SEARCH

SEARCH BY CITATION

Keywords:

  • epithelial defense;
  • mucin 1;
  • antibacterial proteins;
  • epithelial regeneration;
  • susceptibility genes;
  • inflammatory bowel disease

Abstract

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

An interleukin (IL)-10 family cytokine, IL-22 is characterized by several unique biological properties, including 1) the target restricted to innate cells; 2) the distinct expression pattern between large and small intestines; 3) alteration of the cellular source depending on several factors; 4) the dual abilities to serve as protective versus proinflammatory mediators in inflammatory responses; and 5) the close association with some major inflammatory bowel disease (IBD) susceptibility genes. The major functions of IL-22 in the intestine are the stimulation of epithelial cells to produce a wide variety of antibacterial proteins, the reinforcement of mucus barrier through stimulation of mucin 1 production under intestinal inflammatory conditions, and the enhancement of epithelial regeneration with goblet cell restitution. Through these beneficial functions, IL-22 contributes to the improvement of some types of experimental chronic colitis, which are mediated by T helper (Th)1 or Th2 responses. Most important, studies using both loss-of-function and gain-of-function approaches have clearly demonstrated the ability of IL-22 to promote intestinal wound healing from acute intestinal injury. These findings highlight IL-22 as an attractive and promising target for future IBD therapy. Alternatively, the enormous progress in the field of IL-22 biology has also suggested more complicated mechanisms with the IL-22 pathway than previously predicted. This review article briefly summarizes previous and current knowledge on IL-22 particularly associated with intestinal inflammation. (Inflamm Bowel Dis 2012;)

Interleukin (IL)-22 is an IL-10 cytokine family member that was originally discovered in 2000 from a mouse T cell line stimulated with IL-9.1 Enormous progress in this area has since been seen particularly during last 5 years.2–6 The growing body of evidence highlights several characteristic properties with IL-22. The first characteristic is the cellular targets. IL-22 can specifically target innate cells such as intestinal and respiratory epithelial cells, keratinocytes, and hepatocytes—this is due to the restricted expression of IL-22 receptor (IL-22R) on these innate, but not adaptive immune, cells.7 The second characteristic is the unique expression pattern in the intestine. IL-22 expression in the large intestine of mice and humans is elicited under inflammatory conditions,8–10 whereas IL-22 is constitutively expressed in the normal small intestine.11, 12 The third characteristic is the dual abilities to serve as protective versus proinflammatory factors—presumably depending on the tissue targeted, the disease mechanism involved, or the local cytokine environment exposed. For example, IL-22 contributes to the improvement of experimental colitis and hepatitis,9, 10, 13 but it also causes psoriasis.14, 15 Therefore, IL-22 has been metaphorically called “a sheep in wolf's clothing”16 or “a two-headed cytokine.”2 The fourth characteristic is the close association of IL-22 with inflammatory bowel disease (IBD) susceptibility genes. Several IBD susceptibility genes such as IL-23R, IL-10R2, and signal transducer and activator of transcription (STAT)3 are functionally associated with IL-22 directly or indirectly.17 Therefore, these findings suggest that further work on IL-22 would have the potential to not only dissect the fundamental mechanism of IBD, but also provide an important rationale to develop novel therapeutic measures for this disorder.

DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

IL-22 is constitutively expressed in the small intestine of humans and mice to preserve the intestinal homeostasis against enteric microorganisms.11, 12, 18 In contrast, IL-22 expression is hardly detectable in the normal colon of humans8, 9, 19, 20 and mice.9, 10, 21 Diverse intestinal inflammatory conditions, which range from IBD to infectious colitis, elicit the expression of IL-22 in the colon.8–10, 19–21 Interestingly, the expression level of IL-22 in the inflamed colon tends to be higher in Crohn's disease (CD) patients as compared with ulcerative colitis (UC) patients.8, 9, 19 In CD, serum IL-22 levels are significantly higher in patients with risk-increasing il23r variants than in those with risk-decreasing il23r variants.22

In mice, IL-22 is highly expressed in the inflamed colon of T helper (Th)1-mediated colitis model (CD45RB model) as compared with Th2-mediated colitis model (T-cell receptor [TCR]α knockout [KO] mice).9 The CD45RB model has widely been used for the study of human CD,23 and the TCRα KO model shares some characteristic features with human UC.24 These findings suggest that colonic IL-22 expression, which can be elicited by inflammatory insults, is further conditioned by the local cytokine environments in the inflamed colon (e.g., Th1 vs. Th2). Indeed, in skin, atopic dermatitis with significant contribution from Th2 responses exhibits lower levels of IL-22 expressions as compared with psoriasis characterized by enhanced Th1/Th17 responses.25

CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

IL-22 can be produced by a wide variety of innate and adaptive immune cells, including Th17 CD4+ T cells, Th22 CD4+ T cells, CD8+ T cells, TCRγδ T cells, dendritic cells (DCs), natural killer (NK) cells, lymphoid tissue inducer (LTi) cells, and innate lymphoid cells (ILCs).2–6 Interestingly, the major cellular source of IL-22 seems to differ depending on the tissue involved4 (Fig. 1). For example, Th22 cells, which express skin homing receptors (CCR4 and CCR10) and produce IL-22 but not IL-17, represent the major source of IL-22 in the skin.26, 27 In pulmonary immune response, TCRγδ T cells and Th17 cells primarily contribute to the production of IL-22.28, 29 In human tonsile, stage-3 immature conventional NK cells serve as the source of IL-22.30 IL-1β is required to retain the expression of aryl hydrocarbon receptor (AHR) and thus IL-22 in the immature NK cells.30 Similarly, such immature NK cells are also the source of IL-22 in human uterine mucosa.31

thumbnail image

Figure 1. Cellular sources of IL-22. Potential major cellular sources in the small intestine (SI, orange), skin (pink), lung (green), tonsile and uterine (yellow), and colon (blue) are shown. Some innate cells in the colon may represent a same linage with different differentiation stages.

Download figure to PowerPoint

In the small intestine under healthy steady state and also under an inflammatory condition caused by Citrobacter rodentium infection, RAR-related orphan receptor (ROR)γt-dependent innate lymphoid cells (ILCs), which share some characteristics with NK cells and LTi cells (Lin Thy1+ cKit+ CD4+ CD3), are primarily responsible for the production of IL-22.11, 12, 18, 32, 33 These IL-22-producing ILCs are referred as “ILC22 cells.”32 The ILC22 cells include NK receptor-expressing LTi cells, ILCs (LinThy1+CD127+cKit+CD3) expressing a natural cytotoxicity receptor NKp46 with low to no NK1.1 expression, and human NK22 cells expressing NKp44, CD56, and CCR6 with low expression of NKp46.32 Recent studies suggest that NKp46+ ILCs are the progeny of LTi cells.33 Gut commensals promote the activation of RORγt in ILC22 cells to enhance their development,11 but microbiota are not strictly required for the development of ILC22 cells, as indicated by the presence of these cells in germ-free mice.18, 34 In response to Toxoplasma gondii infection, a major source of IL-22 in the small intestine may shift from ILC22 cells to CD4+ T cells.35 Commensals may be required for the shift, as IL-22 becomes undetectable in the small intestine of germ-free mice after a monoassociated infection with T. gondii.35

CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

As compared with the other tissues mentioned above, cellular sources of IL-22 in the inflamed colon seem to differ depending on the type of inflammation. NK cells and Th17 CD4+ T cells have been reported to produce IL-22 in the inflamed colon of UC patients.20 In contrast, CD4+ T cells expressing NK group 2 member D (NKG2D) have been proposed to produce IL-22 in the inflamed intestine of CD patients.36 In addition, intestinal NKp46+ NKp44, but not NKp46 NKp44+, NK cells have also been demonstrated to produce IL-22.37 Interestingly, IL-22-producing NKp46+ NKp44 NK cells are more increased in the inflamed colon of CD patients as compared with that of UC patients.37 In addition to such NK cells, ILCs, which are characterized by lineage marker (Lin) CD45+, CD3, IL-7Rα+ phenotype, have recently been identified to exist in human colon.38 These ILCs are further classified into two subsets depending on the expression pattern of neural cell adhesion molecule (NCAM, CD56). CD56+ ILCs produce IL-22 and IL-26 in response to IL-23, while CD56 ILCs produce IL-17A and IL-17F. Interestingly, an increased number of both IL-22-producing CD56+ ILCs and IL-17-producing CD56 ILCs are observed in the inflamed colon of CD patients as compared with UC patients.38 These findings indicate that innate cell populations (NK cells and CD56+ ILCs) producing IL-22 expand more in CD as compared with UC. The enhanced expansion of these NK cells and ILCs may contribute to maintaining higher levels of IL-22 expressions in CD mucosa as compared with UC mucosa.

As observed in IBD patients, major cellular sources of IL-22 in the inflamed colon of mouse IBD models also tend to alter depending upon the fundamental disease mechanisms. In the Th1-mediated experimental colitis model (CD45RB model), both NK cells and Th17 cells are primarily responsible for the production of IL-22 in the inflamed colon.10 The NK cells are further classified into CD27high versus CD27low NK cell subsets. Interestingly, IL-23 can induce the IL-22 expression in both NK subsets, whereas IL-12 and IL-18 induce IL-22 expression only in the CD27high NK cell subset.10 CD11c+ dendritic cells (DCs) may represent a major source of IL-22 in an acute intestinal injury model induced by oral administration of dextran sulfate sodium (DSS).21 In the C. rodentium-induced infectious colitis model, DCs may also serve as a major source of IL-22.39 Alternatively, a recent study demonstrates in the C. rodentium infectious model that RORγt+ LTi cells, but not DCs, produce IL-22 in the inflamed colon, and DCs rather contribute to the activation of the naïve LTi cells through production of IL-23.40 Similarly, IL-23-dependent CD4+ LTi cells, which are characterized by the expression of NKp46 and CD90 and by the localization within the intraepithelial compartment of colon, have been proposed to represent the dominant source of colonic IL-22 in the context of C. rodentium infection.41

SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

IL-22 production by Th17 T cells is induced by IL-23 or IL-6.14 Notably, TGF-β, although critical for Th17 differentiation, inhibits the IL-22 production.14 The inhibition of IL-22 production by TGF-β is mediated by a transcription factor, c-Maf.42 As observed in Th17 cells, IL-23 also acts on ILCs to induce the expression of IL-22.43 AHR, which serves as a cytosolic sensor of aromatic hydrocarbons and plays critical roles in the metabolism of benzopyrene as well as in the acute toxicity of halogenated dioxins, is also required for the ability of Th17 T cells to produce IL-22.44 Significantly decreased expression of AHR is observed in CD patients as compared with UC patients.45 In addition, AHR sustains the expression of NKp46 in small intestinal ILCs through activation of Notch pathway and consequently drives the development of IL-22-producing ILCs.18 AHR is also required for the development of colonic ILCs.46 In the DSS-induced colonic injury model, IL-22 expression in the colon may be induced through TLR4 (LPS), TLR9 (CpG), or to a lesser extent TLR2 (lipteichoic acid).21

RESPONDER CELLS TO IL-22

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

IL-22 is recognized by a heterodimeric receptor consisting of IL-22R1 and IL-10Rβ.2–6 IL-10Rβ is ubiquitously expressed by a majority of cell types, while the expression of IL-22R1 is restricted to innate cells such as epithelial cells, hepatocytes, and keratinocytes.2–6 Therefore, this expression pattern of IL-22R1 allows IL-22 to specifically target innate, but not adaptive immune, cell populations.7 In the intestine of mice and humans, IL-22R1 is expressed by epithelial cells and myofibroblasts.8, 9, 20 However, the responsiveness of myofibroblasts to IL-22 may be much weaker as compared with that of epithelial cells, as indicated by the requirement of high (200 ng/mL) versus low (5 ng/mL) doses of IL-22 for the activation of myofibroblasts versus epithelial cells, respectively.8, 9

ACTIVATION OF STAT3 BY IL-22

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

IL-22 stimulation can activate STAT3, to a lesser extent STAT1, and in certain cells STAT5.47, 48 In addition, the ability of IL-22 to activate Erk1/2, JNK, and p38 MAP kinase pathways has been proposed in a rat hepatoma cell line.47, 48 A high dose of IL-22 also induces a transient activation of Erk1/2 in colonic cancer cell line HT29.19 However, the concept of the Erk1/2 activation by IL-22 has been challenged by some reports showing the inability of IL-22 to activate Erk/1/2 in an HepG2 cell line49 and in primary epithelial cells from human and mouse colons.9 In contrast, the strong activity of IL-22 to stimulate STAT3 has been well confirmed using human colonic biopsies, human colonic cancer cell lines, and primary mouse colonic epithelial cells.9, 10, 20, 21 Most importantly, epithelial STAT3 activation under DSS-induced colitis has been demonstrated to depend more on IL-22 rather than IL-6, a well-known STAT3 activator.21 This observation may be unexpected but consistent with a recent discovery that IL-22R1 uses a novel mechanism to “constitutively” activate STAT3 through constitutive interaction of its C-terminal tail with the coiled-coil domain of STAT3.50 Indeed, IL-22 has recently been shown to have a strong ability to activate STAT3 as compared with IL-6.51

IL-22 AND ANTIBACTERIAL PROTEINS

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

IL-22 has been implicated in several important functions in innate cells, including the host defense against microorganisms and wound healing.2–6 One of the major functions of IL-22 is the induction of antibacterial protein expressions. IL-22 stimulates keratinocytes to produce S100A7 and S100A8.52 In collaboration with IL-17, IL-22 also synergistically promotes the expression of β-defensin 2 and S100A9 in keratinocytes.53

Interestingly, even though the expression levels of S100A8 (also called MRP8), S100A9 (also called MRP14), regenerating gene (Reg) IIIγ and RegIIIβ are different, they are significantly enhanced and commonly observed in the colonic epithelial cells of different types of experimental “chronic” colitis models, including Th1-mediated and Th2-mediated colitis models.54 Alternatively, in the DSS-induced “acute” colonic injury model, the expression pattern of these molecules differs in the acute versus recovery phases.54 RegIIIγ was initially thought to play a role in cell regeneration, but subsequent studies have identified the ability to serve as an antibacterial protein against Gram(+) bacteria.55 Interestingly, IL-22 stimulates epithelial cells to produce RegIIIγ and RegIIIβ in the context of infection with a Gram(-) bacteria, C. rodentium,39 whereas Listeria monocytogenes stimulates the production of RegIIIγ in an MyD88-dependent manner.56 In the DSS-induced colonic injury model, IL-22-dependent induction of RegIIIγ and β expressions through STAT3 has been proposed,21 but a recent study suggests that IL-23 (the inducer of IL-22 expression) rather than IL-22 directly induces the expression of RegIIIγ and β.57 An IL-17 family member, IL-17C, which is produced by intestinal epithelial cells, has recently been shown to act in synergy with IL-22 to induce the expression of antibacterial proteins, including S100A8, S100A9, RegIIIβ, and RegIIIγ.58 The ability of IL-22 to promote the expression of β-defensin 2 has also been shown using a colonic cancer cell line, HT29.19 In CD patients, IL-22 induces the production of lipopolysaccharide (LPS)-binding protein by hepatocytes, which may contribute to the prevention of LPS-induced systemic responses.49

IL-22 AND INTESTINAL MUCUS BARRIER

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

Intestinal mucus functions as a lubricant and a physiological barrier between luminal contents and the mucosal surface.59 Mucin 1 (Muc1), which is a heavily O-glycosylated membrane-bound mucin, represents one of the major components in the intestinal mucus.59 Bacteria-derived adenosine 5′-triphosphate (ATP) stimulates the development of intestinal Th17 T cells,60 and a segmented filamentous bacterium also leads to the appearance of intestinal Th17 cells.61 Interestingly, a recent study proposes the ability of Muc1 to suppress the expansion of both Th17 cells and IL-17-producing ILCs, presumably by blocking the translocation of bacterial products from intestinal lumen into intestinal lamina propria.62

The protective roles of Muc1 in both Th2-mediated colitis of TCRα KO mice and Th1-mediated colitis of the CD45RB model have recently been shown using loss-of-function systems (Muc1 KO mice).62 Alternatively, forced overexpressions (Muc1 transgenic mouse system) of “hypoglycosylated” Muc1 make breaches in the static mucus barrier63 and exacerbate Th1/Th17-mediated colitis in IL-10 KO mice,64 suggesting that complete glycosylation of Muc1 is required for eliciting the protective function in colitis. Indeed, impaired glycosylation in the mucus exacerbates or causes colitis.65, 66 Interestingly, the ability of IL-22 to promote the production of functional Muc1 through activation of STAT3, but not STAT1, has been demonstrated using human colonic cancer cell lines (T84 and HT29) and primary colonic epithelial cells from mice.9, 67 Consistent with these findings, binding of STAT3 within the promoter region of the muc1 gene has been demonstrated.68 Most notably, Muc1 expression was abolished in a patient with the early onset form of IBD, who had a functional polymorphism within il10rb, a receptor for IL-22.51

IL-22 AND EPITHELIAL REGENERATION

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

IL-22 has been demonstrated to promote the epithelial cell regeneration with goblet cell restitution under intestinal inflammatory conditions, but it may play no obvious role in normal colonic epithelial homeostasis in the healthy state.9, 21 Consistent with these observations, STAT3 activation through IL-22 enhances the transcription of antiapoptotic and pro-proliferative genes such as birc5, pla2g5, smo, myc, and mcl1 under inflammatory conditions.69 In addition, IL-22 stimulates a colonic cancer cell line to express a molecule termed “deleted in malignant brain tumor 1 (DMBT1)” that may play a role in epithelial cell differentiation.70 RegIα, which serves as a trophic and antiapoptotic factor, is also reported to be induced in the inflamed colon of UC patients by IL-22.20

PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

Recent accumulating evidence indicates dual abilities of IL-22 to serve as protective versus inflammatory mediators depending on several factors (Fig. 2). The protective role of IL-22 has been shown in ConA-induced hepatitis,13 alcoholic fatty liver and liver damage,71 GVHD associated with heart allografts,72 autoimmune myocarditis,73 allergic airway inflammation,74 and uveitis.75 In contrast, the proinflammatory role of IL-22 has also been demonstrated in collagen-induced arthritis.76 In skin, IL-22 causes psoriasis,15 but it may also suppress acne vice versa.77 IL-22 may play no role in experimental autoimmune encephalomyelitis.78 In infectious models, deficiency of IL-22 makes mice highly susceptible to a broad spectrum of pathogens, including Klebsiella pneumoniae,29 Mycobacterium tuberculosis,79 and cutaneous Staphylococcus aureus.80

thumbnail image

Figure 2. Role of IL-22 in inflammatory responses. Experimental diseases, in which IL-22 has been shown to play a proinflammatory role, are indicated in pink boxes. Experimental diseases, in which IL-22 has been demonstrated to play a protective role, are listed in blue boxes.

Download figure to PowerPoint

ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

In addition, IL-22 plays dual roles in intestinal infection, presumably depending on the type of pathogen. IL-22 provides a protective role against C. rodentium-induced colitis,18, 39, 41, 46 systemic infection with Salmonella enterica,81 and gastrointestinal Candidasis in the absence of IL-17R.82 In contrast, IL-22 is required for the development of T. gondii-induced immunopathology in the small intestine.35

The potential role of IL-22 in IBD has also been explored using mouse model systems (Fig. 2). In a Th2-mediated chronic colitis model (TCRα KO mice), supplementation of IL-22 expressions in the inflamed colon through a local gene delivery system improves colitis by reinforcing intestinal mucus barrier function.9 In a Th1-mediated colitis model (CD45RB model), there is no significant difference in colitis severity when IL-22-deficient versus IL-22-intact CD4+ CD45RBhigh T cells are transferred into recipient recombination activation gene (RAG)1 KO mice that have endogenous IL-22 productions by innate cells.10, 83 In contrast, IL-22-deficient CD4+ CD45RBhigh T cells cause more severe colitis as compared with IL-22-intact CD4+ CD45RBhigh T cells when IL-22-deficient and RAG1-deficient double knockout mice are used as the recipient.10 These findings suggest that both donor T cell-derived and recipient (NK cell)-derived IL-22 participate in the suppression of this colitis, but host innate cell-derived IL-22 has a more prominent role in this regard.10 In contrast, the proinflammatory role of memory CD4+ T cell-derived IL-22 in a new colitis model has also been proposed.84 The authors propose that adoptive transfer of CD25+ cell-depleted CD45RBlow memory CD4+ T cells can induce colitis in recipient RAG1 KO mice, but IL-22-deficient CD25+ cell-depleted CD45RBlow memory CD4+ T cells are unable to do it.

Unlike the IBD models mentioned above, expression of IL-22 is not elicited in the trinitrobenzene sulfonic acid (TNBS)-induced colitis model, and thus a strategy to induce the expression of IL-22 can be applied for the treatment of this colitis.45 Administration of an AHR agonist, Ficz, augments the colonic IL-22 expression and suppresses TNBS colitis.45 Neutralization of the IL-22 activity by treatment with anti-IL-22 monoclonal antibodies (mAbs) abolishes the beneficial effect of Ficz on this colitis. Ficz also has a therapeutic effect on Th1-mediated colitis of the CD45RB model.45

ROLE OF IL-22 IN INTESTINAL WOUND HEALING

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

DSS-induced acute colonic injury spontaneously recovers after termination of DSS treatment, allowing us to closely examine the intestinal wound healing process.24, 85 In this model, the ability of IL-22 to promote intestinal wound healing has been well proven using different experimental approaches.9, 10, 21, 45, 57 IL-22 KO mice exhibit impaired recovery from DSS-induced acute colonic injury.21 Administration of neutralizing anti-IL-22 Abs also delays the recovery in wildtype mice.9 No recovery is observed in IL-22-deficient and RAG1-deficient double knockout mice lacking both T and B cells.10

In addition to these loss-of-function systems, the role of IL-22 in intestinal wound healing after exposure to DSS has been explored using gain-of-function systems that may be applicable to IBD patients. Supplementation of IL-22 expressions in the colon through a local gene delivery system promotes the recovery with enhanced goblet cell restitution.9 In addition, treatment with Ficz, which is capable of augmenting the IL-22 expression, suppresses the development of DSS-induced chronic colitis that is induced by repeated administrations of DSS at each interval.45 Interestingly, recovery from DSS-induced acute colonic injury is significantly impaired in IL-23R-deficient and RAG2-deficient double knockout mice that lack IL-22 expression, and administration of recombinant IL-22 rescues the recovery in these mice.57

REGULATION OF IL-22 FUNCTION

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

The function of IL-22 is positively or negatively regulated by some other factors. In psoriasis, the cooperative role of IL-22, IL-17, and IFN-γ may be required to fully establish the pathogenesis.86 IL-22 can induce psoriasis-like skin alteration, including acanthosis and hypogranularity, and IL-17 and IFN-γ are also necessary to induce the recruitment of inflammatory cells such as T cells and neutrophils into the region.86 In bleomycin-induced airway inflammation, IL-22 plays a proinflammatory role in the presence of IL-17A and, in turn, plays a protective role in the absence of IL-17A.87 This finding suggests that IL-17A governs the proinflammatory versus tissue-protective properties of IL-22.87 In addition, the lymphotoxin (LT) pathway, which is induced by the interaction of LTβR with LTβ, but not with LIGHT, controls the protective function of IL-22 against C. rodentium.40

Importantly, the soluble class II cytokine receptor, designated IL-22Ra2 (also called IL-22 binding protein, IL-22BP, or CRF2-10), exists in our bodies.88–90 IL-22BP has high affinity binding capability for IL-22 and serves as an endogenous inhibitor of IL-22 activity.88–90 The cellular source of IL-22BP has not been fully established, but IL-22BP is highly expressed in placenta, spleen, skin, and lung and to lesser extent in large and small intestine of humans.88 IL-22BP expressions are also detectable in normal colon of mice.9 Interestingly, distinct expression patterns of IL-22 versus IL-22BP are observed in DSS-induced acute colonic injury—IL-22 expressions increase whereas IL-22BP expressions decrease.9 Supplementation of IL-22BP expressions in the inflamed colon through a local gene delivery system significantly delays the recovery from the DSS-induced acute colonic injury and also suppresses goblet cell restitution.9 These findings indicate that IL-22 activity in the colon is controlled by its endogenous inhibitor IL-22BP.

ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

An attractive biological property with IL-22 is the functional association with some major IBD susceptibility genes (Fig. 3). Interaction of IL-23 with IL-23R has been implicated in the maintenance of IL-22-producing Th17 cells91, 92 and in the development of IL-22-producing innate cells, including ILCs, LTi cells, and NK cells.10, 37, 38, 41, 43 Functional polymorphisms within the Il23r gene are negatively associated with the development of both CD and UC.91, 92 IL-22 binds to a heterodimeric receptor composed of IL-10Rβ and IL-22R1. Polymorphisms of il10rb are positively associated with both CD and UC.93 In addition, il22 is located within a UC-risk locus on chromosome 12q15.94 The receptor ligation by IL-22 induces rapid activation of STAT3 through Janus kinase (JAK)2 and TYK2. These stat3, jak2, and tyk2 all are well-defined susceptibility genes of CD and to lesser extent UC.91, 92 The STAT3 activation then stimulates epithelial cells to produce Muc1.9, 67, 68 A recent genome-wide association study proposes muc1 as a potential candidate gene associated with CD.95

thumbnail image

Figure 3. Functional linkage of IL-22 to some IBD susceptibility genes. Ligations of IL-23R by IL-23 maintain the expansion of IL-22-producing Th17 cells and induce the development of IL-22-producing ILCs. Subsequent ligation of IL-10R2/IL-22R1 receptor complex by IL-22 activates JAK2/STAT3 pathway in epithelial cells. The activated STAT3 then stimulates epithelial cells to produce RegIII and Muc1 and also promotes epithelial cell regeneration. Well-defined IBD association genes are indicated in blue boxes, and potential IBD association genes indicated in yellow boxes.

Download figure to PowerPoint

CONCLUSION

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES

Despite only 10 years of history since the discovery, enormous efforts and rapid progression in the field of IL-22 have been seen. Indeed, as mentioned above, several unique biological properties of IL-22 have been defined. Importantly, the ability of IL-22 to promote intestinal wound healing in mice has been reproducibly confirmed by independent groups using different experimental approaches, and recent advances in genome-wide association studies have suggested the close association of the IL-22 pathway with some major IBD susceptibility genes. These facts clearly highlight IL-22 as a promising target for IBD therapy. However, given the potential of IL-22 to serve as both protective and proinflammatory mediators, depending on several factors, further extensive work on IL-22 would be necessary to bring novel and practical intervention for improving the lives of patients with IBD in an effective and safe manner.

REFERENCES

  1. Top of page
  2. Abstract
  3. DISTINCT EXPRESSION PATTERN OF IL-22 IN LARGE VERSUS SMALL INTESTINES
  4. CELLULAR SOURCES OF IL-22 IN THE SMALL INTESTINE
  5. CELLULAR SOURCES OF IL-22 IN THE LARGE INTESTINE
  6. SIGNALING MACHINERY TO INDUCE IL-22 EXPRESSION
  7. RESPONDER CELLS TO IL-22
  8. ACTIVATION OF STAT3 BY IL-22
  9. IL-22 AND ANTIBACTERIAL PROTEINS
  10. IL-22 AND INTESTINAL MUCUS BARRIER
  11. IL-22 AND EPITHELIAL REGENERATION
  12. PROTECTIVE VERSUS PROINFLAMMATORY ROLES OF IL-22 IN INFLAMMATORY RESPONSES
  13. ROLES OF IL-22 IN INTESTINAL INFLAMMATIONS
  14. ROLE OF IL-22 IN INTESTINAL WOUND HEALING
  15. REGULATION OF IL-22 FUNCTION
  16. ASSOCIATION OF IL-22 WITH IBD SUSCEPTIBILITY GENES
  17. CONCLUSION
  18. Acknowledgements
  19. REFERENCES