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. 2005 Feb;114(2):166–170. doi: 10.1111/j.1365-2567.2005.02094.x

Interleukin-24 and its receptors

Mai Wang 1, Peng Liang 1
PMCID: PMC1782067  PMID: 15667561

Abstract

Interleukin 24 (IL-24) is a new member of the IL-10 family of cytokines and it signals through two heterodimeric receptors: IL-20R1/IL-20R2 and IL-22R1/IL-20R2. Upon binding to its receptors, IL-24 induces rapid activation of Stat-1 and Stat-3 transcription factors, which appear to play a role in cell survival and proliferation. Under physiological conditions, the major sources of IL-24 are the activated monocytes and T helper 2 cells, whereas the major IL-24 target tissues, based on the receptor expression pattern, are non-haematopoietic in origin, and include skin, lung and reproductive tissues. Structurally and functionally, IL-24 is highly conserved across species. This review highlights our current knowledge of IL-24 as a cytokine, with much less emphasis placed on the non-receptor-mediated functions (a subject of several reviews) focused on in much of the earlier literature on IL-24. The potential roles of IL-24 as part of a complex cytokine network in wound healing, psoriasis and cancer are discussed.

Keywords: IL-24, IL-20, mob-5, MDA-7

The discovery of interleukin-24 genes

In the era of molecular biology, a new gene is often discovered well before its biochemical and biological functions are known. This is certainly true for most of the new members of the interleukin (IL)-10 family of cytokines identified since 2000,1–3 including IL-24. The discovery of IL-24 followed four routes in different biological contexts. In the mid-1990s, Paul Fisher's group at Columbia University identified a gene by subtraction hybridization, which they called mda-7 (melanoma differentiation-associated protein 7).4 By using cDNA libraries prepared from a human melanoma cell line, in the presence or absence of treatment with both interferon-β and mezerein [which is a protein kinase C (PKC) activator], mda-7 was identified as one of the genes induced by treatment thought to cause terminal cell differentiation.4 While looking for gene expression changes during tissue repair by using a rat skin wound healing model, Soo and colleagues at UCLA used differential display (DD) and identified a gene whose expression was dramatically induced during the wound healing process; they named the gene c49a.5 At about the same time, the laboratory led by Peng Liang at Vanderbilt University reported the identification of mob-5 – a gene induced by ras oncogenes in rat embryonic fibroblasts – and showed that this gene encodes a cytokine-like secreted protein.6 It became apparent that c49a and mob-5 were, in fact, the same gene, which is highly homologous in amino acid sequence to the human gene mda-7 (Table 1). Although it was noted that MDA-7 had a putative signal peptide sequence, the protein was thought to be an intracellular protein based on data from in vitro transcription/translation as well as immunostaining.4 The first experimental evidence showing that MDA-7 and MOB-5 were secreted cytokine-like proteins came when the proteins and their derivatives tagged with human placental alkaline phosphatase (AP-TAG) were found in the culture media of cells over-expressing the genes.6 The murine homologue (fisp) of c49a/mob-5 was identified by representational difference analysis (RDA) at Tularik Inc., as an IL-4-induced gene that encodes a secreted protein selectively expressed by the T helper 2 (Th2) cell lineage.7 MDA-7 was renamed as IL-24 in 2002 after the discovery of its cell-surface receptors.8

Table 1. Conservation of the interleukin (IL)-24 primary sequence across species.

Amino acid sequence homology
Gene Species Alternative name MDA-7 Mob-5 FISP
hIL-24 Human MDA-7 100% 68% 69%
rIL-24 Rat MOB-5, C49A 68% 100% 93%
mIL-24 Mouse FISP 69% 93% 100%
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h, human; m, murine; r, recombinant.

Conservation of IL-24 across species

IL-24 proteins across species are highly homologous in amino acid sequence (Table 1). Without counting the divergent signal peptide sequences,7 the homology in mature cytokine sequences across species could be much higher. This high degree of cross-species homology is typical for other known cytokines, which is in contrast to a 20–30% homology among all members of the IL-10 family of cytokines.1–3 The mature IL-24 from both rat and mouse, when expressed by HEK-293 cells, has a molecular weight (MW) of ≈ 23 000,6,7 whereas the secreted human IL-24 has an MW of 33 000.8 The higher than predicted MW for the human IL-24 was shown to be a result of asparagine-linked (N-linked) glycosylation of the cytokine.8 However, the differential glycosylation between rodent and human IL-24 had little effect on receptor binding and activation.9 The rodent IL-24 can bind to and activate the human IL-24 receptors.9

The rodent and human IL-24 genes are highly homologous not only at the level of cDNA and protein sequences, but also at the genomic loci within the gene cluster of the IL-10 family of cytokines and their exon–intron organizations.9 The human IL-24 gene has been located to chromosome 1, within a 195-kb cytokine cluster containing four genes, comprising IL-10, IL-19, IL-20 and IL-24 in linear order.10 The rat IL-24 gene is located on chromosome 13q13, with the same gene cluster arrangement as the human IL-10 family of cytokines.9 Comparison between human and rodent IL-24 genes revealed that they share a very similar exon size and organization, except for exon 2 of the human IL-24 gene, which encodes the signal peptide.9 The size of exons 3–5 and the coding region of exon 6 in the rodent IL-24 gene are identical to exons 4–6 and the coding region of exon 7 in the human IL-24 gene, which encode the corresponding amino acids based on protein alignment.9

IL-10 family of cytokines and discovery of IL-24 receptors

IL-10 was discovered over a decade ago as a potent immuno-modulator capable of eliciting a wide range of cellular effects, notably to inhibit the production of pro-inflammatory cytokines.11 Recently, two more members of the IL-10 family of cytokines – IL-20 and IL-22 – and their receptors have been identified largely by a bioinformatical approach.12–14 IL-20 and IL-22 share 20–30% homology to each other and to IL-10. While IL-22 is linked to acute-phase protein production in hepatoma cells and in inflammation,15,16 IL-20 appears to be involved in epidermal functions.12 IL-20 transgenic mice die soon after birth and exhibit psoriasis-like skin as a result of hyper-proliferation, as well as abnormal differentiation of the epidermis.12 Based on the knowledge that IL-24 shares a 20–30% amino acid homology to IL-10, IL-20 and IL-22, two functional heterodimeric receptors for IL-24 (IL-20R1/IL-20R2 and IL-22R1/IL-20R2; Fig. 1) were identified through biochemical approaches by using the ligand affinity-tagged to the secreted human placental alkaline phosphatase (IL-24-AP).8 The same IL-24 receptors were also independently assigned by using ligand-dependent STAT (signal transducer and activator of transcription) activation as a readout for receptor activation.17 Although the four members of the IL-10 family of cytokines share only 20–30% sequence homology among each other, their extensive receptor subunit sharing and swapping provides unmistakable evidence for their grouping (Table 2). Now there are total of at least six members of the IL-10 family of cytokines, with IL-19 and 26 being added to the list (Table 2).17–19 IL-24, like the rest of the IL-10 family of cytokines, signals through its corresponding heterodimeric receptors, consisting of R1 (with a long cytoplasmic tail) and R2 (with a short cytoplasmic tail) receptor subunits (Table 2). Of particular interest is the fact that both IL-24 and IL-20 can bind to [with similar affinity (Kd = 2–8 nm)8,12] and signal through two heterodimeric receptors, one being a novel heterodimer, IL-22R1/IL-20R2, the other being the known IL-20 receptor (IL-20R1/IL-20R2)12,20 (Table 2). Binding of IL-24 to both receptors leads to the activation of Stat1 and Stat3,8,17 similarly to other members of the IL-10 family of cytokines.21

Figure 1.

Figure 1

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Schematic diagram of interleukin (IL)-24 binding to its two receptors (IL-20R1/IL-20R2 and IL-22R1/IL-20R2).

Table 2. Known ligands/heterodimeric receptors of the interleukin (IL)-10 family.

R1/R2 IL-10R2 IL-20R2
IL-10R1 IL-10 ?
IL-20R1 IL-26 IL-19, IL-20, IL-24
IL-22R1 IL-22 IL-20, IL-24
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Expression pattern of IL-24 and its receptors

IL-24 expression was detected in some cultured melanocytes,4 in peripheral blood mononuclear cells (PBMC) activated by concanavalin A (ConA),8,22,23 phytohaemagglutinin (PHA)23 or IL-4 plus lipopolysaccharide (LPS),24 in splenocytes stimulated with IL-4 plus anti-IL-12 to undergo Th2 differentiation7 and in certain differentiation inducer-treated tumour cells.10 Like other members of the IL-10 family, IL-24 was found to be expressed by the activated Th2 cells.7 Specifically, activation of the T-cell receptor (e.g. by anti-CD3) via stimulation with PKC and IL-4 appeared to be required for the induction of IL-24 expression by the activated Th2 cells.7 IL-24 expression was also detected by reverse transcription–polymerase chain reaction (RT–PCR) in activated T cells and monocytes stimulated with LPS alone,24,25 although an earlier study carried out under similar experimental conditions failed to detect IL-24 secretion by immunoassay.8 Expression of the IL-24 gene in vivo was greatly increased at the edge of excisional skin wounds 12 hr to 5 days after wounding, and the expression gradually returned to baseline levels by 14 days.5 As elevated expression of the gene occurred before and during the proliferation phase of repair, it appears that IL-24 may be involved in cell proliferation.5 IL-24 was also identified as an immediate target gene of oncogenic ras.6 Expression of IL-24 could be induced by both oncogenic h-ras and k-ras in rat embryonic fibroblasts (Rat1) and rat intestinal epithelial (RIE) cells through a mitogen-activated protein (MAP) kinase-dependent pathway.6 IL-24 was also found to be over-expressed in colorectal cancers with microsatellite instability.26 In psoriatic skin lesions, IL-24 expression was found in the infiltrating monocytes in the dermis.27

In contrast to the IL-10 receptor (IL-10R1/IL-10R2), which is constitutively expressed by most haemopoietic cells,11 constitutive expression of the IL-24 receptors (IL-20R2 with at least one of the R1 receptor chains) was not found in the haemopoietic cells tested.12,25 Although IL-20R1 and IL-22R1 receptor chains are widely expressed, expression of the IL-24 receptor appears to depend on the restrictive expression of IL-20R2 in certain non-haemopoietic tissues, including skin, lung, testis and ovary, implicating a pleotropic role of IL-24 outside the haemopoietic system.12 Keratinocytes not only express IL-24 receptors, but can also be activated by IL-24.8,9,12 Over-expression of IL-24 receptors has been noted in the epidermis of psoriatic skin,12,27 suggesting a potential link between the over-activation of IL-24 or IL-20 (which share the same receptors) signalling pathways and disease. Ras oncogenes are able to induce both IL-246 and expression of its receptor.9

Biological functions of IL-24

Although the precise biological functions of IL-24 remain to be determined, it is clear from the current literature that IL-24 can function either through its cell-surface receptors as a classical cytokine,8,9 or intracellularly as a cytototoxic agent, in a non-receptor-mediated manner, to certain cancer cells.28 The latter, in fact, comprise the bulk of the published IL-24 (MDA-7) literature mainly from three groups of scientists (Columbia University, Introgen Therapeutics and the M.D. Anderson Cancer center) who collaborate directly or indirectly in the hope that IL-24 can be an anti-cancer drug, through adenovirus-mediated gene therapy.29–31 As this apparently non-physiological function of IL-24 is not dependent on the activation of the IL-24 receptor28 and has been a subject of several recent reviews,32,33 here we shall focus mainly on the receptor-mediated functions of IL-24. But, before doing so, one clarification must be made to the functional definition of IL-24. In the ignorance of MDA-7 being a secreted cytokine, the gene was touted as a ‘tumour-suppressor’ based on the findings that, when ectopically expressed, it could cause either growth arrest or apopotosis of cancer-derived cells, but not of any normal cells.23,34–36 However, there has been absolutely no evidence that MDA-7/IL-24 can be justified as a tumour suppressor (like p53, RB pTen), as no loss-of-function mutations, loss of heterozyocity (LOH) or germline mutations in the gene, which define a tumour suppressor, have been found or linked to any tumour phenotype in humans or animals.

Based on the expression pattern of IL-24 and of its receptor in vivo, one of the major physiological functions of the IL-24 signalling pathway appears to concern epidermal functions, such as wound healing,5 and its abnormality may contribute to pathological skin conditions such as psoriasis.12,27 The finding (based on receptor expression and ligand-mediated activation) that keratinocytes from the epidermis are one of the major IL-24 target cells, seems to support this prediction.8,9,12 Under pathological skin conditions, such as psoriasis, infiltrating monocytes that migrate to the dermal layer directly beneath the psoriatic epidermis appears to be the source of IL-24 production.27 Thus, constitutive production of IL-24 by the infiltrating monocytes in the dermis may lead to persistent receptor activation and cell proliferation by the nearby keratinocytes in the epidermis, leading to the development of psoriasis. One puzzle surrounding the redundancy in receptor utilization by IL-24, IL-19 and IL-20 has been whether these cytokines induce identical signals downstream, or whether they compete for the same receptors for a different biological end-point. Much of this could depend on where and when the cytokines and their receptors are expressed. It is interesting to note that in psoriasis, while the expression of IL-19 and IL-20 becomes constitutive in the epidermis, IL-24 is produced by the infiltrating monocytes in the dermal layer beneath the psoriatic lesions.27 Therefore, persistent activation of both autocrine (for IL-19 and IL-20) and paracrine (for IL-24) loops may be involved in the development and maintenance of the disease. In vitro, IL-3-dependent murine proB cells can not only survive but also proliferate in the presence of IL-24 in an IL-24 receptor-dependent manner,9,20 suggesting that IL-24 can function as a survival (anti-apoptotic) or a growth factor. Ras oncogenes can induce not only IL-24,6 but also expression of its receptor,6,9 suggesting that either a paracrine or an autocrine loop of IL-24 may contribute to the survival and proliferation of tumour cells. In contrast, IL-24 was shown to have either growth-inhibitory or apoptotic effects on certain IL-24 receptor-negative and -positive cells when expressed intracellularly or added to the culture media,20 but the effects appeared to be independent of IL-24 receptor activation.20,28,36 However, contradictory findings were recently reported, which showed that intracellularly expressed IL-24 was anti-apoptotic through the sensitization in nuclear factor-κB (NF-κB) activation by tumour necrosis factor-α (TNF-α),37 which appears to be more consistent with findings from studies of the receptor-mediated effects of IL-24.9,20

IL-24 can induce expression of other cytokines, such as TNF-α, IL-6 and interferon-γ (IFN-γ), by PBMC,23 suggesting that IL-24 may be a member of a complex cascade of cytokines involved in inflammation. IL-24 was recently shown to be able to inhibit angiogenesis by endothelial cells in a receptor-dependent manner,38 although no receptor expression was clearly demonstrated in these cells. Curiously, the kinetics of stat-3 activation by IL-24, which occurs within minutes instead of hours, as shown in the angiogenesis study,38 seemed to suggest an indirect effect of IL-24 receptor activation.

Future directions

Transgenic models for IL-24, when available, will certainly help to achieve a much better understanding of the function of IL-24. It will be interesting to determine whether IL-24 transgenic mice have phenotypes similar to those of IL-20 transgenic mice, which showed hyper-proliferation of the epidermis and postnatal lethality.12 Although IL-24 shares two heterodimeric receptors with IL-19 and IL-20, the R2 subunit of the receptors, namely IL-20R2, is shared by both and is absolutely required for receptor activation.8,9,12,17,20 Thus, IL-20R2 knockout mice should yield much needed information regarding the biological functions of all three cytokines.

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