Interleukin 22 Explained

Interleukin-22 (IL-22) is a protein that in humans is encoded by the IL22 gene.^[1]

Structure

IL-22 is an α-helical cytokine. IL-22 binds to a heterodimeric cell surface receptor composed of IL-10R2 and IL-22R1 subunits. IL-22R is expressed on tissue cells, and it is absent on immune cells.^[2]

Crystallization is possible if the N-linked glycosylation sites are removed in mutants of IL-22 bound with high-affinity cell-surface receptor sIL-22R1. The crystallographic asymmetric unit contained two IL-22-sIL-22R1 complexes.

Function

IL-22 is produced by several populations of immune cells at a site of inflammation. Producers are αβ T-cell classes T_h1, T_h22 and T_h17 along with γδ T cells, NKT, ILC3, neutrophils and macrophages. IL-22 takes effect on non-hematopoietic cells – mainly stromal and epithelial cells. Effects involve stimulation of cell survival, proliferation and synthesis of antimicrobials including S100, Reg3β, Reg3γ and defensins. IL-22 thus participates in both wound healing and in protection against microbes.^[3] IL-22 dysregulation takes part in pathogenesis of several autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis and psoriasis.^[4]  

IL-22 biological activity is initiated by binding to a cell-surface complex composed of IL-22R1 and IL-10R2 receptor chains and further regulated by interactions with a soluble binding protein, IL-22BP, which shares sequence similarity with an extracellular region of IL-22R1 (sIL-22R1). IL-22 and IL-10 receptor chains play a role in cellular targeting and signal transduction to selectively initiate and regulate immune responses.^[5] IL-22 can contribute to immune disease through the stimulation of inflammatory responses, S100s and defensins. IL-22 also promotes hepatocyte survival in the liver and epithelial cells in the lung and gut similar to IL-10.^[6] In some contexts, the pro-inflammatory versus tissue-protective functions of IL-22 are regulated by the often co-expressed cytokine IL-17A ^[7]

Target tissue

Targets of this cytokine are mostly non-hematopoietic cells – epithelial and stromal cells of following tissues and organs: liver, lung, skin, thymus, pancreas, kidney, gastrointestinal tract, synovial tissues, heart, breast, eye and adipose tissue.

Signaling

IL-22 is a member of a group of cytokines called the IL-10 family or IL-10 superfamily (including IL-19, IL-20, IL-24, and IL-26),^[8] a class of potent mediators of cellular inflammatory responses. It shares use of IL-10R2 in cell signaling with other members of this family, IL-10, IL-26, IL-28A/B and IL-29.^[9]

IL-22, signals through the interferon receptor-related proteins CRF2-4 and IL-22R.^[10] It forms cell surface complexes with IL-22R1 and IL-10R2 chains resulting in signal transduction through receptor, IL-10R2. The IL-22/IL-22R1/IL-10R2 complex activates intracellular kinases (JAK1, Tyk2, and MAP kinases) and transcription factors, especially STAT3. It can induce IL-20 and IL-24 signaling when IL-22R1 pairs with IL-20R2.

Regulation of production

IL-22 production is induced mainly through IL-23 receptor signalling. IL-23 is produced by dendritic cells after recognition of ligands by specific Toll-like receptors especially in combination with Dectin-1 and or NOD2 signalling. IL-1β stimulates IL-22 production too. On the other hand IL-22 binding protein is a soluble inhibitor which blocks receptor binding site of IL-22.

Further reading

• Weger W, Hofer A, Wolf P, El-Shabrawi Y, Renner W, Kerl H, Salmhofer W . Common polymorphisms in the interleukin-22 gene are not associated with chronic plaque psoriasis . Experimental Dermatology . 18 . 9 . 796–8 . September 2009 . 19469905 . 10.1111/j.1600-0625.2009.00840.x . 22906785 . free .
• Davila S, Froeling FE, Tan A, Bonnard C, Boland GJ, Snippe H, Hibberd ML, Seielstad M . 6 . New genetic associations detected in a host response study to hepatitis B vaccine . Genes and Immunity . 11 . 3 . 232–8 . April 2010 . 20237496 . 10.1038/gene.2010.1 . free .
• Silverberg MS, Cho JH, Rioux JD, McGovern DP, Wu J, Annese V, Achkar JP, Goyette P, Scott R, Xu W, Barmada MM, Klei L, Daly MJ, Abraham C, Bayless TM, Bossa F, Griffiths AM, Ippoliti AF, Lahaie RG, Latiano A, Paré P, Proctor DD, Regueiro MD, Steinhart AH, Targan SR, Schumm LP, Kistner EO, Lee AT, Gregersen PK, Rotter JI, Brant SR, Taylor KD, Roeder K, Duerr RH . 6 . Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study . Nature Genetics . 41 . 2 . 216–20 . February 2009 . 19122664 . 2652837 . 10.1038/ng.275 .
• de Moura PR, Watanabe L, Bleicher L, Colau D, Dumoutier L, Lemaire MM, Renauld JC, Polikarpov I . 6 . Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22 . FEBS Letters . 583 . 7 . 1072–7 . April 2009 . 19285080 . 10.1016/j.febslet.2009.03.006 . 24846059 . free .
• Wong CK, Lun SW, Ko FW, Wong PT, Hu SQ, Chan IH, Hui DS, Lam CW . 6 . Activation of peripheral Th17 lymphocytes in patients with asthma . Immunological Investigations . 38 . 7 . 652–64 . 2009 . 19811428 . 10.1080/08820130903062756 . 36646289 .
• Shen H, Goodall JC, Hill Gaston JS . Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis . Arthritis and Rheumatism . 60 . 6 . 1647–56 . June 2009 . 19479869 . 10.1002/art.24568 . free .
• Thompson CL, Plummer SJ, Tucker TC, Casey G, Li L . Interleukin-22 genetic polymorphisms and risk of colon cancer . Cancer Causes & Control . 21 . 8 . 1165–70 . August 2010 . 20339910 . 10.1007/s10552-010-9542-5 . 22534683 .
• Hughes T, Becknell B, McClory S, Briercheck E, Freud AG, Zhang X, Mao H, Nuovo G, Yu J, Caligiuri MA . 6 . Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH 17 cytokine interleukin-22 . Blood . 113 . 17 . 4008–10 . April 2009 . 19244159 . 2673127 . 10.1182/blood-2008-12-192443 .
• Siezen CL, Bont L, Hodemaekers HM, Ermers MJ, Doornbos G, Van't Slot R, Wijmenga C, Houwelingen HC, Kimpen JL, Kimman TG, Hoebee B, Janssen R . 6 . Genetic susceptibility to respiratory syncytial virus bronchiolitis in preterm children is associated with airway remodeling genes and innate immune genes . The Pediatric Infectious Disease Journal . 28 . 4 . 333–5 . April 2009 . 19258923 . 10.1097/INF.0b013e31818e2aa9 . 25601837 . free .
• Pitta MG, Romano A, Cabantous S, Henri S, Hammad A, Kouriba B, Argiro L, el Kheir M, Bucheton B, Mary C, El-Safi SH, Dessein A . 6 . IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani . The Journal of Clinical Investigation . 119 . 8 . 2379–87 . August 2009 . 19620772 . 2719936 . 10.1172/JCI38813 .
• Pan HF, Zhao XF, Yuan H, Zhang WH, Li XP, Wang GH, Wu GC, Tang XW, Li WX, Li LH, Feng JB, Hu CS, Ye DQ . 6 . Decreased serum IL-22 levels in patients with systemic lupus erythematosus . Clinica Chimica Acta; International Journal of Clinical Chemistry . 401 . 1–2 . 179–80 . March 2009 . 19046958 . 10.1016/j.cca.2008.11.009 .
• Liu Y, Yang B, Zhou M, Li L, Zhou H, Zhang J, Chen H, Wu C . 6 . Memory IL-22-producing CD4+ T cells specific for Candida albicans are present in humans . European Journal of Immunology . 39 . 6 . 1472–9 . June 2009 . 19449309 . 10.1002/eji.200838811 . free .
• Sekikawa A, Fukui H, Suzuki K, Karibe T, Fujii S, Ichikawa K, Tomita S, Imura J, Shiratori K, Chiba T, Fujimori T . 6 . Involvement of the IL-22/REG Ialpha axis in ulcerative colitis . Laboratory Investigation; A Journal of Technical Methods and Pathology . 90 . 3 . 496–505 . March 2010 . 20065946 . 10.1038/labinvest.2009.147 . free .
• He M, Liang P . IL-24 transgenic mice: in vivo evidence of overlapping functions for IL-20, IL-22, and IL-24 in the epidermis . Journal of Immunology . 184 . 4 . 1793–8 . February 2010 . 20061404 . 10.4049/jimmunol.0901829 . free .
• Wolk K, Witte E, Warszawska K, Schulze-Tanzil G, Witte K, Philipp S, Kunz S, Döcke WD, Asadullah K, Volk HD, Sterry W, Sabat R . 6 . The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis . European Journal of Immunology . 39 . 12 . 3570–81 . December 2009 . 19830738 . 10.1002/eji.200939687 . free .
• Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, Cianfarani F, Odorisio T, Traidl-Hoffmann C, Behrendt H, Durham SR, Schmidt-Weber CB, Cavani A . 6 . Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling . The Journal of Clinical Investigation . 119 . 12 . 3573–85 . December 2009 . 19920355 . 2786807 . 10.1172/JCI40202 .
• Dhiman R, Indramohan M, Barnes PF, Nayak RC, Paidipally P, Rao LV, Vankayalapati R . IL-22 produced by human NK cells inhibits growth of Mycobacterium tuberculosis by enhancing phagolysosomal fusion . Journal of Immunology . 183 . 10 . 6639–45 . November 2009 . 19864591 . 10.4049/jimmunol.0902587 . free .
• Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, Lennerz JK, Doherty JM, Mills JC, Colonna M . 6 . A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity . Nature . 457 . 7230 . 722–5 . February 2009 . 18978771 . 3772687 . 10.1038/nature07537 . 2009Natur.457..722C .
• Sanjabi S, Zenewicz LA, Kamanaka M, Flavell RA . Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity . Current Opinion in Pharmacology . 9 . 4 . 447–53 . August 2009 . 19481975 . 2755239 . 10.1016/j.coph.2009.04.008 .
• Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A . Circulating Th17, Th22, and Th1 cells are increased in psoriasis . The Journal of Investigative Dermatology . 130 . 5 . 1373–83 . May 2010 . 20032993 . 2892169 . 10.1038/jid.2009.399 .

Notes and References

1. Dumoutier L, Van Roost E, Colau D, Renauld JC . Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor . Proceedings of the National Academy of Sciences of the United States of America . 97 . 18 . 10144–9 . August 2000 . 10954742 . 27764 . 10.1073/pnas.170291697 . 2000PNAS...9710144D . free .
2. Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R . IL-22 increases the innate immunity of tissues . Immunity . 21 . 2 . 241–54 . August 2004 . 15308104 . 10.1016/j.immuni.2004.07.007 . free .
3. Dudakov JA, Hanash AM, van den Brink MR . Interleukin-22: immunobiology and pathology . Annual Review of Immunology . 33 . 1 . 747–85 . 2015-03-21 . 25706098 . 10.1146/annurev-immunol-032414-112123 . 4407497 .
4. Pan HF, Li XP, Zheng SG, Ye DQ . Emerging role of interleukin-22 in autoimmune diseases . Cytokine & Growth Factor Reviews . 24 . 1 . 51–7 . February 2013 . 22906768 . 10.1016/j.cytogfr.2012.07.002 . 4003867 .

5. Jones BC, Logsdon NJ, Walter MR . Structure of IL-22 bound to its high-affinity IL-22R1 chain . Structure . 16 . 9 . 1333–44 . September 2008 . 18599299 . 2637415 . 10.1016/j.str.2008.06.005 .

6. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A . Interleukin-10 and the interleukin-10 receptor . Annual Review of Immunology . 19 . 683–765 . 2001 . 11244051 . 10.1146/annurev.immunol.19.1.683 . .
7. Sonnenberg GF, Nair MG, Kirn TJ, Zaph C, Fouser LA, Artis D . Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A . The Journal of Experimental Medicine . 207 . 6 . 1293–305 . June 2010 . 20498020 . 2882840 . 10.1084/jem.20092054 .
8. Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB . Interleukin-10 and related cytokines and receptors . Annual Review of Immunology . 22 . 929–79 . 2004 . 15032600 . 10.1146/annurev.immunol.22.012703.104622 .
9. Witte K, Witte E, Sabat R, Wolk K . IL-28A, IL-28B, and IL-29: promising cytokines with type I interferon-like properties . Cytokine & Growth Factor Reviews . 21 . 4 . 237–51 . August 2010 . 20655797 . 10.1016/j.cytogfr.2010.04.002 .
10. Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, Wood WI, Goddard AD, Gurney AL . 6 . Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R . The Journal of Biological Chemistry . 275 . 40 . 31335–9 . October 2000 . 10875937 . 10.1074/jbc.M005304200 . free .