Entry - *605330 - INTERLEUKIN 22; IL22 - OMIM - (OMIM.ORG)

 
 
* 605330

INTERLEUKIN 22; IL22


Alternative titles; symbols

INTERLEUKIN 10-RELATED T CELL-DERIVED INDUCIBLE FACTOR; ILTIF


HGNC Approved Gene Symbol: IL22

Cytogenetic location: 12q15   Genomic coordinates (GRCh38) : 12:68,248,242-68,253,604 (from NCBI)


TEXT

▼ Cloning and Expression

IL10-related T cell-derived inducible factor (ILTIF), a cytokine structurally related to IL10 (124092), was originally identified in the mouse as a gene induced by IL9 (146931) in T cells and mast cells (Dumoutier et al., 2000). By PCR amplification with specific primers for mouse Iltif and use of 5-prime RACE, Dumoutier et al. (2000) cloned human ILTIF cDNA, which encodes a deduced 179-amino acid protein that shares 79% and 25% sequence identity with mouse Iltif and human IL10, respectively.

Xie et al. (2000) cloned IL22 and IL22R (605457). Sequence analysis predicted that the N-terminal 33 amino acids of IL22 function as a signal sequence. Northern blot analysis revealed only trace expression in several peripheral tissues.


▼ Gene Structure

By genomic sequence analysis, Dumoutier et al. (2000) determined that IL22 contains 5 coding exons of similar sizes to the IL10 gene, as well as an additional noncoding exon.


▼ Mapping

Using FISH, Dumoutier et al. (2000) mapped the IL22 gene to chromosome 12q15, close to the IFNG and the herpesvirus saimiri-induced AK155 (602519) genes. They mapped the mouse gene to chromosome 10.


▼ Gene Function

Dumoutier et al. (2000) found that recombinant human ILTIF activated signal transducer and activator of transcription factor-1 (STAT1; 600555) and STAT3 (102582) in several hepatoma cell lines. ILTIF stimulation of HepG2 human hepatoma cells upregulated production of acute phase reactants, such as serum amyloid A, alpha-1-antichymotrypsin, and haptoglobin. Although IL10 and ILTIF have distinct activities, antibodies directed against the beta chain of the IL10 receptor blocked induction of acute phase reactants by ILTIF, indicating that this chain is a common component of the IL10 and ILTIF receptors. Similar acute phase reactant induction was observed in mouse liver upon ILTIF injection, and ILTIF expression increased rapidly after lipopolysaccharide injection, suggesting that this cytokine contributes to the inflammatory response in vivo.

Using RT-PCR analysis, Xie et al. (2000) showed that IL22 was upregulated in activated T cells. Gel shift analysis showed that STAT1, STAT3, and STAT5 (601511) were tyrosine phosphorylated in a renal carcinoma cell line, a colon adenocarcinoma cell line, and transfected cell lines expressing both IL22R and IL10RB (123889), but not either alone, in response to IL22; these cell lines were unresponsive to IL10. In contrast, an IL10RA (146933)- and IL10RB-expressing lymphoblast cell line responded only to IL10 and not to IL22. Xie et al. (2000) found that IL22 had no effect on the production of tumor necrosis factor (TNF; 191160) and did not inhibit the action of IL10. IL22 treatment had no effect on IFNG (147570) production by Th1 lymphocytes, but did modestly inhibit IL4 (147780) production by Th2 lymphocytes.

By RT-PCR using stimulated and unstimulated subpopulations of blood mononuclear cells, Wolk et al. (2004) showed that IL22R1 was not expressed on resting or activated immune cells. RT-PCR detected ubiquitous expression of IL10R2, whereas IL22R1 expression was restricted to skin and respiratory and digestive tissues. IL22R1 expression in keratinocytes was upregulated by IFNG. IL22 activated STAT3 and increased expression of HBD2 (DEFB4; 602215), HBD3 (DEFB103; 606611), and psoriasin (S100A7; 600353), but not HBD1 (DEFB1; 602056). Skin from patients with psoriasis or atopic dermatitis expressed high levels of IL22 and beta-defensins, whereas skin from healthy individuals did not. Wolk et al. (2004) proposed that IL22 acts not between cells of the immune system, but instead is a T-cell mediator that directly promotes the innate, nonspecific immunity of tissues.

Zheng et al. (2007) showed that IL22 is preferentially produced by Th17 cells and mediates the acanthosis induced by IL23 (see 161561). Zheng et al. (2007) found that IL23 or IL6 (147620) can directly induce the production of IL22 from both murine and human naive T cells. Moreover, the production of IL22 and IL17 (603149) from Th17 cells is differentially regulated. Transforming growth factor-beta (190180), although crucial for IL17 production, actually inhibits IL22 production. Furthermore, IL22 mediates IL23 induced acanthosis and dermal inflammation through the activation of STAT3 in vivo. Zheng et al. (2007) concluded that Th17 cells, through the production of both IL22 and IL17, might have essential functions in host defense and in the pathogenesis of autoimmune diseases such as psoriasis. IL22, as an effector cytokine produced by T cells, mediates the crosstalk between the immune system and epithelial cells.

Using an in vitro model of the human blood-brain barrier (BBB) with brain-derived microvascular endothelial cells, Kebir et al. (2007) demonstrated that IL17 (IL17A; 603149) and IL22, a product of Th17 lymphocytes, disrupted BBB tight junctions in vitro. CD45RO (151460)-positive cells expressing IL17 and IL22 were present in multiple sclerosis (MS; see 126200) lesions, and IL17R (605461) and IL22R were expressed on BBB endothelial cells in MS lesions, but not control brain material. Th17 lymphocytes transmigrated efficiently across BBB endothelial cells, expressed high levels of granzyme B (GZMB; 123910), killed human neurons, and promoted central nervous system inflammation through CD4-positive lymphocyte recruitment.

Aujla et al. (2008) showed that Il17a and Il22 were both crucial for maintaining local control of the gram-negative pulmonary pathogen Klebsiella pneumoniae in mice. Both Il17a and Il22 upregulated CXC chemokines (e.g., CXCL1; 155730) and Gmcsf (CSF2; 138960) in lung, but only Il22 increased lung cell proliferation and transepithelial resistance to injury. Aujla et al. (2008) concluded that Th17 cells and their effector molecules, such as IL22, are involved in host defense against extracellular pathogens at mucosal sites.

Cella et al. (2009) reported the characterization of a human natural killer (NK) cell subset located in mucosa-associated lymphoid tissues, such as tonsils and Peyer patches, which is hard-wired to secrete IL22, IL26 (605679), and leukemia inhibitory factor (LIF; 159540). These NK cells, which they referred to as NK22 cells, are triggered by acute exposure to IL23. In vitro, NK22-secreted cytokines stimulated epithelial cells to secrete IL10 (124092), proliferate, and express a variety of mitogenic and antiapoptotic molecules. NK22 cells are also found in mouse mucosa-associated lymphoid tissues and appear in the small intestine lamina propria during bacterial infection, suggesting that NK22 cells provide an innate source of IL22 that may help constrain inflammation and protect mucosal sites.

Using RT-PCR analysis, Wolk et al. (2011) demonstrated reduced expression of the defensins BD1, BD2, and BD3 in acne inversa (AI) lesions compared with psoriatic skin lesions. BD1 and BD3 expression was also significantly reduced in AI lesions compared with atopic dermatitis (AD) lesions. Expression of most cytokines was higher in AI, AD, and psoriatic lesions compared with healthy skin. However, expression of IL22 and IL20 (605619) was significantly lower in AI lesions than in psoriatic or AD lesions. Moreover, expression of the IL20 or IL22 receptor subunits IL22R1, IL20R1 (IL20RA; 605620), and IL20R2 (IL20RB; 605621) was reduced, but expression of the IL22 inhibitor, IL22BP (606648), was higher in AI than in psoriatic lesions. Expression of BD2 and BD3 positively correlated with expression of IL22 and IL20 in AI and psoriatic lesions. IL10 inhibited IL22 production and was overexpressed in AI lesions. Wolk et al. (2011) concluded that IL22 deficiency may contribute to the pathogenesis of certain chronic disorders, such as AI, in which antimicrobial defense is weak.

Huber et al. (2012) described the crucial role of IL22BP in controlling tumorigenesis and epithelial cell proliferation in the colon. IL22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 (606416) or NLRP6 (609650) inflammasomes led to an IL18 (600953)-dependent downregulation of IL22BP, thereby increasing the ratio of IL22/IL22BP. IL22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumor development if uncontrolled during the recovery phase. Thus, the IL22-IL22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

Smith et al. (2013) showed that Il22, independent of Il6, could induce hepcidin (HAMP; 606464) production in mice, with a subsequent decrease in circulating serum iron and hemoglobin levels and a concomitant increase in splenic iron accumulation. This response was attenuated in the presence of the Il22r-associated signaling kinase, Tyk2 (176941). Antibody blockade of hepcidin partially reversed the effects on iron biology caused by Il22r stimulation. Smith et al. (2013) proposed that IL22 is involved in regulating hepcidin production and iron homeostasis.

Using flow cytometric analysis of tonsil- or lamina propria-derived CD127 (IL7R; 146661)-positive/RORC (602943)-positive innate lymphoid cells (ILCs), Glatzer et al. (2013) determined that IL22 was produced only by the NKp44 (NCR2; 604531)-positive subset. Anti-NKp44-mediated triggering of NKp44, but not other receptors on ILCs, elicited TNF and IL2 (147680), but not IL22 or GMCSF (CSF2; 138960) production. Stimulation of ILCs with cytokines resulted in production of IL22, but only low TNF. Engagement of both NKp44, through antibody or influenza virus, and cytokine receptors synergistically led to ILC activation and enhanced IL22 production. Glatzer et al. (2013) concluded that NKp44-positive/RORC-positive/CD127-positive ILCs can be activated without cytokines and can switch between IL22 and TNF production, depending on the triggering stimulus.

Zhang et al. (2014) reported that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (see 147660) and required the flagellin receptors Tlr5 (603031) and Nlrc4 (606831). Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22, which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced Nlrc4-dependent production of Il18 and immediate elimination of RV-infected cells. Administration of Il22 and Il18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV. Zhang et al. (2014) proposed activation of innate immunity with flagellin, IL22, or IL18 as a strategy to combat emerging and recalcitrant viral pathogens.

Wang et al. (2014) found that induction of Il22 from innate lymphoid cells and Cd4+ T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of Il23 (see 605580), a cytokine upstream of Il22, is compromised during infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous Il22 and Il23 were able to restore the mucosal host defense. Wang et al. (2014) further unveiled unexpected functions of IL22 in regulating metabolism. Mice deficient in Il22 receptor (see IL22RA1, 605457) and fed with high-fat diet are prone to developing metabolic disorders; strikingly, administration of exogenous Il22 in genetically obese leptin receptor (LEPR; 601007)-deficient (db/db) mice and in mice fed with high-fat diet reversed many of the metabolic symptoms, including hyperglycemia and insulin resistance. IL22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine function, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. Wang et al. (2014) concluded that the IL22 pathway is a novel target for therapeutic intervention in metabolic diseases.

Using ex vivo organoid cultures, Lindemans et al. (2015) showed that mouse innate lymphoid cells, which potently produce Il22 after intestinal injury, increased the growth of mouse small intestine organoids in an Il22-dependent fashion. Recombinant IL22 directly targeted intestinal stem cells (ISCs) and augmented growth of both mouse and human intestinal organoids. Il22 induced Stat3 phosphorylation in Lgr5 (606667)-positive ISCs, and Stat3 was crucial for both organoid formation and Il22-mediated regeneration. Mice receiving allogeneic bone marrow transplants and Il22 treatment had enhanced recovery of ISCs, increased epithelial regeneration, and reduced intestinal pathology and mortality from graft-versus-host disease. Organoid cultures deficient in Atoh1 (601461) also underwent Il22-induced epithelial regeneration, indicating that Paneth cells were not required. Lindemans et al. (2015) concluded that, through IL22, the immune system is able to support intestinal epithelium by activating ISCs to promote regeneration.

By genomewide expression analysis, Duffin et al. (2016) observed significantly reduced levels of prostaglandin E synthase-2 (PTGES2; 608152) and prostaglandin receptor EP4 (PTGER4; 601586) and elevated blood neutrophil counts in human neonates with sepsis compared with controls. Likewise, patients with inflammation, sepsis, and/or trauma also showed downregulation of EP4 and upregulation of HPGD (601688), a mediator of prostaglandin E2 (PGE2) degradation. By suppressing Pge2 production with indomethacin and challenging mice with lipopolysaccharide, Duffin et al. (2016) observed enhanced production of Tnf and Il6 and development of inflammation, accompanied by translocation of gut bacteria into sterile tissue. Treatment with Ep4 agonists prevented the inflammatory response. Pge2-Ep4 signaling promoted homeostasis of type-3 innate lymphoid cells (ILCs) and induced them to produce Il22. Disruption of the ILC-Il22 axis impaired Pge2-mediated inhibition of systemic inflammation. Duffin et al. (2016) concluded that the ILC-IL22 axis is essential to protect against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation.

Yu et al. (2018) demonstrated that rhesus macaque Il22 is highly similar to human IL22 in both structure and function.

Gronke et al. (2019) showed that IL22, which is produced by group 3 innate lymphoid cells and gamma-delta-T cells, is an important regulator of the DNA damage response (DDR) machinery in intestinal epithelial stem cells. Using a mouse model that enables sporadic inactivation of the Il22 receptor (IL22RA1; 605457) in colon epithelial stem cells, Gronke et al. (2019) demonstrated that IL22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of Il22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations, and were more likely to give rise to colon cancer. Gronke et al. (2019) identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AHR; 600253), and AhR-mediated signaling in group 3 innate lymphoid cells and gamma-delta-T cells controlled their production of Il22. Mice fed with diets depleted of glucosinolates produced only very low levels of Il22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. Gronke et al. (2019) concluded that their work identified a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signaling, in turn, ensures on-demand production of IL22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.

Talbot et al. (2020) showed in mice how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses that are controlled by type 3 innate lymphoid cells (ILC3). Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP; 192320). Projections of VIP-producing neurons in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2; 601970). Production of IL22 by ILC3, which is upregulated by the presence of commensal microorganisms such as segmented filamentous bacteria, is inhibited upon engagement of VIPR2. As a consequence, levels of antimicrobial peptide derived from epithelial cells are reduced but the expression of lipid-binding proteins and transporters is increased. During food consumption, the activation of VIP-producing neurons thus enhances the growth of segmented filamentous bacteria associated with the epithelium, and increases lipid absorption. Talbot et al. (2020) concluded that their results revealed a feeding- and circadian-regulated dynamic neuroimmune circuit in the intestine that promotes a trade-off between innate immune protection mediated by IL22 and the efficiency of nutrient absorption.


▼ Animal Model

Using a mouse model of Th2 cell-mediated ulcerative colitis (see 266600), Sugimoto et al. (2008) showed that microinjection of mouse Il22 into inflamed intestine rapidly ameliorated local inflammation via enhanced mucous production. Il22 enhanced Stat3 activation within colonic epithelial cells and induced both Stat3-dependent expression of mucous-associated molecules (e.g., MUC1; 158340) and restitution of mucous-producing goblet cells. Treatment with IL22bp (IL22RA2; 606648) inhibited Il22 activity and suppressed goblet cell restitution. Sugimoto et al. (2008) proposed that local IL22 gene delivery may be a potent treatment for ulcerative colitis.

Ma et al. (2008) produced a mouse model of psoriasis-like skin inflammation using adoptive transfer of Cd4-positive/Cd45rb (151460)-hi/Cd25 (IL2RA; 147730)-negative cells to pathogen-free SCID mice. Psoriasis-like lesions had elevated expression of antimicrobial peptide and proinflammatory cytokine mRNA, and disease progression depended on expression of the p40 subunit of Il12 and Il23 (IL12B; 161561). Treatment of mice with neutralizing antibody to Il22 prevented disease development and reduced acanthosis, inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of Il22 into skin induced expression of antimicrobial peptides and inflammatory cytokines. Ma et al. (2008) concluded that IL22 is required for development of autoreactive Th17-dependent skin disease and suggested that IL22 antagonism may be therapeutic for human psoriasis.

Using Il22-deficient mice and a rodent attaching and effacing (A/E) bacterial pathogen, Zheng et al. (2008) showed that Il22, induced in an Il23-dependent manner, had a crucial role in the early phase of host defense and in preventing epithelial damage, systemic bacterial burden, and mortality. Instead of adaptive immunity, Il22 was required for induction of the Reg family of antimicrobial proteins, including Reg3b and Reg3g (609933), in colonic epithelial cells. Exogenous mouse or human REG3G improved survival of Il22-deficient mice after infection with the A/E pathogen. Zheng et al. (2008) concluded that IL22 has a role in innate immune function and regulates early defense mechanisms against A/E bacterial pathogens.

Kudva et al. (2011) found that mice lacking Il17a, Il17f (606496), Il17ra, or Il22, all of which are components of Th17 immunity, had impaired clearance of Staphylococcus aureus. Deletion of Il22 did not diminish neutrophil recruitment. Wildtype mice challenged with influenza A and then by S. aureus had increased inflammation and decreased clearance of both pathogens, accompanied by greater production of type I IFN (e.g., IFNA1; 147660) and type II IFN (i.e., IFNG) in lung, compared with mice infected with virus alone. Coinfection with influenza A substantially decreased Il17, Il22, and Il23 (605580) production after S. aureus infection in a type II IFN-independent and type I IFN-dependent manner. Overexpression of Il23 in coinfected mice rescued induction of Il17 and Il22 and markedly improved bacterial clearance. Kudva et al. (2011) concluded that type I IFNs induced by influenza A infection inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.

Dudakov et al. (2012) found that thymic regeneration is centered on IL22 and triggered by the depletion of CD4+CD8+ double-positive thymocytes. Intrathymic levels of IL22 were increased after thymic insult, and thymic recovery was impaired in Il22-deficient mice. IL22, which signaled through thymic epithelial cells and promoted their proliferation and survival, was upregulated by radio-resistant ROR-gamma-t (RORC)-positive/CCR6 (601835)-positive/NKp46 (604530)-negative lymphoid tissue inducer cells after thymic injury in an IL23-dependent manner. Dudakov et al. (2012) found that administration of IL22 enhanced thymic recovery after total body irradiation.

Il22 is highly expressed in intestines of Salmonella-infected rhesus macaques and mice. Behnsen et al. (2014) treated wildtype and Il22-deficient mice with streptomycin prior to infection with the bacterium to induce inflammation in the cecum (i.e., a colitis mouse model) and found greater Salmonella colonization in normal mice with inflamed intestines compared with Il22-deficient mice. Il22 induced expression of both Lcn2 (600181) and calprotectin (123885), which sequester essential metal ions from microbes. However, S. typhimurium could overcome metal starvation mediated by Lcn2 and calprotectin. Accordingly, Il22 boosted S. typhimurium colonization of inflamed intestines by suppressing commensal bacteria susceptible to antimicrobial proteins. Behnsen et al. (2014) concluded that IL22 is exploited by pathogens to suppress the growth of competing commensal bacteria in favor of pathogens that colonize mucosal surfaces.


▼ REFERENCES

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  26. Zheng, Y., Valdez, P. A., Danilenko, D. M., Hu, Y., Sa, S. M., Gong, Q., Abbas, A. R., Modrusan, Z., Ghilardi, N., de Sauvage, F. J., Ouyang, W. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14: 282-289, 2008. [PubMed: 18264109, related citations] [Full Text]


Contributors:
Ada Hamosh - updated : 09/29/2020
Ada Hamosh - updated : 05/22/2019
Bao Lige - updated : 11/01/2018
Paul J. Converse - updated : 09/01/2016
Paul J. Converse - updated : 08/19/2016
Ada Hamosh - updated : 1/26/2015
Ada Hamosh - updated : 1/9/2015
Paul J. Converse - updated : 9/25/2014
Paul J. Converse - updated : 9/19/2014
Paul J. Converse - updated : 8/13/2014
Ada Hamosh - updated : 12/4/2012
Ada Hamosh - updated : 4/24/2012
Paul J. Converse - updated : 2/13/2012
Paul J. Converse - updated : 4/29/2011
Ada Hamosh - updated : 2/18/2009
Paul J. Converse - updated : 5/29/2008
Paul J. Converse - updated : 4/17/2008
Paul J. Converse - updated : 11/2/2007
Ada Hamosh - updated : 2/27/2007
Paul J. Converse - updated : 3/31/2006
Paul J. Converse - updated : 2/28/2001
Paul J. Converse - updated : 12/6/2000
Creation Date:
Victor A. McKusick : 10/12/2000
Edit History:
alopez : 04/05/2023
alopez : 09/29/2020
alopez : 05/22/2019
mgross : 11/01/2018
carol : 01/08/2018
mgross : 09/01/2016
mgross : 08/19/2016
mgross : 08/12/2015
mcolton : 7/10/2015
alopez : 1/26/2015
alopez : 1/9/2015
mgross : 10/2/2014
mgross : 10/1/2014
mcolton : 9/25/2014
mcolton : 9/19/2014
mgross : 8/18/2014
mcolton : 8/13/2014
alopez : 12/6/2012
terry : 12/4/2012
alopez : 4/24/2012
terry : 4/24/2012
mgross : 2/16/2012
terry : 2/13/2012
mgross : 5/4/2011
mgross : 5/4/2011
terry : 4/29/2011
mgross : 3/2/2011
terry : 2/25/2011
alopez : 2/24/2009
terry : 2/18/2009
carol : 8/14/2008
mgross : 6/2/2008
terry : 5/29/2008
mgross : 4/25/2008
terry : 4/17/2008
carol : 2/21/2008
mgross : 11/2/2007
alopez : 3/8/2007
alopez : 3/8/2007
terry : 2/27/2007
mgross : 4/3/2006
mgross : 4/3/2006
terry : 3/31/2006
cwells : 2/28/2001
cwells : 2/28/2001
cwells : 2/28/2001
cwells : 2/27/2001
mgross : 12/6/2000
mgross : 12/6/2000
carol : 10/18/2000
carol : 10/16/2000
carol : 10/12/2000

* 605330

INTERLEUKIN 22; IL22


Alternative titles; symbols

INTERLEUKIN 10-RELATED T CELL-DERIVED INDUCIBLE FACTOR; ILTIF


HGNC Approved Gene Symbol: IL22

Cytogenetic location: 12q15   Genomic coordinates (GRCh38) : 12:68,248,242-68,253,604 (from NCBI)


TEXT

Cloning and Expression

IL10-related T cell-derived inducible factor (ILTIF), a cytokine structurally related to IL10 (124092), was originally identified in the mouse as a gene induced by IL9 (146931) in T cells and mast cells (Dumoutier et al., 2000). By PCR amplification with specific primers for mouse Iltif and use of 5-prime RACE, Dumoutier et al. (2000) cloned human ILTIF cDNA, which encodes a deduced 179-amino acid protein that shares 79% and 25% sequence identity with mouse Iltif and human IL10, respectively.

Xie et al. (2000) cloned IL22 and IL22R (605457). Sequence analysis predicted that the N-terminal 33 amino acids of IL22 function as a signal sequence. Northern blot analysis revealed only trace expression in several peripheral tissues.


Gene Structure

By genomic sequence analysis, Dumoutier et al. (2000) determined that IL22 contains 5 coding exons of similar sizes to the IL10 gene, as well as an additional noncoding exon.


Mapping

Using FISH, Dumoutier et al. (2000) mapped the IL22 gene to chromosome 12q15, close to the IFNG and the herpesvirus saimiri-induced AK155 (602519) genes. They mapped the mouse gene to chromosome 10.


Gene Function

Dumoutier et al. (2000) found that recombinant human ILTIF activated signal transducer and activator of transcription factor-1 (STAT1; 600555) and STAT3 (102582) in several hepatoma cell lines. ILTIF stimulation of HepG2 human hepatoma cells upregulated production of acute phase reactants, such as serum amyloid A, alpha-1-antichymotrypsin, and haptoglobin. Although IL10 and ILTIF have distinct activities, antibodies directed against the beta chain of the IL10 receptor blocked induction of acute phase reactants by ILTIF, indicating that this chain is a common component of the IL10 and ILTIF receptors. Similar acute phase reactant induction was observed in mouse liver upon ILTIF injection, and ILTIF expression increased rapidly after lipopolysaccharide injection, suggesting that this cytokine contributes to the inflammatory response in vivo.

Using RT-PCR analysis, Xie et al. (2000) showed that IL22 was upregulated in activated T cells. Gel shift analysis showed that STAT1, STAT3, and STAT5 (601511) were tyrosine phosphorylated in a renal carcinoma cell line, a colon adenocarcinoma cell line, and transfected cell lines expressing both IL22R and IL10RB (123889), but not either alone, in response to IL22; these cell lines were unresponsive to IL10. In contrast, an IL10RA (146933)- and IL10RB-expressing lymphoblast cell line responded only to IL10 and not to IL22. Xie et al. (2000) found that IL22 had no effect on the production of tumor necrosis factor (TNF; 191160) and did not inhibit the action of IL10. IL22 treatment had no effect on IFNG (147570) production by Th1 lymphocytes, but did modestly inhibit IL4 (147780) production by Th2 lymphocytes.

By RT-PCR using stimulated and unstimulated subpopulations of blood mononuclear cells, Wolk et al. (2004) showed that IL22R1 was not expressed on resting or activated immune cells. RT-PCR detected ubiquitous expression of IL10R2, whereas IL22R1 expression was restricted to skin and respiratory and digestive tissues. IL22R1 expression in keratinocytes was upregulated by IFNG. IL22 activated STAT3 and increased expression of HBD2 (DEFB4; 602215), HBD3 (DEFB103; 606611), and psoriasin (S100A7; 600353), but not HBD1 (DEFB1; 602056). Skin from patients with psoriasis or atopic dermatitis expressed high levels of IL22 and beta-defensins, whereas skin from healthy individuals did not. Wolk et al. (2004) proposed that IL22 acts not between cells of the immune system, but instead is a T-cell mediator that directly promotes the innate, nonspecific immunity of tissues.

Zheng et al. (2007) showed that IL22 is preferentially produced by Th17 cells and mediates the acanthosis induced by IL23 (see 161561). Zheng et al. (2007) found that IL23 or IL6 (147620) can directly induce the production of IL22 from both murine and human naive T cells. Moreover, the production of IL22 and IL17 (603149) from Th17 cells is differentially regulated. Transforming growth factor-beta (190180), although crucial for IL17 production, actually inhibits IL22 production. Furthermore, IL22 mediates IL23 induced acanthosis and dermal inflammation through the activation of STAT3 in vivo. Zheng et al. (2007) concluded that Th17 cells, through the production of both IL22 and IL17, might have essential functions in host defense and in the pathogenesis of autoimmune diseases such as psoriasis. IL22, as an effector cytokine produced by T cells, mediates the crosstalk between the immune system and epithelial cells.

Using an in vitro model of the human blood-brain barrier (BBB) with brain-derived microvascular endothelial cells, Kebir et al. (2007) demonstrated that IL17 (IL17A; 603149) and IL22, a product of Th17 lymphocytes, disrupted BBB tight junctions in vitro. CD45RO (151460)-positive cells expressing IL17 and IL22 were present in multiple sclerosis (MS; see 126200) lesions, and IL17R (605461) and IL22R were expressed on BBB endothelial cells in MS lesions, but not control brain material. Th17 lymphocytes transmigrated efficiently across BBB endothelial cells, expressed high levels of granzyme B (GZMB; 123910), killed human neurons, and promoted central nervous system inflammation through CD4-positive lymphocyte recruitment.

Aujla et al. (2008) showed that Il17a and Il22 were both crucial for maintaining local control of the gram-negative pulmonary pathogen Klebsiella pneumoniae in mice. Both Il17a and Il22 upregulated CXC chemokines (e.g., CXCL1; 155730) and Gmcsf (CSF2; 138960) in lung, but only Il22 increased lung cell proliferation and transepithelial resistance to injury. Aujla et al. (2008) concluded that Th17 cells and their effector molecules, such as IL22, are involved in host defense against extracellular pathogens at mucosal sites.

Cella et al. (2009) reported the characterization of a human natural killer (NK) cell subset located in mucosa-associated lymphoid tissues, such as tonsils and Peyer patches, which is hard-wired to secrete IL22, IL26 (605679), and leukemia inhibitory factor (LIF; 159540). These NK cells, which they referred to as NK22 cells, are triggered by acute exposure to IL23. In vitro, NK22-secreted cytokines stimulated epithelial cells to secrete IL10 (124092), proliferate, and express a variety of mitogenic and antiapoptotic molecules. NK22 cells are also found in mouse mucosa-associated lymphoid tissues and appear in the small intestine lamina propria during bacterial infection, suggesting that NK22 cells provide an innate source of IL22 that may help constrain inflammation and protect mucosal sites.

Using RT-PCR analysis, Wolk et al. (2011) demonstrated reduced expression of the defensins BD1, BD2, and BD3 in acne inversa (AI) lesions compared with psoriatic skin lesions. BD1 and BD3 expression was also significantly reduced in AI lesions compared with atopic dermatitis (AD) lesions. Expression of most cytokines was higher in AI, AD, and psoriatic lesions compared with healthy skin. However, expression of IL22 and IL20 (605619) was significantly lower in AI lesions than in psoriatic or AD lesions. Moreover, expression of the IL20 or IL22 receptor subunits IL22R1, IL20R1 (IL20RA; 605620), and IL20R2 (IL20RB; 605621) was reduced, but expression of the IL22 inhibitor, IL22BP (606648), was higher in AI than in psoriatic lesions. Expression of BD2 and BD3 positively correlated with expression of IL22 and IL20 in AI and psoriatic lesions. IL10 inhibited IL22 production and was overexpressed in AI lesions. Wolk et al. (2011) concluded that IL22 deficiency may contribute to the pathogenesis of certain chronic disorders, such as AI, in which antimicrobial defense is weak.

Huber et al. (2012) described the crucial role of IL22BP in controlling tumorigenesis and epithelial cell proliferation in the colon. IL22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 (606416) or NLRP6 (609650) inflammasomes led to an IL18 (600953)-dependent downregulation of IL22BP, thereby increasing the ratio of IL22/IL22BP. IL22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumor development if uncontrolled during the recovery phase. Thus, the IL22-IL22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

Smith et al. (2013) showed that Il22, independent of Il6, could induce hepcidin (HAMP; 606464) production in mice, with a subsequent decrease in circulating serum iron and hemoglobin levels and a concomitant increase in splenic iron accumulation. This response was attenuated in the presence of the Il22r-associated signaling kinase, Tyk2 (176941). Antibody blockade of hepcidin partially reversed the effects on iron biology caused by Il22r stimulation. Smith et al. (2013) proposed that IL22 is involved in regulating hepcidin production and iron homeostasis.

Using flow cytometric analysis of tonsil- or lamina propria-derived CD127 (IL7R; 146661)-positive/RORC (602943)-positive innate lymphoid cells (ILCs), Glatzer et al. (2013) determined that IL22 was produced only by the NKp44 (NCR2; 604531)-positive subset. Anti-NKp44-mediated triggering of NKp44, but not other receptors on ILCs, elicited TNF and IL2 (147680), but not IL22 or GMCSF (CSF2; 138960) production. Stimulation of ILCs with cytokines resulted in production of IL22, but only low TNF. Engagement of both NKp44, through antibody or influenza virus, and cytokine receptors synergistically led to ILC activation and enhanced IL22 production. Glatzer et al. (2013) concluded that NKp44-positive/RORC-positive/CD127-positive ILCs can be activated without cytokines and can switch between IL22 and TNF production, depending on the triggering stimulus.

Zhang et al. (2014) reported that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (see 147660) and required the flagellin receptors Tlr5 (603031) and Nlrc4 (606831). Flagellin-induced activation of Tlr5 on dendritic cells elicited production of the cytokine Il22, which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced Nlrc4-dependent production of Il18 and immediate elimination of RV-infected cells. Administration of Il22 and Il18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV. Zhang et al. (2014) proposed activation of innate immunity with flagellin, IL22, or IL18 as a strategy to combat emerging and recalcitrant viral pathogens.

Wang et al. (2014) found that induction of Il22 from innate lymphoid cells and Cd4+ T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of Il23 (see 605580), a cytokine upstream of Il22, is compromised during infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous Il22 and Il23 were able to restore the mucosal host defense. Wang et al. (2014) further unveiled unexpected functions of IL22 in regulating metabolism. Mice deficient in Il22 receptor (see IL22RA1, 605457) and fed with high-fat diet are prone to developing metabolic disorders; strikingly, administration of exogenous Il22 in genetically obese leptin receptor (LEPR; 601007)-deficient (db/db) mice and in mice fed with high-fat diet reversed many of the metabolic symptoms, including hyperglycemia and insulin resistance. IL22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine function, decreases endotoxemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. Wang et al. (2014) concluded that the IL22 pathway is a novel target for therapeutic intervention in metabolic diseases.

Using ex vivo organoid cultures, Lindemans et al. (2015) showed that mouse innate lymphoid cells, which potently produce Il22 after intestinal injury, increased the growth of mouse small intestine organoids in an Il22-dependent fashion. Recombinant IL22 directly targeted intestinal stem cells (ISCs) and augmented growth of both mouse and human intestinal organoids. Il22 induced Stat3 phosphorylation in Lgr5 (606667)-positive ISCs, and Stat3 was crucial for both organoid formation and Il22-mediated regeneration. Mice receiving allogeneic bone marrow transplants and Il22 treatment had enhanced recovery of ISCs, increased epithelial regeneration, and reduced intestinal pathology and mortality from graft-versus-host disease. Organoid cultures deficient in Atoh1 (601461) also underwent Il22-induced epithelial regeneration, indicating that Paneth cells were not required. Lindemans et al. (2015) concluded that, through IL22, the immune system is able to support intestinal epithelium by activating ISCs to promote regeneration.

By genomewide expression analysis, Duffin et al. (2016) observed significantly reduced levels of prostaglandin E synthase-2 (PTGES2; 608152) and prostaglandin receptor EP4 (PTGER4; 601586) and elevated blood neutrophil counts in human neonates with sepsis compared with controls. Likewise, patients with inflammation, sepsis, and/or trauma also showed downregulation of EP4 and upregulation of HPGD (601688), a mediator of prostaglandin E2 (PGE2) degradation. By suppressing Pge2 production with indomethacin and challenging mice with lipopolysaccharide, Duffin et al. (2016) observed enhanced production of Tnf and Il6 and development of inflammation, accompanied by translocation of gut bacteria into sterile tissue. Treatment with Ep4 agonists prevented the inflammatory response. Pge2-Ep4 signaling promoted homeostasis of type-3 innate lymphoid cells (ILCs) and induced them to produce Il22. Disruption of the ILC-Il22 axis impaired Pge2-mediated inhibition of systemic inflammation. Duffin et al. (2016) concluded that the ILC-IL22 axis is essential to protect against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation.

Yu et al. (2018) demonstrated that rhesus macaque Il22 is highly similar to human IL22 in both structure and function.

Gronke et al. (2019) showed that IL22, which is produced by group 3 innate lymphoid cells and gamma-delta-T cells, is an important regulator of the DNA damage response (DDR) machinery in intestinal epithelial stem cells. Using a mouse model that enables sporadic inactivation of the Il22 receptor (IL22RA1; 605457) in colon epithelial stem cells, Gronke et al. (2019) demonstrated that IL22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of Il22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations, and were more likely to give rise to colon cancer. Gronke et al. (2019) identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AHR; 600253), and AhR-mediated signaling in group 3 innate lymphoid cells and gamma-delta-T cells controlled their production of Il22. Mice fed with diets depleted of glucosinolates produced only very low levels of Il22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. Gronke et al. (2019) concluded that their work identified a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signaling, in turn, ensures on-demand production of IL22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.

Talbot et al. (2020) showed in mice how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses that are controlled by type 3 innate lymphoid cells (ILC3). Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP; 192320). Projections of VIP-producing neurons in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2; 601970). Production of IL22 by ILC3, which is upregulated by the presence of commensal microorganisms such as segmented filamentous bacteria, is inhibited upon engagement of VIPR2. As a consequence, levels of antimicrobial peptide derived from epithelial cells are reduced but the expression of lipid-binding proteins and transporters is increased. During food consumption, the activation of VIP-producing neurons thus enhances the growth of segmented filamentous bacteria associated with the epithelium, and increases lipid absorption. Talbot et al. (2020) concluded that their results revealed a feeding- and circadian-regulated dynamic neuroimmune circuit in the intestine that promotes a trade-off between innate immune protection mediated by IL22 and the efficiency of nutrient absorption.


Animal Model

Using a mouse model of Th2 cell-mediated ulcerative colitis (see 266600), Sugimoto et al. (2008) showed that microinjection of mouse Il22 into inflamed intestine rapidly ameliorated local inflammation via enhanced mucous production. Il22 enhanced Stat3 activation within colonic epithelial cells and induced both Stat3-dependent expression of mucous-associated molecules (e.g., MUC1; 158340) and restitution of mucous-producing goblet cells. Treatment with IL22bp (IL22RA2; 606648) inhibited Il22 activity and suppressed goblet cell restitution. Sugimoto et al. (2008) proposed that local IL22 gene delivery may be a potent treatment for ulcerative colitis.

Ma et al. (2008) produced a mouse model of psoriasis-like skin inflammation using adoptive transfer of Cd4-positive/Cd45rb (151460)-hi/Cd25 (IL2RA; 147730)-negative cells to pathogen-free SCID mice. Psoriasis-like lesions had elevated expression of antimicrobial peptide and proinflammatory cytokine mRNA, and disease progression depended on expression of the p40 subunit of Il12 and Il23 (IL12B; 161561). Treatment of mice with neutralizing antibody to Il22 prevented disease development and reduced acanthosis, inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of Il22 into skin induced expression of antimicrobial peptides and inflammatory cytokines. Ma et al. (2008) concluded that IL22 is required for development of autoreactive Th17-dependent skin disease and suggested that IL22 antagonism may be therapeutic for human psoriasis.

Using Il22-deficient mice and a rodent attaching and effacing (A/E) bacterial pathogen, Zheng et al. (2008) showed that Il22, induced in an Il23-dependent manner, had a crucial role in the early phase of host defense and in preventing epithelial damage, systemic bacterial burden, and mortality. Instead of adaptive immunity, Il22 was required for induction of the Reg family of antimicrobial proteins, including Reg3b and Reg3g (609933), in colonic epithelial cells. Exogenous mouse or human REG3G improved survival of Il22-deficient mice after infection with the A/E pathogen. Zheng et al. (2008) concluded that IL22 has a role in innate immune function and regulates early defense mechanisms against A/E bacterial pathogens.

Kudva et al. (2011) found that mice lacking Il17a, Il17f (606496), Il17ra, or Il22, all of which are components of Th17 immunity, had impaired clearance of Staphylococcus aureus. Deletion of Il22 did not diminish neutrophil recruitment. Wildtype mice challenged with influenza A and then by S. aureus had increased inflammation and decreased clearance of both pathogens, accompanied by greater production of type I IFN (e.g., IFNA1; 147660) and type II IFN (i.e., IFNG) in lung, compared with mice infected with virus alone. Coinfection with influenza A substantially decreased Il17, Il22, and Il23 (605580) production after S. aureus infection in a type II IFN-independent and type I IFN-dependent manner. Overexpression of Il23 in coinfected mice rescued induction of Il17 and Il22 and markedly improved bacterial clearance. Kudva et al. (2011) concluded that type I IFNs induced by influenza A infection inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.

Dudakov et al. (2012) found that thymic regeneration is centered on IL22 and triggered by the depletion of CD4+CD8+ double-positive thymocytes. Intrathymic levels of IL22 were increased after thymic insult, and thymic recovery was impaired in Il22-deficient mice. IL22, which signaled through thymic epithelial cells and promoted their proliferation and survival, was upregulated by radio-resistant ROR-gamma-t (RORC)-positive/CCR6 (601835)-positive/NKp46 (604530)-negative lymphoid tissue inducer cells after thymic injury in an IL23-dependent manner. Dudakov et al. (2012) found that administration of IL22 enhanced thymic recovery after total body irradiation.

Il22 is highly expressed in intestines of Salmonella-infected rhesus macaques and mice. Behnsen et al. (2014) treated wildtype and Il22-deficient mice with streptomycin prior to infection with the bacterium to induce inflammation in the cecum (i.e., a colitis mouse model) and found greater Salmonella colonization in normal mice with inflamed intestines compared with Il22-deficient mice. Il22 induced expression of both Lcn2 (600181) and calprotectin (123885), which sequester essential metal ions from microbes. However, S. typhimurium could overcome metal starvation mediated by Lcn2 and calprotectin. Accordingly, Il22 boosted S. typhimurium colonization of inflamed intestines by suppressing commensal bacteria susceptible to antimicrobial proteins. Behnsen et al. (2014) concluded that IL22 is exploited by pathogens to suppress the growth of competing commensal bacteria in favor of pathogens that colonize mucosal surfaces.


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Contributors:
Ada Hamosh - updated : 09/29/2020
Ada Hamosh - updated : 05/22/2019
Bao Lige - updated : 11/01/2018
Paul J. Converse - updated : 09/01/2016
Paul J. Converse - updated : 08/19/2016
Ada Hamosh - updated : 1/26/2015
Ada Hamosh - updated : 1/9/2015
Paul J. Converse - updated : 9/25/2014
Paul J. Converse - updated : 9/19/2014
Paul J. Converse - updated : 8/13/2014
Ada Hamosh - updated : 12/4/2012
Ada Hamosh - updated : 4/24/2012
Paul J. Converse - updated : 2/13/2012
Paul J. Converse - updated : 4/29/2011
Ada Hamosh - updated : 2/18/2009
Paul J. Converse - updated : 5/29/2008
Paul J. Converse - updated : 4/17/2008
Paul J. Converse - updated : 11/2/2007
Ada Hamosh - updated : 2/27/2007
Paul J. Converse - updated : 3/31/2006
Paul J. Converse - updated : 2/28/2001
Paul J. Converse - updated : 12/6/2000

Creation Date:
Victor A. McKusick : 10/12/2000

Edit History:
alopez : 04/05/2023
alopez : 09/29/2020
alopez : 05/22/2019
mgross : 11/01/2018
carol : 01/08/2018
mgross : 09/01/2016
mgross : 08/19/2016
mgross : 08/12/2015
mcolton : 7/10/2015
alopez : 1/26/2015
alopez : 1/9/2015
mgross : 10/2/2014
mgross : 10/1/2014
mcolton : 9/25/2014
mcolton : 9/19/2014
mgross : 8/18/2014
mcolton : 8/13/2014
alopez : 12/6/2012
terry : 12/4/2012
alopez : 4/24/2012
terry : 4/24/2012
mgross : 2/16/2012
terry : 2/13/2012
mgross : 5/4/2011
mgross : 5/4/2011
terry : 4/29/2011
mgross : 3/2/2011
terry : 2/25/2011
alopez : 2/24/2009
terry : 2/18/2009
carol : 8/14/2008
mgross : 6/2/2008
terry : 5/29/2008
mgross : 4/25/2008
terry : 4/17/2008
carol : 2/21/2008
mgross : 11/2/2007
alopez : 3/8/2007
alopez : 3/8/2007
terry : 2/27/2007
mgross : 4/3/2006
mgross : 4/3/2006
terry : 3/31/2006
cwells : 2/28/2001
cwells : 2/28/2001
cwells : 2/28/2001
cwells : 2/27/2001
mgross : 12/6/2000
mgross : 12/6/2000
carol : 10/18/2000
carol : 10/16/2000
carol : 10/12/2000



NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.
Printed: June 20, 2025