| 2001 |
IL-22RA2 (IL-22BP) is a naturally expressed soluble receptor that binds specifically to IL-22 and neutralizes IL-22-induced proliferation of BaF3 cells expressing IL-22 receptor subunits, acting as an endogenous IL-22 antagonist. |
Binding assay, BaF3 cell proliferation neutralization assay, Northern blot, PCR, in situ hybridization |
Proceedings of the National Academy of Sciences of the United States of America |
High |
11481447
|
| 2008 |
IL-22BP binds IL-22 on a surface that overlaps with the IL-22RA1 (IL-22R) binding site, thereby competitively preventing IL-22R from binding IL-22. Comprehensive mutagenesis identified specific IL-22 amino acid residues critical for binding IL-22R, IL-10R2, and IL-22BP, with IL-22R and IL-10R2 binding sites juxtaposed on adjacent surfaces contributed mostly by helices A, D, and F and loop AB. |
Comprehensive mutagenesis combined with mammalian cell expression, ELISA, cell-based assays, and structural analysis |
Journal of molecular biology |
High |
18675824
|
| 2009 |
Crystal structure of the IL-22/IL-22BP complex at 2.75 Å resolution revealed IL-22BP residues critical for IL-22 binding; site-directed mutagenesis confirmed these residues functionally. Comparison with the IL-22/IL-22R1 structure showed overlapping binding surfaces on IL-22, consistent with IL-22BP's inhibitory mechanism. |
X-ray crystallography (2.75 Å), site-directed mutagenesis, functional binding assays |
FEBS letters |
High |
19285080
|
| 2012 |
IL-22BP is highly expressed by dendritic cells in the colon under steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes leads to IL-18-dependent downregulation of IL-22BP, thereby increasing the IL-22/IL-22BP ratio and allowing uncontrolled IL-22 activity that can promote tumor development during the recovery phase. |
IL-22BP-deficient mouse models, inflammasome-deficient (NLRP3, NLRP6) mice, IL-18 neutralization, in vivo colitis/tumorigenesis models, gene expression analysis |
Nature |
High |
23075849
|
| 2013 |
In both rats and mice, the constitutive steady-state source of IL-22BP is a subset of conventional dendritic cells (CD103+CD11b+ DC in mouse intestinal lamina propria). In humans, IL-22BP is expressed in immature monocyte-derived DCs and is strongly induced by retinoic acid, but dramatically reduced upon DC maturation. |
Flow cytometry, immunohistochemistry, in situ hybridization, retinoic acid treatment of human monocyte-derived DCs, rat and mouse tissue analysis |
Mucosal immunology |
High |
23653115
|
| 2015 |
In human gut, eosinophils are the most abundant source of IL-22BP protein. IL-22BP-deficient rats confirmed that endogenous IL-22BP is effective at blocking the protective actions of IL-22 during acute colitis. |
Immunohistochemistry, flow cytometry, IL-22BP-deficient rat model of acute colitis |
Mucosal immunology |
High |
26329427
|
| 2016 |
CD4+ T cells produce IL-22BP, and T cell-derived IL-22BP is required for IBD development in mouse models. Anti-TNF-α therapy in IBD patients reduces IL-22BP expression in intestinal CD4+ T cells without affecting IL-22 levels, suggesting suppression of IL-22BP is a mechanism of anti-TNF-α action. |
Cell isolation from IBD patients, adoptive transfer mouse models of IBD, IL-22BP conditional KO mice, anti-TNF-α treatment and gene expression analysis |
Science (New York, N.Y.) |
High |
27846573
|
| 2017 |
IL-22BP is highly expressed by CD11b+CD8α- dendritic cells in the subepithelial dome of Peyer's patches and blocks IL-22 signaling in follicle-associated epithelium (FAE). IL-22BP-deficient mice show altered FAE properties (enhanced mucus, antimicrobial proteins, fucosylation) and decreased uptake of bacterial antigens into Peyer's patches without affecting M cell function. |
IL-22BP-deficient (Il22ra2-/-) mice, immunostaining, gene expression analysis, bacterial antigen uptake assays, flow cytometry |
The Journal of experimental medicine |
High |
28512157
|
| 2017 |
In acute liver injury (ischemia-reperfusion and acetaminophen models), IL-22BP plays a protective role by controlling IL-22-induced CXCL10 expression in hepatocytes, which limits infiltration of inflammatory CD11b+Ly6C+ monocytes. This was demonstrated using Il22bp-deficient and Il22 × Il22bp double-deficient mice, and CXCL10 neutralization reversed the increased susceptibility of Il22bp-deficient mice. |
IL-22BP-KO mice, IL-22×IL-22BP double-KO mice, ischemia-reperfusion and acetaminophen liver injury models, CXCL10 neutralization, flow cytometry, gene expression analysis |
Journal of immunology (Baltimore, Md. : 1950) |
High |
29109123
|
| 2018 |
Prostaglandin E2 (PGE2) is a potent suppressor of IL-22BP expression in monocyte-derived dendritic cells in vitro. In psoriasis, IL-22BP is strongly downregulated in affected skin, correlating with inflammatory mediators that trigger DC maturation. |
In vitro MoDC maturation assays, PGE2 treatment, imiquimod mouse model of psoriasis, patient skin biopsy analysis, gene expression |
Scientific reports |
Medium |
29572462
|
| 2019 |
IL-22BP constitutively expressed in the lung inhibits IL-22 activity. In IL-22BP-knockout mice during H1N1 influenza infection, loss of IL-22BP creates a pro-IL-22 environment that reduces pulmonary inflammation and promotes tight junction formation (Cldn4, Tjp1, Tjp2). Recombinant IL-22 administration in vivo reduces inflammation and fluid leak. |
IL-22BP-KO mice (il-22ra2-/-), H1N1 influenza infection model, in vitro human bronchial epithelial cells, membrane resistance measurement, tight junction protein expression, recombinant IL-22 administration |
Mucosal immunology |
Medium |
31597930
|
| 2020 |
CIA-DCs, a transcriptionally distinct subset of conventional dendritic cells associated with cryptopatches and isolated lymphoid follicles, are the major steady-state cellular source of IL-22BP in the intestine. Their programming requires CCR6+ ILC3-derived lymphotoxin-β receptor signaling. Mice lacking CIA-DC-derived IL-22BP exhibit diminished epithelial lipid transporter expression, reduced lipid resorption, and altered body fat homeostasis. |
Single-cell RNA sequencing, multidimensional flow cytometry, conditional IL-22BP knockout, lymphotoxin-β receptor signaling analysis, lipid absorption assays |
Immunity |
High |
33207209
|
| 2020 |
A rare signal peptide coding variant in IL22RA2 (rs28385692, Leu16Pro) decreases secretion of all three IL-22BP isoforms (IL-22BPi1, IL-22BPi2, IL-22BPi3) to approximately 50-60% of normal levels. In silico analysis predicted disruption of the alpha helix of the H-region of the signal peptide and decreased hydrophobicity affecting the cleavage site. |
Genotyping, in silico signal peptide analysis, cell-based secretion assays measuring isoform secretion levels |
Cells |
Medium |
31936765
|
| 2023 |
SMAD7 transcriptionally upregulates IL-22RA2 by facilitating nuclear translocation and DNA binding of C/EBPβ to the IL22RA2 promoter, thereby dampening IL-22/STAT3 signaling and inflammation in skin. Mice overexpressing SMAD7 in keratinocytes were resistant to imiquimod-induced inflammation in an IL-22RA2-dependent manner. |
Transgenic mouse models, RNA-sequencing, chromatin immunoprecipitation (C/EBPβ binding to IL22RA2 promoter), in vivo imiquimod inflammation models, topical SMAD7 protein application |
The Journal of investigative dermatology |
Medium |
37211203
|
| 2023 |
In zebrafish, metaphocytes (tissue-resident macrophage/DC-like cells of non-hematopoietic origin) are the major IL-22BP-producing cells in barrier tissues, regulated by the ETS transcription factor Spic. Depletion of metaphocytes causes dysregulated barrier immunity phenotypically resembling IL-22BP-deficient mice. |
Zebrafish genetic models, Spic-deficient fish, metaphocyte depletion, live imaging, comparison to IL-22BP-deficient mouse phenotype |
Cell reports |
Medium |
37148242
|
| 2014 |
In Il22ra2-deficient mice undergoing EAE (experimental autoimmune encephalomyelitis), disease course was paradoxically less severe, with less demyelination and less immune cell infiltration in the CNS, suggesting that in CNS inflammation, IL-22 (made more available by absence of IL-22BP) acts protectively rather than pathogenically. |
Il22ra2-deficient C57BL/6 mice, MOG-EAE model, histopathology, gene expression in lymphoid tissues and CNS |
Genes and immunity |
Medium |
25008863
|
| 2019 |
In mandarin fish, IL-22BP interacts directly with IL-22 (confirmed by yeast two-hybrid assay) and completely inhibits IL-22-induced downstream antimicrobial gene expression. Two hot-spot residues for IL-22 binding identified in mammalian IL-22BP are conserved in sequence and function in fish IL-22BP, indicating conserved interaction mode. |
Yeast two-hybrid assay, co-incubation inhibition assay, gene expression analysis (hepcidin, LEAP-2), sequence conservation analysis |
Developmental and comparative immunology |
Medium |
30902735
|
| 2025 |
In pancreatitis, IL-22BP modulates IL-22 signaling by controlling canonical IL-22/STAT3 signaling and Bcl-XL expression. Loss of IL-22BP reduces acute pancreatitis severity but promotes chronic fibrosis through persistent p-STAT3 signaling, epithelial (acinar-to-ductal metaplasia), fibroblast proliferation, and myeloid cell infiltration. |
IL-22BP-KO mice, cerulein-induced acute and chronic pancreatitis models, histology, multiplex immunofluorescence, flow cytometry, p-STAT3 and Bcl-XL expression analysis |
Cellular and molecular gastroenterology and hepatology |
Medium |
40274099
|