Interleukin-22: A novel T- and NK-cell derived cytokine that regulates the biology of tissue cells

Abstract

Interleukin (IL)-22, discovered in 2000, is a member of the IL-10 family of cytokines. The major sources of IL-22 are activated T1- and NK-cells. IL-22 acts via a heterodimeric receptor complex consisting of IL-22R1 and IL-10R2. Neither resting nor activated immune cells express IL-22R1 or respond to IL-22. In contrast, tissue cells at outer body barriers, i.e. of the skin, kidney, and the digestive and respiratory systems are targets of this cytokine. IL-22 functions by promoting the anti-microbial defense, protecting against damage, and re-organizing non-immune tissues. Furthermore, IL-22 induces acute phase reactants. These findings indicate that IL-22 represents a novel type of immune mediator that, although produced by immune cells, regulates tissue protection and homeostasis.

Introduction

Cytokines are small, secreted proteins with a molecular weight between 6 and 60 kDa that are produced by numerous cell types, mostly after cellular activation, and play an important role in intercellular communication. Not only do they serve in the reaction of the immune system to pathogens, but they also regulate hematopoiesis, wound healing, angiogenesis, and physiological and pathological tissue re-organization. Cytokines elicit biological effects by binding to the extracellular moiety of specific, transmembrane receptor proteins in the outer membrane of cells. Mediated by the intracellular moiety of such receptors, this binding induces a coordinated series of events within the cell that lead to, e.g. changed gene expression patterns, altered cytoskeleton organization, or release of secretory vesicles.

In 2000, Renauld's group described a secreted, α-helical protein that they had discovered during a search for differentially expressed genes in interleukin (IL)-9-stimulated murine BW5147 T-lymphoma cells [1]. Due to its limited primary structure similarity to the well-known anti-inflammatory and immunosuppressive cytokine IL-10, this protein was named IL-TIF for “IL-10-related T cell-derived Inducible Factor”. Shortly thereafter, the human counterpart was identified in two studies. In one of these, the same group cloned the human gene product using anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) based on the sequence information from the murine cDNA [2]. Almost simultaneously, Gurney's group described the identical human protein discovered during a bioinformatic search for novel cytokines [3]. Based on its structural similarity with IL-10, its use of a similar receptor complex (see below), and its expression in immune cells, it was quickly renamed IL-22 [3].

At the same time, three further structurally related, secreted proteins were found and named interleukins, partially without any knowledge of their biological function: IL-19, IL-20, and IL-26 [4], [5], [6]. In addition to these three cytokines, a molecule already known since 1995 as melanoma differentiation associated gene 7 [7] was then recognized as a cytokine and kinsman of IL-10 (now designated as IL-24). This was the nascent hour for the IL-10 cytokine family [8]. This family now comprises IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28α, IL-28β, and IL-29. IL-28α, IL-28β, and IL-29 (also designated as interferon-λs), the youngest members, are somewhat extraordinary in that they form a theoretical bridge to the type I interferon cytokine family as their amino acid (aa) sequences show even greater similarity to the type I interferons, and their activity in intracellular viral defense mimics functional aspects of type I interferons [9], [10].

Interestingly, the members of the IL-10 family are encoded by genes that have a very similar structure which, incidentally, is completely different from that of the intron-less type I interferon encoding genes. The IL-10 family member genes are located in the human genome in three clusters: the first comprising the genes for IL-10, IL-19, IL-20, and IL-24 on chromosome 1q; the second comprising the IL-26 and IL-22-encoding genes located on chromosome 12q; and the third comprising the genes for IL-28α, IL-28β, and IL-29 on chromosome 19q [11], [12], [13].

All IL-10 family members exert their biological effects via heterodimeric receptor complexes composed of a type 1 receptor chain (R1) and a type 2 receptor chain (R2). These receptors chains are related by their extracellular moieties and belong to the cytokine receptor family class 2 (CRF2), which additionally comprises the receptors of the type I and type II interferons and tissue factor, a receptor for the coagulant component VIIa [11], [12], [13]. As a convention, the R1 chains of such complexes are defined as the receptor chains with the longer intracellular moiety able to bind signal transducers and activators of transcription (STAT) molecules. For IL-10, it is believed that ligand binding initially occurs to the R1 chain (IL-10R1). This induces a conformational change in the IL-10 protein that enables it to bind secondarily to the R2 chain (IL-10R2), leading to an aggregation of the two receptor chains and initiation of signal transduction [14], [15]. When the receptor chains for the novel IL-10 family members were discovered, some surprising features of this receptor family were revealed. First, the R1 chains are not the primary binding chains for all IL-10 family members. In fact, in the case of IL-19, IL-20, and IL-24, the initial binding occurs to the R2 chain. Second, the assignment of receptor chains to the ligands is not quite as transparent as assigning one ligand per receptor. Although the IL-10 family comprises nine cytokines, there are only four R1 chains and two R2 chains for these cytokines (Table 1). In fact, some of the IL-10 family members share receptor chains. For instance, the IL-10R2 chain, which for years has been well established as the R2 chain for the IL-10 receptor, turned out to be also part of the receptor complexes for IL-22, IL-26, IL-28α, IL-28β, and IL-29. Moreover, not only single receptor chains are shared among different IL-10 family members but even whole receptor complexes (Table 1). For instance, the complex composed of IL-20R1 and IL-20R2 is used by IL-19, IL-20, and IL-24. The situation regarding the assignment of receptors in this family becomes even more complicated considering that some cytokines are actually able to bind to more than one receptor complex. This is the case for IL-20 and IL-24, which signal via both the IL-20R1/IL-20R2 complex and the IL-22R1/IL-20R2 complex.

Despite the structural relation and the use of similar or partly identical receptors, the novel IL-10 family members including IL-22 do not seem to be functionally related to the IL-10. IL-22 in particular represents a novel type of immune mediator. This article will review the current knowledge on IL-22 and, beyond this, will take the opportunity to speculate about its biological significance.