domain, which can be cleaved by the cysteine protease calpain, though this cleavage is not necessary for its biological activity.

IL-1F5, IL-1F6, IL-1F8, IL-1F9, and IL-33 are biologically active as full-length molecules, although their activity is weaker than that of forms lacking the full N-terminus. The inflammasome does not process these molecules.

Receptors and Signaling Pathways of IL-1 Family Members

IL family members signal through a group of closely related receptors. Many of the genes encoding these receptors are also clustered in a small region of human chromosome 2. These receptors contain extracellular immunoglobulin domains and intracellular Toll/IL-1 receptor (TIR) domains.

For example, when IL-1 binds to its primary receptor subunit (IL-1 receptor type 1, IL-1R1), it recruits a second receptor subunit (IL-1 receptor accessory protein, IL-1RAP). The formation of this receptor heterodimer initiates signaling, as the juxtaposition of the two TIR domains allows for the recruitment of adaptor proteins such as MyD88, IRAK4, and TRAF6. The resulting biological response often involves the activation of the NF-κB and MAPK pathways.

IL-1α and IL-1β: Key Regulators of Inflammation

IL-1α and IL-1β were the first members of the IL family to be discovered and studied. Although they signal through the same receptor complex and share the same biological activities, they differ significantly in several aspects:

Distribution: IL-1β is secreted and circulates systemically, while IL-1α is typically membrane-bound and acts locally.

Source of Production: IL-1β is mainly produced by monocytes and macrophages, whereas IL-1α is expressed more broadly, including by keratinocytes and endothelial cells.

Gene Regulation: These genes are differentially regulated during development and in response to environmental stimuli, leading to distinct functional roles in immune responses. For instance, IL-1α plays a critical role in T cell activation during contact hypersensitivity, while IL-1β is crucial for inducing fever.

Intracellular Function: IL-1α's pro-domain contains a nuclear localization sequence, and nuclear IL-1α has intrinsic transcriptional transactivation activity, influencing gene expression and cell survival.

Due to their potent and widespread functions, the biological activities of IL-1α and IL-1β are tightly regulated. Under normal conditions, their expression is low and requires induction at the transcriptional and translational levels. Their processing and secretion are also regulated, with loss of control leading to syndromes characterized by fever, rash, and arthritis.

Figure 2. IL-1α and IL-1β interactions in tumor sites. (Apte RN, et al., 2017)

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IL-18: A Promoter of TH1 Responses

Macrophages, dendritic cells, and epithelial cells such as keratinocytes primarily express IL-18. Unlike IL-1, the precursor form of IL-18 is constitutively expressed but requires cleavage by caspase-1 for activation. IL-18's activity is regulated by a soluble IL-18 binding protein (IL-18BP), which is distantly related to IL-1 receptors.

IL-18 plays a key role in promoting TH1-type immune responses by stimulating T cells and NK cells to produce interferon-gamma (IFN-γ), thus enhancing cell-mediated immunity. In addition, IL-18 can synergize with IL-12 to enhance TH1 cell differentiation.

IL-33: A Key Regulator of TH2 Responses

IL-33 is a recently discovered IL family member that, unlike others, is typically not expressed by hematopoietic cells but abundantly expressed in various tissues. IL-33 was initially described as a nuclear protein, particularly prominent in high endothelial venules, and its cytokine activity was discovered later.

The N-terminal pro-domain of IL-33 contains a helix-turn-helix motif, characteristic of DNA-binding proteins. In its nuclear form, IL-33 interacts with histones 2A and 2B in heterochromatin, acting as a transcriptional repressor by promoting chromatin compaction.

IL-33 exerts its function by binding to the ST2 receptor (also known as IL-1RL1). The IL-33-ST2 complex recruits a shared receptor subunit, IL-1RAP, to initiate signaling. Soluble forms of ST2 can bind IL-33, inhibiting its activity.

IL-33 plays a pivotal role in innate allergic immune responses and enhances TH2 immune reactions. It directly acts on eosinophils, mast cells, and basophils, promoting their survival, adhesion, and cytokine production. Additionally, IL-33 enhances TH2 cell differentiation, contributing to immune responses against allergic diseases and parasitic infections.

Other Members of the IL Family

IL-1F5, IL-1F6, IL-1F8, and IL-1F9: These four members interact with the same receptor, IL-1RL2. They are highly expressed in the skin and other tissues, with their expression strongly induced in monocytes. IL-1F6, IL-1F8, and IL-1F9 activate NF-κB and MAPK, similar to IL-1, IL-18, and IL-33. IL-1F5 acts as an antagonist, binding IL-1RL2 and blocking the binding of agonistic ligands and recruitment of IL-1RAP.

IL-1F7: IL-1F7 is the only IL family member without a mouse homolog. It has several splice variants, with IL-1F7b being the most biologically relevant. IL-1F7 primarily functions as an intracellular negative regulator, inhibiting the production of pro-inflammatory cytokines after LPS stimulation. It interacts with the TGFβ signaling protein SMAD3, possibly mediating its inhibitory effect on cytokine secretion through this interaction.

IL-1F10: Little is known about IL-1F10. It is expressed in the basal epithelium of the skin and proliferating B cells in the germinal centers of tonsils. Its gene structure and amino acid sequence suggest a closer relationship to IL-1Ra and IL-1F5, rather than to other family members, hinting that it may have antagonistic functions.

Regulatory Role of SIGIRR in IL-1R Family

SIGIRR (single immunoglobulin IL-1R-related molecule, also known as TIR8) is another important member of the IL-1R family. It is predominantly expressed by epithelial cells and regulates signaling for IL-1, IL-18, IL-33, IL-1F6, IL-1F8, and IL-1F9, as well as Toll-like receptor (TLR) signaling. In the absence of SIGIRR, responses to IL family members are enhanced.

SIGIRR inhibits IL-1 signaling and suppresses the development of TH17 cells. Mice lacking SIGIRR exhibit more severe symptoms in models of inflammatory bowel disease and asthma, experience higher levels of liver necrosis and mortality after Mycobacterium tuberculosis infection, and are more susceptible to colon cancer due to excessive inflammatory responses.

In summary, members of the IL family play multiple roles in the immune system, both by being produced by innate immune cells and by regulating these cells in return, forming complex feedback networks.