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Originally published online as doi:10.1189/jlb.0204117 on May 3, 2004

Published online before print May 3, 2004
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(Journal of Leukocyte Biology. 2004;76:314-321.)
© 2004 by Society for Leukocyte Biology

The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain

Raymond P. Donnelly*,1, Faruk Sheikh*, Sergei V. Kotenko{dagger} and Harold Dickensheets*

* Division of Therapeutic Proteins, Center for Drug Evaluation & Research, Food and Drug Administration, Bethesda, Maryland; and
{dagger} Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, Newark

1Correspondence: FDA-CDER, Division of Therapeutic Proteins, HFM-538, 1401 Rockville Pike, Rockville, MD 20852. E-mail: donnelly{at}cber.fda.gov


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE IL-10R COMPLEX
 THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
 NOTE
 REFERENCES
 
Several novel interleukin (IL)-10-related cytokines have recently been discovered. These include IL-22, IL-26, and the interferon-{lambda} (IFN-{lambda}) proteins IFN-{lambda}1 (IL-29), IFN-{lambda}2 (IL-28A), and IFN-{lambda}3 (IL-28B). The ligand-binding chains for IL-22, IL-26, and IFN-{lambda} are distinct from that used by IL-10; however, all of these cytokines use a common second chain, IL-10 receptor-2 (IL-10R2; CRF2-4), to assemble their active receptor complexes. Thus, IL-10R2 is a shared component in at least four distinct class II cytokine-receptor complexes. IL-10 binds to IL-10R1; IL-22 binds to IL-22R1; IL-26 binds to IL-20R1; and IFN-{lambda} binds to IFN-{lambda}R1 (also known as IL-28R). The binding of these ligands to their respective R1 chains induces a conformational change that enables IL-10R2 to interact with the newly formed ligand-receptor complexes. This in turn activates a signal-transduction cascade that results in rapid activation of several transcription factors, particularly signal transducer and activator of transcription (STAT)3 and to a lesser degree, STAT1. Activation by IL-10, IL-22, IL-26, or IFN-{lambda} can be blocked with neutralizing antibodies to the IL-10R2 chain. Although IL-10R2 is broadly expressed on a wide variety of tissues, only a subset of these tissues expresses the ligand-binding R1 chains. The receptors for these cytokines are often present on cell lines derived from various tumors, including liver, colorectal, and pancreatic carcinomas. Consequently, the receptors for these cytokines may provide novel targets for inhibiting the growth of certain types of cancer.

Key Words: IFN-{lambda} • STAT3/STAT1 • hepatocytes • 1SGF3 • IL-22BP


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE IL-10R COMPLEX
 THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
 NOTE
 REFERENCES
 
Several comprehensive reviews have been published in recent years regarding the interleukin (IL)-10 signal-transduction pathway and the biological activities that are induced by signaling through IL-10 receptors (IL-10Rs) [1 , 2 ]. In this overview, we will briefly summarize the sequence of events by which binding of IL-10 to the IL-10R complex leads to the induction of gene expression in macrophages. However, the primary focus of this overview will be to discuss the role of the IL-10R2 chain as a shared component in the receptor complexes for several novel IL-10-related cytokines. These include IL-22, IL-26, and the interferon-{lambda} (IFN-{lambda}) proteins IFN-{lambda}1 (IL-29), IFN-{lambda}2 (IL-28A), and IFN-{lambda}3 (IL-28B).

The IL-10R2 chain was originally shown by Kotenko et al. [3 ] to be an essential component of the IL-10R complex. IL-10 initially binds to its specific ligand-binding chain IL-10R1 [4 ]. Once IL-10 is bound to IL-10R1, IL-10R2 is required to assemble the active IL-10R complex. Ligand-mediated assembly of the IL-10R1 and IL-10R2 chains catalyzes rapid activation of signal transducer and activator of transcription (STAT)3 and induction of STAT3-responsive genes. For several years, it was assumed that IL-10R2, like IL-10R1, is a unique component of the IL-10R complex. However, it is now clear that the IL-10R2 chain is used for signaling by several other class II cytokines, including IL-22, IL-26, and the IFN-{lambda} proteins. Therefore, the IL-10R2 chain is a common component of the functional receptor complexes for multiple class II cytokines.


   THE IL-10R COMPLEX
TOP
 ABSTRACT
 INTRODUCTION
 THE IL-10R COMPLEX
THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
 NOTE
 REFERENCES
 
IL-10 was originally identified as a soluble factor produced by activated murine CD4+ T helper-type 2 (Th2) cells, which can inhibit production of cytokines such as IL-2 and IFN-{gamma} by Th1 cells [5 ]. Shortly thereafter, it was determined that the ability of IL-10 to inhibit cytokine production by T cells was indirectly mediated via its inhibitory effects on antigen-presenting cells (APC) such as monocytes, macrophages, and dendritic cells (DC) [6 , 7 ]. Therefore, IL-10 acts directly on APC to inhibit expression of costimulatory surface molecules such as major histocompatibility complex (MHC) class II and B7 as well as cytokines that are necessary for optimal T cell activation [8 , 9 ]. By inhibiting expression of these molecules by APC, IL-10 indirectly suppresses activation of T cells and production of T cell-derived cytokines such as IFN-{gamma} and IL-2. In addition to its effects on APC, IL-10 can exert direct effects on B and T lymphocytes (CD4+ and CD8+), natural killer (NK) cells, mast cells, and eosinophils. For example, IL-10 is a potent growth factor for activated B cells [10 ] and can prevent activation-induced apoptosis in T cells [11 ]. Although IL-10 primarily inhibits T cell activation via its inhibitory effects on APC, T cells express IL-10Rs, and IL-10 can act directly on T cells to inhibit production of certain cytokines, particularly IL-2 [12 , 13 ].

The ligand-binding chain of the IL-10R complex, IL-10R1, was first reported in 1993 [4 ]. The cDNA for the mouse IL-10R1 gene was isolated from cDNA libraries prepared from a murine mast cell line, MC/9, and a murine macrophage cell line, J774. Expression of these cDNAs in COS-7 cells generated an IL-10R protein (~110 kDa), which bound radiolabeled IL-10 with an affinity comparable to that previously shown for native IL-10Rs. Furthermore, when expressed in a mouse pre-B cell line, Ba/F3, the recombinant murine (rm)IL-10R1 chain enabled these cells to proliferate in response to IL-10 treatment.

The gene for the human (h)IL-10R1 chain was cloned from a cDNA library prepared from a human Burkitt lymphoma cell line, BJAB [14 ]. The hIL-10R1 gene encodes a 3.6-kb mRNA transcript and similar to the mIL-10R1 gene, generates an IL-10-binding protein, 90–110 kDa in size when expressed in COS-7 cells. The full-length protein consists of 557 amino acids and is ~60% identical to the murine homologue. Sequence analysis of the mIL-10R1 and hIL-10R1 proteins revealed that the actual molecular mass of these molecules (~60 kDa) was much less than that determined by chemical cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These findings indicated that a large portion of the total mass of the IL-10R1 molecule is a result of carbohydrate. The hIL-10R1 chain exhibits a dissociation constant for IL-10 in the range of 200–250 pM when expressed in Ba/F3 cells.

For IL-10 to transduce a signal from the cell membrane to the nucleus, it requires the participation of another class II cytokine receptor, IL-10R2, originally known as CRF2-4, which was initially cloned as an orphan receptor encoded by a gene, CRFB4, closely linked to the IFN-{alpha} receptor (IFN-{alpha}R) genes on chromosome 21 [15 ]. The precise function of this receptor chain was unknown until 1997 when Kotenko et al. [3 ] showed that CRF2-4 was in fact an essential second chain in the IL-10R complex. IL-10 mediates signal transduction in IL-10R-positive target cells by activating the receptor-associated Janus tyrosine kinases (JAK)1 and Tyk2 [16 ]. JAK1 is associated with IL-10R1, and Tyk2 is associated with IL-10R2 (CRF2-4). The ligand-mediated association of the IL-10R1 and IL-10R2 chains activates these kinases and catalyzes phosphorylation of specific tyrosine residues on the intracellular domain of the IL-10R1 chain [17 ]. Either or both of these phosphotyrosine residues can serve as docking sites for the latent cytosolic transcription factor STAT3, which binds to the activated (tyrosine-phosphorylated) receptor via its central Src homology 2 domain and is in turn phosphorylated on tyrosine by the activated receptor-associated Janus kinases. This results in the formation of phosphorylated STAT3 homodimers, which then translocate to the nucleus and bind with high affinity to STAT-binding elements in the promoters of various IL-10-responsive genes.

Several groups have used cDNA microarray screens to examine the repertoire of genes that are induced by IL-10 in macrophages [18 , 19 ]. These studies have facilitated the identification of a number of IL-10-inducible genes. These include a variety of membrane receptors, secretory proteins, and transcription factors. Activation of gene expression by IL-10 is STAT3-dependent [19 , 20 ]. IL-10 also inhibits induction of many genes by lipopolysaccharide (LPS), including proinflammatory cytokines such as tumor necrosis factor {alpha} and IL-1ß. Although the exact mechanism by which IL-10 inhibits expression of proinflammatory genes has not yet been defined, the inhibitory effects of IL-10 also appear to be STAT3-dependent [20 , 21 ].


   THE IL-22R COMPLEX
TOP
 ABSTRACT
 INTRODUCTION
 THE IL-10R COMPLEX
 THE IL-22R COMPLEX
THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
 NOTE
 REFERENCES
 
IL-22 was originally discovered as an IL-10-related T cell-derived inducible factor [22 ]. IL-22 exhibits ~22% homology to IL-10 at the amino acid level [22 ]. IL-22 is coexpressed together with IFN-{gamma} and IL-26 by activated T cells [23 ]. IL-22 is preferentially expressed by Th1 cells. Therefore, IL-22 can be classified as a Th1-type lymphokine together with IFN-{gamma} and IL-26. In fact, the genes for IL-22, IFN-{gamma}, and IL-26 are located in close proximity to one another on chromosome 12q14+3. This suggests that the proteins encoded by these genes may share certain functional activities. This topic will be discussed in greater detail later in this overview.

IL-22 signals through a receptor complex composed of the ligand-binding chain IL-22R1 (CRF2-9) and the accessory chain IL-10R2 (CRF2-4) [24 , 25 ]. IL-22 strongly activates STAT3 and to a lesser degree, STAT1 and STAT5 [26 ]. It was previously believed that the IL-10R2 chain is a unique component of the IL-10R complex. Demonstration that IL-10R2 is also an essential part of the IL-22R complex provided the first example of the shared use of IL-10R2 by a distinct class II cytokine receptor complex. As shown in Figure 1A , a neutralizing anti-IL-10R2 monoclonal antibody (mAb), 1A8.3 [27 ], blocked activation of STAT3 by IL-22 but not IL-20 in an epidermal carcinoma cell line, A431. These findings indicate that IL-10R2 is an essential component of the receptor complex for IL-22 but not IL-20, which requires a different second chain, IL-20R2 (CRF2-11), to mediate signal transduction [28 ]. The R1 chain for IL-20, IL-20R1 (zcytor7, CRF2-8), is also distinct from that used by IL-22 [28 ]. The magnitude of STAT3 activation induced by IL-20 is consistently lower than that induced by IL-22. Signaling through IL-20R complexes may be less efficient than signaling through IL-22R complexes, or A-431 cells may simply express fewer IL-20Rs than IL-22Rs.



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  		Figure 1. (A) A neutralizing anti-IL-10R2 mAb blocks activation of STAT3 by IL-22 but not IL-20. A-431 cells were treated with IL-22 (10 ng/mL) or IL-20 (10 ng/mL) for 30 min at 37°C in the presence or absence of the anti-IL-10R2 mAb, 1A8.3 [27 ]. Whole cell lysates were then prepared, and total STAT3 protein was immunoprecipitated using a rabbit anti-STAT3 antiserum. The levels of tyrosine-phosphorylated STAT3 (pY-STAT3) were then measured by Western blotting with a phospho-STAT3-specific antiserum. (B) Soluble (s)IL-10R2 does not inhibit signaling through IL-22R or IL-26R. IL-22 (10 ng/mL) or IL-26 (10 ng/mL) was preincubated with a 100-fold excess of sIL-10R2-Fc fusion protein (R&D Systems, Minneapolis, MN) for 15 min at room temperature. These mixtures were subsequently incubated with COLO-205 cells for 30 min at 37°C. The levels of tyrosine-phosphorylated STAT3 were then measured by Western blotting.

 
Although IL-10R2 is required to assemble functional IL-22R complexes, it does not directly bind IL-22 in the fluid phase. As shown in Figure 1B , preincubation of IL-22 or IL-26 with sIL-10R2 protein did not decrease the activation of STAT3 by either cytokine in a cell line, COLO-205, which responds to both of these cytokines. These findings indicate that IL-22 does not bind to the IL-10R2 chain. IL-10R2 serves to recruit an additional kinase, Tyk2, to the receptor complex [26 ]. This facilitates transphosphorylation of the receptor chains and the generation of STAT docking sites on the intracellular domain of the IL-22R1 chain. Therefore, although IL-10R2 does not participate in the initial binding of ligand, it plays an indispensable role in signal transduction. Although both IL-10 and IL-22 require the IL-10R2 chain for signaling, IL-22 activates additional signaling pathways such as the mitogen-activated protein kinase pathway, which is not activated by signaling through IL-10R complexes [26 ].

To date, no comprehensive analysis of IL-22-inducible genes has been published; however, several IL-22-inducible genes have been identified. IL-22Rs are expressed on a number of tissues, including kidney, pancreas, and liver [25 ]. A previous study showed that IL-22 up-regulates expression of various acute-phase reactants in hepatocytes [29 ]. These include serum amyloid A, {alpha}1-antichymotrypsin, and haptoglobin. In addition, we showed that IL-22 up-regulates expression of the suppressor of cytokine signaling-3 (SOCS-3) gene in a hepatoma cell line [30 ]. It is noteworthy that SOCS-3 is also highly inducible by IL-10 in monocytes [31 ].

To identify additional IL-22-inducible genes, we examined the effects of IL-22 on gene expression by primary human hepatocytes. Confluent cultures of freshly isolated human hepatocytes were incubated with IL-22 (10 ng/mL) for 3 h at 37°C. RNA extracts were then prepared and analyzed by RNase protection assay. As shown in Figure 2 , IL-22 up-regulated expression of several chemokine genes in hepatocytes, including IFN-inducible protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), and IL-8. Although IL-10 is known to inhibit expression of IL-8 in monocytes, IL-22 did not suppress expression of IL-8 by hepatocytes. In fact, IL-22 itself induced expression of IL-8 by hepatocytes. This indicates that the inhibitory mechanism activated by IL-10 in monocytes is not inducible by IL-22 in hepatocytes. The biological activities induced by IL-22 are only beginning to be defined, but it is likely that IL-22 will be found to play a significant role in regulating liver function. Recent studies support a potential, therapeutic role for rIL-22 in protection against hepatitis [32 ].



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  		Figure 2. IL-22 up-regulates gene expression in hepatocytes. Confluent cultures of primary human hepatocytes (Clonetics, Walkersville, MD) were treated with IL-1 (1 ng/mL), IL-22 (10 ng/mL), or both for 3 h at 37°C. Total RNA extracts were prepared, and the levels of several chemokine genes were measured by RNase protection assay. Ltn, Lymphotactin; RANTES, regulated on activation, normal T expressed and secreted; MIP-1, macrophage-inflammatory protein-1; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

 

   THE SOLUBLE IL-22 BINDING PROTEIN (sIL-22BP)
TOP
 ABSTRACT
 INTRODUCTION
 THE IL-10R COMPLEX
 THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
 NOTE
 REFERENCES
 
At about the same time that the IL-22R complex was being defined, several groups identified a distinct IL-22BP [30 , 33 34 35 ]. The protein encoded by this gene (CRF2-10 or IL-22RA2) lacks intracellular and transmembrane domains but retains the ability to bind IL-22 with high affinity. As a result, IL-22BP functions as a potent antagonist of IL-22 signaling by binding IL-22 in the fluid phase and preventing its binding to the membrane-associated IL-22R1 chain. IL-22BP is expressed at high levels in several tissues, especially placenta and mammary glands [33 34 35 ]. The high-level expression of IL-22BP in the placenta suggests a possible role for IL-22BP in normal placental development. IL-22BP is also expressed by DC [36 ].

The gene for IL-22BP exhibits ~34% identity to the IL-22R1 extracellular domain. This gene is located on chromosome 6 (6q23+2) in close proximity to two other class II cytokine receptor genes: IFN-{gamma}R1 and IL-20R1 [37 ]. We recently determined that IL-20R1 is in fact the primary ligand-binding chain for IL-26, not IL-20 [38 ]. Therefore, the genes for the class II cytokines, IFN-{gamma}, IL-22, and IL-26, are clustered together on chromosome 12 (12q14+3), and the genes for the ligand-binding receptors, IFN-{gamma}R1, IL-22BP, and IL-20R1 (IL-26R1), are clustered together on chromosome 6. The gene for IL-22R1 is located on chromosome 1 in close proximity to the IFN-{lambda}R1 gene, and therefore, it does not localize to the same gene cluster on chromosome 6, which encodes the other ligand-binding proteins. Nevertheless, the close physical association of these two genes (IL-22R1 and IFN-{lambda}R1) suggests that they may share some common functions.

IL-22BP specifically binds IL-22 and does not bind other IL-10-related cytokines, including IL-10, IL-19, IL-20, IL-24, IL-26, or IFN-{lambda}. To illustrate this specificity, we treated A-431 cells with rhIL-20 or IL-22 in the presence of a tenfold molar excess of purified rhIL-22BP. As shown in Figure 3 , IL-22BP blocked activation of STAT3 by IL-22 but did not block activation of STAT3 by IL-20. The affinity of IL-22BP for IL-22 appears to be even higher than the membrane-associated IL-22R, IL-22R1. IL-22BP inhibits the ability of IL-22 to induce STAT activation and subsequent gene expression in IL-22R-positive target cells [30 , 33 , 34 ]. This suggests that IL-22BP has evolved to selectively regulate IL-22 signaling.



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  		Figure 3. The IL-22BP selectively inhibits IL-22 signaling. A431 cells were treated for 30 min at 37°C with IL-20 (10 ng/mL) or IL-22 (10 ng/mL) in the presence or absence of a tenfold molar excess of purified IL-22BP/Fc fusion protein (R&D Systems). At the end of the incubation period, cell lysates were prepared, and the levels of tyrosine-phosphorylated STAT3 (pY-STAT3) were measured by Western blotting.

 
IL-22 is coexpressed together with IFN-{gamma} and IL-26 by activated Th1 cells, but IL-22BP does not inhibit signaling through IFN-{gamma}Rs or IL-26R (ref. [38 ] and unpublished). IL-22, like IFN-{gamma}, may be overexpressed in certain disease states. If this turns out to be the case, IL-22BP might be very useful as a therapeutic agent to block IL-22 activity. It is interesting that IL-22 transgenic mice die within a few days after birth with skin abnormalities that are similar to those observed in patients with psoriasis [39 ]. Moreover, subcutaneous administration of IL-22 causes epidermal thickening and immune cell infiltration that can be neutralized by IL-22BP [39 ].


   THE IL-26R COMPLEX
TOP
 ABSTRACT
 INTRODUCTION
 THE IL-10R COMPLEX
 THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
 NOTE
 REFERENCES
 
IL-26 (AK155) was originally identified by Knappe et al. [40 ] as a secretory protein produced by herpesvirus saimiri-transformed T lymphocytes. The gene encoding this protein was identified by subtractive hybridization and was found to exhibit weak but significant homology to IL-10 (~25%). IL-26 is expressed by normal T cells and certain T cell clones following stimulation by antigen or mitogenic lectins [23 , 40 ]. Until very recently, the receptor for this cytokine was unknown. However, we determined that IL-26 signals through a novel receptor pair consisting of the transmembrane proteins: IL-20R1 and IL-10R2 [38 ]. IL-20R1 was originally identified as one of the components of the IL-20R complex [28 ]. It is surprising that IL-20R1 does not bind IL-19 or IL-20 with high affinity [41 ]. However, it does serve as the high-affinity, ligand-binding chain for IL-26, and it can be argued that this protein should actually be referred to as "IL-26R1", as a soluble form of IL-20R1 containing its complete extracellular domain binds IL-26 with high affinity but does not bind IL-19 or IL-20 [38 , 41 ].

IL-20 is one of several IL-10-related class II cytokines that were cloned in recent years. IL-20 signals through a heterodimeric receptor complex composed of IL-20R1 and IL-20R2 [28 ]. This receptor complex was originally defined based on its ability to reconstitute IL-20 signaling in COS-7 cells (monkey kidney fibroblasts). However, subsequent studies by several groups showed that the IL-20R1:IL-20R2 complex can also be used for signaling by at least two other IL-10-related cytokines: IL-19 and IL-24 (MDA-7) [42 , 43 ]. Therefore, this receptor complex is shared by several cytokines, including IL-19, IL-20, and IL-24. The shared use of receptor proteins by several different cytokines is a recurrent feature of cytokine signaling. For example, the common {gamma} chain ({gamma}c) is an essential component of at least six distinct cytokine-receptor complexes, including those for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.

In view of its homology to IL-10, we reasoned that IL-26 might also use the IL-10R2 chain as a part of its receptor complex. We found that neutralizing anti-IL-10R2 antibodies can block IL-26 signaling in IL-26-reponsive target cells [38 ]. These findings indicated that IL-10R2 is a component of the IL-26R complex. As mentioned above, IL-10R2 does not initially bind any of the IL-10-related cytokines. It participates in ligand-receptor complex formation only after the ligand first binds to a primary ligand-binding chain such as IL-10R1 or IL-22R1. To identify the ligand-binding chain for IL-26, we transfected several tumor cell lines with gene expression constructs encoding specific class II receptor chains, including IL-20R1. As shown in Figure 4 , forced expression of IL-20R1 in a colorectal carcinoma cell line, HT-29, enabled these cells to respond to IL-26. IL-26 did not activate STAT3 in wild-type HT-29 cells, but it did activate STAT3 in the IL-20R1-transfected cells. These findings demonstrate that IL-20R1 is the ligand-binding chain for IL-26 and an essential component of the IL-26R complex. The wild-type HT-29 cells were fully responsive to IL-22, as this cell line constitutively expresses IL-22R1 and IL-10R2 [42 ]. Like IL-22, IL-26 activates STAT3 and to a lesser degree, STAT1.



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  		Figure 4. Reconstitution of the IL-26R complex in HT-29 cells by forced expression of the IL-20R1 chain. HT-29 cells were stably transfected with an expression construct encoding the full-length IL-20R1 protein. Wild-type HT-29 cells and IL-20R1-transfected HT-29 cells were treated with IFN-{alpha}, IL-19, IL-20, IL-22, or IL-26 (10 ng/mL) for 30 min at 37°C. At the end of the incubation period, cell lysates were prepared, and the levels of tyrosine-phosphorylated STAT3 (pY-STAT3) were measured by Western blotting. CON, control.

 
Activated T cells produce IL-22 and IL-26 [23 , 40 ]. The genes encoding IL-22, IL-26, and IFN-{gamma} are located close to one another on chromosome 12. The close proximity of the IL-22 and IL-26 genes to the IFN-{gamma} gene suggests that IL-22 and/or IL-26 may share certain functional activities that are also mediated by IFN-{gamma}. Like IFN-{gamma}, IL-22 and IL-26 are predominantly expressed by Th1 cells, suggesting transcriptional coregulation of their genes. Also, as shown in Figure 2 , IL-22 induces expression of genes such as IP-10, MCP-1, and IL-8, which are known to be inducible by IFN-{gamma} in many cell types. Although leukocytes such as T cells and macrophages express IL-10R2, they do not express IL-22R1 or IL-20R1 [23 ]. Consequently, these cells do not respond to treatment with IL-22 or IL-26. So far, the receptors for IL-22 and IL-26 have only been found on nonhematopoietic tissues such as colon, liver, lung, and skin. In contrast, IL-10Rs (IL-10R1) are only found on hematopoietic cells such as T cells and macrophages.

The IL-20R1 gene is not expressed in leukocytes or in lymphoid tissues such as the spleen [28 ]. We have also not been able to detect IL-20R1 gene expression by CD14+ monocytes or monocyte-derived DC (unpublished). These findings are consistent with similar findings by Wolk et al. [23 ], who also did not detect expression of IL-20R1 by purified populations of monocytes, NK cells, B cells, or T cells. However, a recent study indicated that IL-20 can stimulate hematopoiesis of multipotential progenitor cells, suggesting that there is a subset of hematopoietic cells that expresses IL-20Rs [44 ]. The IL-20R1 gene is expressed by a variety nonhematopoietic tissues, including prostate, testis, ovary, small intestine, and colon [28 ]. We recently showed that IL-20R1 is also highly expressed in skin and lung tissue [38 ]. It is also expressed at high levels in various brain compartments, especially the cerebellum, medulla, and spinal cord. We observed that transcription of the IL-20R1 gene gives rise to two distinct mRNA species. These transcripts are distinguishable by Northern blotting and display markedly different sizes: ~3.6 kb and 1.8 kb. It is likely that these mRNA transcripts represent alternative splice variants of the IL-20R1 gene. It is also possible that the smaller mRNA species encodes a sIL-20R1 protein or a membrane-associated form of IL-20R1 that lacks the intracellular domain.


   THE IFN-{lambda}R COMPLEX
TOP
 ABSTRACT
 INTRODUCTION
 THE IL-10R COMPLEX
 THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
CONCLUSIONS
 NOTE
 REFERENCES
 
The IFN-{lambda} gene family is composed of three distinct genes: IFN-{lambda}1 (IL-29), IFN-{lambda}2 (IL-28A), and IFN-{lambda}3 (IL-28B) [45 , 46 ]. The IFN-{lambda} proteins exhibit only weak homology to IL-10; however, like IL-10, they also use the IL-10R2 chain as a component of their receptor complex. The IFN-{lambda}R complex consists of the unique ligand-binding chain, IFN-{lambda}R1 (also known as IL-28R), and the accessory receptor chain, IL-10R2. Although signaling through IL-10R, IL-22R, and IL-26R complexes results predominantly in the activation of STAT3, signaling through the IFN-{lambda}R complex results predominantly in the activation of STAT1 and STAT2. These STATs together with the accessory factor, IFN regulatory factor 9 (IRF-9; p48), form the transcription factor complex known as IFN-stimulated gene factor-3 (ISGF3). Activation of ISGF3 is characteristically associated with induction of type I IFN (IFN-{alpha}/ß)-responsive genes.

The IFN-{lambda} genes are coexpressed together with other type I IFNs (IFN-{alpha} and IFN-ß) by virus-infected cells [45 , 46 ]. Although virtually any cell type following viral infection can express IFN-{lambda}, DC appear to be major producers of IFN-{lambda} [47 ]. Monocyte-derived DC express low levels of IFN-{lambda} when stimulated with Toll-like receptor agonists such as LPS or poly I:C; however, plasmacytoid DC (pDC) express high levels of IFN-{lambda} following viral infection [47 , 48 ].

In light of the fact that the IFN-{lambda} proteins activate IFN-stimulated response elements and induce antiviral activity, we consider these cytokines to be a novel group of "interferons" (i.e., IFN-{lambda}1, -2, and -3) [45 ]. However, another group, which independently identified this trio of cytokines, has chosen to refer to these proteins as "interleukins" (i.e., IL-29 and IL-28A and -B) [46 ]. Consequently, there are two distinct nomenclatures currently used to refer to these cytokines.

We and others showed that IFN-{lambda} signaling can be reconstituted in naïve target cells by forced expression of IFN-{lambda}R1 (IL-28R) and IL-10R2 [45 , 46 ]. Similar to IL-22R and IL-26R signaling, IFN-{lambda} signaling can be blocked by addition of neutralizing anti-IL-10R2 antibodies. IFN-{lambda}Rs are expressed at variable levels on most cell types; however, signaling through IFN-{lambda}Rs is generally weaker than signaling through type-I receptors (IFN-{alpha}/ßRs). Signaling through IFN-{lambda}Rs results in induction of many of the same genes that are induced by signaling through IFN-{alpha}/ßRs [45 ]. These include genes such as MxA, 2',5'-oligoadenylate synthetase, and protein kinase R, which are believed to be important in mediating at least some of the antiviral activities induced by type-I IFNs [49 ].

Type I IFNs (IFN-{alpha} and IFN-ß) are widely used as biologic agents for treating several diseases [50 ]. IFN-{alpha} is commonly used as a primary treatment for chronic hepatitis C virus infection and other clinical indications, including hepatitis B, melanoma, hairy cell leukemia, and non-Hodgkin’s lymphoma. IFN-ß is used to treat multiple sclerosis. Despite the effectiveness of these cytokines as therapeutic agents, there are many side-effects associated with the use of these proteins. These adverse reactions include fatigue, fever, anorexia, myelosuppression, and depression. Receptors for IFN-{alpha} and IFN-ß are expressed on virtually all somatic cells, including hematopoietic cells such as lymphocytes and monocytes. In contrast, although receptors for IFN-{lambda} are broadly expressed on nonhematopoietic tissues, they do not seem to be present on leukocytes. This may provide a therapeutic advantage for IFN-{lambda} as a clinical agent because treatment with this cytokine would be less likely to cause the myelosuppression that is typically associated with IFN-{alpha} therapy.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 THE IL-10R COMPLEX
 THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
NOTE
 REFERENCES
 
As discussed in this overview, there are now four distinct cytokines that are known to use the IL-10R2 chain as a part of their receptor complexes: IL-10, IL-22, IL-26, and IFN-{lambda}. In fact, there are three distinct IFN-{lambda} genes: IFN-{lambda}1 (IL-29), IFN-{lambda}2 (IL-28A), and IFN-{lambda}3 (IL-28B); so, in total, there are actually six separate ligands that require the IL-10R2 chain for signaling. With the exception of IL-10, the cytokines that require the IL-10R2 chain for signaling are produced by leukocytes but exert their actions on nonhematopoietic cells (Fig. 5 ). IL-10 is the exception because it is produced by leukocytes (monocytes and T cells) and acts in an autocrine manner to stimulate effector functions in leukocytes. IL-22 and IL-26 are produced by T cells, particularly CD4+ Th1 cells, but are only active on nonhematopoietic tissues. For example, the following tissues are known to be responsive to IL-22: skin, liver, kidney, pancreas, colon, and lung. Similarly, IL-26 is active on skin and lung epithelial cells as well as certain colorectal carcinomas but not leukocytes. Virtually any somatic cell type following virus infection can produce IFN-{lambda}; however, DC are particularly potent producers of this cytokine. IFN-{lambda}Rs are expressed on most cell types except leukocytes.



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  		Figure 5. The primary producers of and cellular targets for IL-10, IL-22, IL-26, and IFN-{lambda}. IL-22 and IL-26 are produced by activated T cells and can act upon a variety of target tissues, including kidney, liver, pancreas, and keratinocytes in the skin. IL-10 is produced by T cells and monocytes and is active only on leukocytes. IFN-{lambda} can be produced by virtually any virus-infected cell type; however, myeloid and pDC are major producers of IFN-{lambda} as well as type-I IFNs (IFN-{alpha} and IFN-ß). IFN-{lambda}Rs are expressed on most cell types with the notable exception of leukocytes.

 
As depicted in Figure 6 , IL-10, IL-22, IL-26, and IFN-{lambda} are initially bound by their specific ligand-binding chains IL-10R1, IL-22R1, IL-20R1, and IL-28R1 (IFN-{lambda}R1), respectively. The IL-10R2 chain is then recruited to the intermediate complexes formed by the binding of ligand to these receptors. Once the receptor complexes are fully assembled, the JAKs (JAK1 and Tyk2) associated with the intracellular domains of these receptors are activated, and they rapidly transphosphorylate the receptor chains on specific tyrosine residues. These phosphotyrosines then serve as transient docking sites for STAT transcription factors. IL-10, IL-22, and IL-26 predominantly activate STAT3 and to a lesser degree, STAT1; however, IFN-{lambda} activates several STAT proteins, including STAT1 and STAT2, which can combine with another cytosolic protein, IRF-9 (p48), to form the ISGF3 transcription factor complex. The ability of IFN-{lambda} to activate ISGF3 formation is reminiscent of signaling by type-I IFNs and suggests that IFN-{lambda} is evolutionarily related to the type-I IFNs.



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  		Figure 6. The IL-10R2 chain is a shared component in several class II cytokine receptor complexes. The second chain of the IL-10R complex, IL-10R2, is a common component of several class II cytokine receptor complexes, including the receptors for IL-10, IL-22, IL-26, and IFN-{lambda} (IL-28/IL-29). Although the IL-10R2 chain is broadly expressed on most cell types, expression of the ligand-binding chains [IL-10R1, IL-22R1, IL-20R1, and IFN-{lambda}R1 (IL-28R)] is limited to only certain cell types or tissues. Signaling through these receptor complexes results in preferential activation of specific STATs. This in turn results in the activation of distinct, gene-expression profiles.

 
The IL-10R2 chain is expressed at variable levels on virtually all somatic cells that have been examined. The one notable exception is the brain, where the IL-10R2 chain seems to be expressed at very low levels [38 , 51 ]. In contrast, the ligand-binding R1 chains for these cytokines are differentially expressed on various tissues. For example, IL-10Rs (IL-10R1) are only expressed on hematopoietic cells such as lymphocytes and monocytes. They are not normally present on nonhematopoietic cells. IL-22 receptors (IL-22R1) are expressed on many tissues but are particularly abundant on skin, liver, kidney, and pancreatic cells. The ligand-binding chain for IL-26, IL-20R1, is also expressed on many tissues; however, neither IL-20R1 nor IL-22R1 is expressed on leukocytes [23 ]. Consequently, neither IL-22 nor IL-26 can exert functional activity on leukocytes. Therefore, although T cells are major producers of IL-22 and IL-26, they are not primary targets for these cytokines. In contrast, many nonhematopoietic cell types express IL-22R1, IL-20R1, or both. As a result, these cells can respond to IL-22, IL-26, or both. IL-20R1, like IL-22R1, is expressed at high levels on epithelial cells in the skin, colon, and small intestine. Many tumor cell lines derived from the liver or colon express IL-22R1, IL-20R1, or both [36 ]. As a result, these cell lines are highly responsive to IL-22, IL-26, or both.

Class II cytokines have already proven to be useful, therapeutic agents for treating certain diseases [50 ]. Several forms of IFN-{alpha} are used to treat viral hepatitis and certain types of cancer. IFN-ß is used as a treatment for multiple sclerosis. The discovery of new class II cytokines such as IL-22, IL-26, and IFN-{lambda} provides potential, new, therapeutic agents for clinical use. For example, the ability of IL-22 to protect against hepatitis in a murine model suggests a promising application for this cytokine [32 ]. At present, the potential, clinical applications for IL-26 and IFN-{lambda} are unknown, but it is expected that phenotypic analysis of gene knockout mice will provide some important clues to the physiological roles of these cytokines.

In addition to their potential direct effects on the growth and function of cancer cells, these novel class II cytokines may also be used to increase the immunogenicity of tumor cell targets. For example, treatment of tumor cell lines with IL-22 or IFN-{lambda} up-regulates MHC class-I antigen expression [25 , 45 ]. This functional activity is also known to be characteristically inducible by IFN-{alpha} and IFN-ß and may explain, at least in part, how type-I IFNs promote anti-tumor cell immune responses. Increased expression of MHC class I and II antigens on tumor cells is generally associated with induction of more effective host anti-tumor cell immune responses. Therefore, these novel class II cytokines (IL-22, IL-26, and IFN-{lambda}) may help to promote anti-tumor cell immune responses by increasing the ability of tumor cell targets to be recognized and killed by effector cells of the immune system.


   NOTE
TOP
 ABSTRACT
 INTRODUCTION
 THE IL-10R COMPLEX
 THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
 NOTE
REFERENCES
 
The content of this article does not necessarily reflect the views or policies of the FDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the FDA.


   ACKNOWLEDGEMENTS
 
F. S. is the recipient of a Postgraduate Research Fellowship Award from the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the U.S. Department of Energy and the Food and Drug Administration (FDA). S. V. K. is supported in part by U.S. Public Health Service Grant RO1 AI51139 from the National Institute of Allergy and Infectious Diseases and by American Heart Association Grant AHA 0245131N. The authors thank Dr. Kevin Moore (DNAX, Palo Alto, CA) for providing the neutralizing anti-IL-10R2 mAb, 1A8.3.

Received February 27, 2004; revised April 8, 2004; accepted April 9, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 THE IL-10R COMPLEX
 THE IL-22R COMPLEX
 THE SOLUBLE IL-22 BINDING...
 THE IL-26R COMPLEX
 THE IFN-{lambda}R COMPLEX
 CONCLUSIONS
 NOTE
 REFERENCES
 

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