Interleukin-22: A cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection

Abstract

Interleukin (IL)-22 is a member of the IL-10 cytokine family that is produced by special immune cell populations, including Th22, Th1, and Th17 cells, classical and non-classical (NK-22) NK cells, NKT cells, and lymphoid tissue inducer cells. This cytokine does not influence cells of the hematopoietic lineage. Instead, its target cells are certain tissue cells from the skin, liver and kidney, and from organs of the respiratory and gastrointestinal systems. The main biological role of IL-22 includes the increase of innate immunity, protection from damage, and enhancement of regeneration. IL-22 can play either a protective or a pathogenic role in chronic inflammatory diseases depending on the nature of the affected tissue and the local cytokine milieu. This review highlights the primary effects of IL-22 on its target cells, its role in the defense against infections, in tumorigenesis, in inflammatory diseases and allergy as well as the potential of the therapeutic modulation of IL-22 action.

Introduction

Interleukin (IL)-22 was first described in 2000 by the Belgian research group of Renauld et al. [1]. Its initial cloning from murine IL-9-stimulated BW5147 T-lymphoma cells was followed by the identification of human IL-22 independently by the Renauld group and the Gurney research group [2], [3]. The similarities between IL-22 and the well known IL-10 with respect to their primary sequence resulted in the cytokine's initial designation as “IL-10-related T cell-derived inducible factor” (IL-TIF). In addition to IL-22, there are a number of other, mostly newly identified cytokines, which were grouped together with IL-10 into the IL-10 cytokine family. This family now comprises IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26 [4]. The family members share only a limited primary sequence identity of about 13–25% but display a common gene structure, a similar secondary protein structure, and the use of receptors of the same receptor family. The genes for the human IL-10 family members are located on two genomic regions: IL22 and IL26 in proximity to the IFNG gene on chromosome 12q15, and IL10, IL19, IL20 and IL24 on chromosome 1q32. They possess a similar intron–exon structure containing 5 (IL-10, IL-19, IL-20, IL-22, IL-26) or 6 (IL-24) protein coding exons. The resulting mature proteins have lengths of 138–195 amino acids (aa), with IL-22 being composed of 146 aa (Fig. 1). Despite their relatively low sequence identity to one another, the IL-10 family members exhibit a common spatial structure which is like the IFN-γ structure [5], [6]. The presence of conserved cysteine residues and a conserved tryptophan give rise to a bundle-like shape made up of an anti-parallel arrangement of α-helices. Regarding IL-22, its tertiary structure is facilitated by the formation of two intramolecular disulfide bonds, which link the N terminus with the D–E loop (Cys40–Cys132) and helix C to helix F (Cys89–Cys178) [7]. Like IL-19, IL-20, and probably also IL-24, but unlike IL-10 and IL-26, which build dimeric structures, IL-22 in its biologically active form seems to be a monomer. It should be mentioned, however, that de Oliveira et al. reported the possibility for IL-22 to form active dimers and inactive tetramers – if only with high concentrations – with the tetramers likely to represent a pool for the bioactive forms [8]. IL-22 possesses three potential N-linked glycosylation sites, characterized by the sequence motif N–X–S/T (Fig. 1), which in fact have been shown to be mostly all glycosylated, as suggested by the expression of IL-22 in glycosylation-competent S2 Drosophila melanogaster cells [9]. Interestingly, glycosylation of N54 seems to influence the binding of IL-22 to IL-10R2 [10]. However, recombinant IL-22 produced in Escherichia coli is biologically active.

The IL-10 family members use receptors belonging to the cytokine receptor family class 2 (CRF2), whereby functional membrane-associated receptors are always heterodimeric complexes composed of an R1-type receptor chain, which is generally the chain with the longer intracellular moiety and the docking site for signal transducers and activators of transcription (STAT) signal molecules, and an R2-type receptor chain with a shorter intracellular tail. Similar to their ligands, the genes of the CRF2 are grouped in genomic regions. The resulting proteins display a common structure and are composed of an extracellular, a transmembrane and an intracellular domain that varies strongly in its length [11]. The relatively conserved ∼210 aa-long extracellular domain is composed of two characteristic fibronectin type III domains (D1 and D2), each built by an arrangement of seven antiparallel β-sheets and conserved loops, which facilitate ligand binding and differ from the CRF1 in their lack of the W–S–X–W–S sequence motif near the C-terminal end (D2). The intracellular domain, in contrast, is less conserved and possesses binding sites for signaling molecules. The receptor for IL-22 is composed of IL-22R1 and IL-10R2 (Fig. 1) [2], [3], [12]. The IL-10 family members share single receptor chains or even whole receptor complexes [4], [13], and this also applies to both components of the IL-22 receptor complex. In fact, IL-22R1 is additionally a component of one of the receptor complexes for IL-20 and IL-24 (IL-22R1/IL-20R2), and IL-10R2 is a component of the receptor complexes for IL-10 (IL-10R1/IL-10R2), IL-26 (IL-20R1/IL-10R2), and even for IL-28α/β and IL-29 (IL-28R1/IL-10R2). As is the case for all IL-10R2-containing receptor complexes, the R1-type receptor chain IL-22R1 is able to directly bind the ligand, whereas IL-10R2 does not. In fact, IL-22 binds IL-22R1 with high affinity (K_D ≤ 20 nM), but by itself has almost no affinity for IL-10R2 (∼1 mM) [14]. Concordantly, in an ELISA-based system biotinylated IL-22 binds immobilized IL-22R1-Fc homodimers, which are enhanced in the presence of IL-10R2, but does not bind immobilized IL-10R2-Fc homodimers itself [15]. A detailed analysis of the receptor and ligand binding sites conducted by our lab by means of peptide scanning revealed a clear interaction of IL-10R2 with IL-22-derived peptides, but no interaction of IL-22 with IL-10R2-derived peptides [16]. In conclusion, the binding of IL-22 to IL-10R2 probably uses epitopes not accessible on the native IL-22 molecule surface, which has also been shown for IL-10–IL-10R2 interaction [17]. These findings led to a model of IL-22-induced receptor aggregation happening in sequent steps. IL-22 primarily binds IL-22R1, which enables a subsequent binding of IL-10R2 and therefore the completion of the ternary receptor complex formation. Here, the binding of IL-10R2 is enabled by a conformational change of IL-22 induced by the initial IL-22R1 binding. This kind of sequential receptor–ligand interaction is probably common to all IL-10 family members. However, for some IL-10 family members (IL-19 and IL-20) the R2-type receptor chain may be involved in the primary cytokine binding.

The IL-10 family members, like IFN-γ, mainly signal via activation of the Janus kinase (Jak)/STAT pathway [4], [18]. This precedes phosphorylation of receptor-associated tyrosine kinases, which in turn phosphorylate specific receptor tyrosine residues to become binding sites for the STAT src homology 2 (SH2) domains. Receptor-bound STATs are then phosphorylated by the tyrosine kinases, which enables their dimerization and translocation into the nucleus where they bind responsive elements and regulate the expression of their target genes. For the IL-22 receptor complex the tyrosine kinases have been shown to be Jak1 (associated with IL-22R1) and Tyk2 (associated with IL-10R2) [19]. Aside from the classical STAT recruitment via its four potential STAT binding sites, IL-22R1 is pre-associated with the major IL-22 signaling molecule STAT3 as a result of a tyrosine-independent new mode of STAT3 recruitment via interaction of its coiled-coil-domain with the C-terminal end of IL-22R1 [20].

Despite being members of one cytokine family for the above-mentioned family-characteristic similarities, the individual members greatly differ from IL-10 with regard to their biological role.

This review provides an overview of the producers, target cells and primary effects of IL-22, of the role of IL-22 in different conditions including infection, tumor development and chronic inflammatory diseases, as well as the potential of IL-22 therapeutic regulation.