Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens


Infections by attaching and effacing (A/E) bacterial pathogens, such as Escherichia coli O157:H7, pose a serious threat to public health. Using a mouse A/E pathogen, Citrobacter rodentium, we show that interleukin-22 (IL-22) has a crucial role in the early phase of host defense against C. rodentium. Infection of IL-22 knockout mice results in increased intestinal epithelial damage, systemic bacterial burden and mortality. We also find that IL-23 is required for the early induction of IL-22 during C. rodentium infection, and adaptive immunity is not essential for the protective role of IL-22 in this model. Instead, IL-22 is required for the direct induction of the Reg family of antimicrobial proteins, including RegIIIβ and RegIIIγ, in colonic epithelial cells. Exogenous mouse or human RegIIIγ substantially improves survival of IL-22 knockout mice after C. rodentium infection. Together, our data identify a new innate immune function for IL-22 in regulating early defense mechanisms against A/E bacterial pathogens.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Host defense against C. rodentium infection.
Figure 2: IL-22 deficiency renders mice susceptible to C. rodentium infection.
Figure 3: IL-19, IL-20, IL-24 and IL-17 are all dispensable during C. rodentium infection.
Figure 4: Crucial role of IL-22 in early host defense for maintenance of colonic epithelial cell integrity against C. rodentium.
Figure 5: IL-22, produced by DCs, is crucial for innate immune responses against C. rodentium infection.
Figure 6: Reg family proteins mediate important host defense mechanisms downstream of IL-22.

Accession codes


Gene Expression Omnibus


  1. 1

    WHO. The world health report 2004—changing history. 121 (WHO, Geneva, 2004).

  2. 2

    Mead, P.S. & Griffin, P.M. Escherichia coli O157:H7. Lancet 352, 1207–1212 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Centers for Disease Control (CDC). Ongoing multistate outbreak of Escherichia coli serotype O157:H7 infections associated with consumption of fresh spinach–United States, September 2006. MMWR Morb. Mortal. Wkly. Rep. 55, 1045–1046 (2006).

  4. 4

    Eckmann, L. Animal models of inflammatory bowel disease: lessons from enteric infections. Ann. NY Acad. Sci. 1072, 28–38 (2006).

    CAS  Article  Google Scholar 

  5. 5

    Schauer, D.B. & Falkow, S. Attaching and effacing locus of a Citrobacter freundii biotype that causes transmissible murine colonic hyperplasia. Infect. Immun. 61, 2486–2492 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    MacDonald, T.T. & Monteleone, G. Immunity, inflammation and allergy in the gut. Science 307, 1920–1925 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Takahashi, A. et al. Production of β-defensin-2 by human colonic epithelial cells induced by Salmonella enteritidis flagella filament structural protein. FEBS Lett. 508, 484–488 (2001).

    CAS  Article  Google Scholar 

  8. 8

    Bry, L. & Brenner, M.B. Critical role of T cell–dependent serum antibody, but not the gut-associated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an attaching and effacing pathogen. J. Immunol. 172, 433–441 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Maaser, C. et al. Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies. Infect. Immun. 72, 3315–3324 (2004).

    CAS  Article  Google Scholar 

  10. 10

    Simmons, C.P. et al. Impaired resistance and enhanced pathology during infection with a noninvasive, attaching-effacing enteric bacterial pathogen, Citrobacter rodentium, in mice lacking IL-12 or IFN-γ. J. Immunol. 168, 1804–1812 (2002).

    CAS  Article  Google Scholar 

  11. 11

    Goncalves, N.S. et al. Critical role for tumor necrosis factor-α in controlling the number of lumenal pathogenic bacteria and immunopathology in infectious colitis. Infect. Immun. 69, 6651–6659 (2001).

    CAS  Article  Google Scholar 

  12. 12

    Pestka, S. et al. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 22, 929–979 (2004).

    CAS  Article  Google Scholar 

  13. 13

    Renauld, J-C. Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators. Nat. Rev. Immunol. 3, 667–676 (2003).

    CAS  Article  Google Scholar 

  14. 14

    Gurney, A.L. IL-22, a TH1 cytokine that targets the pancreas and select other peripheral tissues. Int. Immunopharmacol. 4, 669–677 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23–induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Brand, S. et al. IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G827–G838 (2006).

    CAS  Article  Google Scholar 

  18. 18

    Levillayer, F., Mas, M., Levi-Acobas, F., Brahic, M. & Bureau, J.F. Interleukin 22 is a candidate gene for Tmevp3, a locus controlling Theiler's virus–induced neurological diseases. Genetics 176, 1835–1844 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by TH17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

    CAS  Article  Google Scholar 

  20. 20

    Misse, D. et al. IL-22 participates in an innate anti–HIV-1 host-resistance network through acute-phase protein induction. J. Immunol. 178, 407–415 (2007).

    CAS  Article  Google Scholar 

  21. 21

    Weber, G.F. et al. Inhibition of interleukin-22 attenuates bacterial load and organ failure during acute polymicrobial sepsis. Infect. Immun. 75, 1690–1697 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Wolk, K. et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur. J. Immunol. 36, 1309–1323 (2006).

    CAS  Article  Google Scholar 

  23. 23

    Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    CAS  Article  Google Scholar 

  24. 24

    Nagalakshmi, M.L., Murphy, E., McClanahan, T. & de Waal Malefyt, R. Expression patterns of IL-10 ligand and receptor gene families provide leads for biological characterization. Int. Immunopharmacol. 4, 577–592 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Andoh, A. et al. Interleukin-22, a Member of the IL-10 subfamily, Induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129, 969–984 (2005).

    CAS  Article  Google Scholar 

  26. 26

    Wolk, K., Kunz, S., Asadullah, K. & Sabat, R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J. Immunol. 168, 5397–5402 (2002).

    CAS  Article  Google Scholar 

  27. 27

    Sa, S.M. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J. Immunol. 178, 2229–2240 (2007).

    CAS  Article  Google Scholar 

  28. 28

    Happel, K.I. et al. Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J. Exp. Med. 202, 761–769 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Toy, D. et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J. Immunol. 177, 36–39 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Kuestner, R.E. et al. Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J. Immunol. 179, 5462–5473 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Witowski, J., Ksiazek, K. & Jorres, A. Interleukin-17: a mediator of inflammatory responses. Cell. Mol. Life Sci. 61, 567–579 (2004).

    CAS  Article  Google Scholar 

  32. 32

    Vallance, B.A., Deng, W., Knodler, L.A. & Finlay, B.B. Mice lacking T and B lymphocytes develop transient colitis and crypt hyperplasia yet suffer impaired bacterial clearance during Citrobacter rodentium infection. Infect. Immun. 70, 2070–2081 (2002).

    CAS  Article  Google Scholar 

  33. 33

    Ganz, T. Defensins and host defense. Science 286, 420–421 (1999).

    CAS  Article  Google Scholar 

  34. 34

    Cash, H.L., Whitham, C.V., Behrendt, C.L. & Hooper, L.V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Kastelein, R.A., Hunter, C.A. & Cua, D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

    CAS  Article  Google Scholar 

  36. 36

    Keilbaugh, S.A. et al. Activation of RegIIIβ/γ and interferon γ expression in the intestinal tract of SCID mice: an innate response to bacterial colonisation of the gut. Gut 54, 623–629 (2005).

    CAS  Article  Google Scholar 

  37. 37

    Ogawa, H. et al. Increased expression of HIP/PAP and regenerating gene III in human inflammatory bowel disease and a murine bacterial reconstitution model. Inflamm. Bowel Dis. 9, 162–170 (2003).

    Article  Google Scholar 

  38. 38

    Ogawa, H., Fukushima, K., Sasaki, I. & Matsuno, S. Identification of genes involved in mucosal defense and inflammation associated with normal enteric bacteria. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G492–G499 (2000).

    CAS  Article  Google Scholar 

  39. 39

    Iovanna, J., Orelle, B., Keim, V. & Dagorn, J.C. Messenger RNA sequence and expression of rat pancreatitis-associated protein, a lectin-related protein overexpressed during acute experimental pancreatitis. J. Biol. Chem. 266, 24664–24669 (1991).

    CAS  PubMed  Google Scholar 

  40. 40

    Moucadel, V. et al. Cdx1 promotes cellular growth of epithelial intestinal cells through induction of the secretory protein PAP I. Eur. J. Cell Biol. 80, 156–163 (2001).

    CAS  Article  Google Scholar 

  41. 41

    Pull, S.L., Doherty, J.M., Mills, J.C., Gordon, J.I. & Stappenbeck, T.S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl. Acad. Sci. USA 102, 99–104 (2005).

    CAS  Article  Google Scholar 

  42. 42

    Kebir, H. et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med. 13, 1173–1175 (2007).

    CAS  Article  Google Scholar 

  43. 43

    Ghilardi, N. et al. Compromised humoral and delayed-type hypersensitivity responses in IL-23–deficient mice. J. Immunol. 172, 2827–2833 (2004).

    CAS  Article  Google Scholar 

  44. 44

    Camerini, V., Panwala, C. & Kronenberg, M. Regional specialization of the mucosal immune system. Intraepithelial lymphocytes of the large intestine have a different phenotype and function than those of the small intestine. J. Immunol. 151, 1765–1776 (1993).

    CAS  PubMed  Google Scholar 

Download references


The authors thank A. Chan, H. Spits, E. Brown and B. Irving, all in Genentech, Inc., for critical suggestions; A. Minn and J. Ding, in Genentech, Inc., for the constructs of RegIII fusion proteins; W. Lee, C. Dela Cruz and the Genentech Histology and Immunohistochemistry Laboratories for technical assistance.

Author information




Y.Z. performed the majority of the experimental work. P.A.V. characterized IL-20Rβ knockout mice, developed IHC staining for IL-22 and contributed partly to Figures 2, 3, 4, 5 and 6. D.M.D. contributed to the majority of the histological analysis. Y.H. characterized the IL-17RC knockout mice and partly contributed to Figure 3. S.M.S. characterized human colon cell lines. Q.G. partly contributed to Figure 4. Z.M. and A.R.A. performed all of the microarray and bioinformatic analyses, respectively, and contributed partly to Figure 6. N.G. and F.J.d.S. provided and characterized p19 knockout mice and contributed partly to Figure 1. W.O. characterized IL-22R expression on various cells. W.O. and Y.Z. devised and planned the project. The manuscript was written by W.O., Y.Z., D.M.D. and P.A.V.

Corresponding author

Correspondence to Wenjun Ouyang.

Ethics declarations

Competing interests

All authors are employed by Genentech.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–7, Supplementary Table 1 and Supplementary Methods (PDF 2267 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Zheng, Y., Valdez, P., Danilenko, D. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14, 282–289 (2008).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing