IL22RA2
From Wikipedia, the free encyclopedia
| interleukin 22 receptor, alpha 2 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | IL22RA2 | ||||||
| NCBI gene | 116379 | ||||||
| HGNC | 14901 | ||||||
| OMIM | 606648 | ||||||
| RefSeq | NM_181310 | ||||||
| UniProt | Q969J5 | ||||||
| Other data | |||||||
| Locus | Chr. 6 q24.1-24.2 | ||||||
| |||||||
Interleukin-22 receptor subunit alpha-2 (IL-22RA2), also known as interleukin-22 binding protein (IL-22BP) is a naturally secreted monomeric protein acting as an interleukin-22 (IL-22) antagonist with inhibitory effects on IL-22 activity in vivo. IL-22BP is in humans encoded by the IL22RA2 gene located on chromosome 6, and in mice is encoded by the il22ra2 gene located on chromosome 10. IL-22BP belongs to the class II cytokine receptor family and it is a soluble receptor homolog of IL-22R (aliases IL-22RA1/IL-22RA/IL-22R1).[1][2]
The main function of IL-22BP is the regulation of IL-22 biological activity through specific binding which blocks the interaction of IL-22 with its cell surface receptor IL-22R and thus prevents the downstream cellular signalling and response. IL-22 and IL-22BP interactions play an important role in health and disease and are involved in the regulation of steady-state homeostasis,[1] inflammatory responses[3] and cancer.[4]
IL-22BP is a soluble monomeric cytokine receptor protein. IL-22BP shares approximately 34% sequence homology with the extracellular domain of one subunit of the heterodimeric membrane-bound IL-22R, which is the main cellular receptor for IL-22 providing the subsequent signalling. This homology extends to the secondary and tertiary structure of the proteins allowing specific binding and protein-protein interactions. IL-22BP also shares homology with other related cytokine receptors IL-10RB, and IL-20RA. IL-22BP is a secreted protein that lacks both transmembrane and intracellular domains, it contains two tandem fibronectin-III domains, glycosylation sites and four conserved cysteine residues. The molecular mass of secreted IL-22BP is approximately 30 kDa.[2][5]
IL-22BP with its five binding loops contacts IL-22 at the site overlapping the IL-22R binding site, successfully blocking the IL-22-IL-22R interaction. The dissociation constant KD for IL-22-IL-22BP is ~ 1 pM highlighting very tight interaction and high affinity, whereas KD for IL-22-IL-22R is only ~ 20 nM meaning much lower affinity. Also, the Koff dissociation rate for the IL22BP-IL-22 complex is over 4 days but Koff dissociation rate for the IL-22R-IL-22 complex is only a few minutes. These chemical properties ensure that IL-22 which is bound to IL-22BP is effectively sequestered from interaction with IL-22R.[6][7]
Function and regulation
Similarly to the expression profile of IL-22, IL-22BP is expressed in lymphoid and barrier tissues such as the spleen, mesenteric lymph nodes, gastrointestinal tract, skin, lungs, and liver among others. IL-22BP is produced by dendritic cells, particularly by specialised intestinal dendritic cell populations.[8][9] Other identified cellular sources of IL-22BP include eosinophils,[10] CD4+ TH lymphocytes[11] and keratinocytes.[12]
The detailed role of IL-22BP-IL-22 interactions is so far the best described in the gastrointestinal tract, where IL-22BP helps to maintain homeostasis and tolerance regulating IL-22 bioavailability. In the gastrointestinal tract, the levels of these two molecules are inverse during different immunological conditions. In healthy, steady-state homeostasis, the levels of IL-22BP are the highest and decrease rapidly during immune response and inflammation when high levels of IL-22 are produced. Inflammation mediators such as prostaglandin E2 (PGE2),[8] IL-18 and other inflammasome components[4] are known to downregulate IL-22BP production, on the other hand, the presence of retinoic acid, metabolite of vitamin A, is known to induce IL-22BP secretion.[8] IL-22BP in the gut is also involved in enabling proper antigen sampling from the intestinal lumen to intestinal lymphoid tissues, which is crucial for maintaining tolerance and homeostasis. Further IL-22BP regulates lipid adsorption and proliferation of intestinal epithelial cells.[13]
To a less extent, the function of IL-22BP is described in other tissues such as skin,[12] lungs[3] and liver. In most of these tissues, IL-22BP is thought to have protective effects. However, as it regulates the dual-natured IL-22 cytokine, which can have both protective and pathological effects, IL-22BP can also have both pro- and anti-inflammatory effects depending on many various conditions and stimuli. The detailed role and involvement of IL-22BP in the health and disease of different tissues remain to be fully explained.[1]