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Gene Review

Il21  -  interleukin 21

Mus musculus

Synonyms: IL-21, Interleukin-21
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Disease relevance of Il21


High impact information on Il21

  • In this issue of Cell, evidence is provided that this homeostatic proliferation, coupled with excess production of a cytokine, IL-21, is a key factor in susceptibility to autoimmune diabetes [9].
  • Furthermore, IL-21 blocked IL-15-induced expansion of resting NK cells, thus preventing the initiation of further innate responses [10].
  • Mice lacking IL-21R (IL-21R(-/-)) had normal NK cell development but no detectable responses to IL-21 [10].
  • We now report that IL-21, a product of activated T cells, may serve this function [10].
  • IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity [10].

Chemical compound and disease context of Il21

  • Using a recombinant vaccinia virus expressing 89.6 Env glycoprotein (vBD3) in a mouse challenge model, we observed that IL-21 plasmid produced sustained resistance to viral transmission when injected 5 days after DNA vaccination [11].
  • Specifically, IL-21 only demonstrated a therapeutic effect in mice challenged with a retinoic acid early inducible-1delta-bearing lymphoma but not in mice bearing parental RMA tumors lacking NKG2D ligands [12].

Biological context of Il21

  • Although B cell subsets expressed somewhat varied levels of the IL-21 receptor, LPS-stimulated follicular and marginal B cell subsets were also dominantly susceptible to IL-21-induced growth arrest and cell death [13].
  • Our data demonstrate that IL-21 is a new modulator of DC-T cell interaction with the potential to induce DC-mediated antigen-specific tolerance [1].
  • In order to study the biological functions of IL-21, we constructed a mIL-21 prokaryotic expression plasmid and expressed the recombinant mIL-21 protein in E. coli in present study [2].
  • IL-21 is capable of co-stimulating mature T cells, B cells, NK cells, and of stimulating CD16 expression on the surface of NK cells to induce ADCC in innate immune response [2].
  • In addition, the activation of primary B cells with IL-4, LPS, or anti-CD40 Ab does not prevent IL-21-mediated apoptosis [14].

Anatomical context of Il21


Associations of Il21 with chemical compounds

  • Interestingly, 2h incubation of these DC with IL-21 before injection completely inhibited the potential of these DC to induce a CHS reaction to the hapten fluorescein 5-isothiocyanate in vivo [1].

Physical interactions of Il21


Regulatory relationships of Il21

  • Functional studies demonstrated that IL-21 substantially inhibited proliferation and induced Bim-dependent apoptosis for LPS or CpG DNA-activated B cells [19].
  • In this study, we demonstrate that in certain tumor models IL-21-enhanced tumor rejection is NKG2D dependent [12].
  • IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice [20].
  • 1. Coinciding with these cellular changes IL-21 enhances cytolytic capacity across a spectrum of target sensitivities and induces IL-10 and IFN-gamma production [21].
  • In support of the latter possibility, we report that the recently described cytokine IL-21 can markedly enhance the proliferation of immature (and mature) NK cells in the presence of doses of IL-2 and IL-15 that by themselves have little growth-promoting activity [22].

Other interactions of Il21


Analytical, diagnostic and therapeutic context of Il21

  • By PCR, we demonstrate here constitutive expression of the specific IL-21 receptor and the common gamma-chain in DC, which together are able to mediate IL-21 signaling [1].
  • Thus, IL-21 is a potential useful therapeutic molecule for immunotherapy of malignancies, by eliciting innate and adaptive anti-tumor responses in tumor-bearing hosts [2].
  • Preliminary study on mouse interleukin-21 application in tumor gene therapy [23].
  • Mouse IL-21 expression was analyzed by Western blotting and its activities were detected by 3H-TdR incorporation and MTT assay [23].
  • Similarly, BCG vaccination induces IL-21 expression by human peripheral blood mononuclear cells (PBMCs) in a partially NKT cell-dependent fashion [24].


  1. Interleukin-21 inhibits dendritic cell-mediated T cell activation and induction of contact hypersensitivity in vivo. Brandt, K., Bulfone-Paus, S., Jenckel, A., Foster, D.C., Paus, R., Rückert, R. J. Invest. Dermatol. (2003) [Pubmed]
  2. Expression, purification and identification of recombinant mouse interleukin 21 protein in E. coli. Tang, W., Chen, G., Gu, Q., Pan, J., Wu, W. Cell. Mol. Immunol. (2006) [Pubmed]
  3. In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Wang, G., Tschoi, M., Spolski, R., Lou, Y., Ozaki, K., Feng, C., Kim, G., Leonard, W.J., Hwu, P. Cancer Res. (2003) [Pubmed]
  4. Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma. Kishida, T., Asada, H., Itokawa, Y., Cui, F.D., Shin-Ya, M., Gojo, S., Yasutomi, K., Ueda, Y., Yamagishi, H., Imanishi, J., Mazda, O. Mol. Ther. (2003) [Pubmed]
  5. Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. Smyth, M.J., Wallace, M.E., Nutt, S.L., Yagita, H., Godfrey, D.I., Hayakawa, Y. J. Exp. Med. (2005) [Pubmed]
  6. IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice. Kishida, T., Hiromura, Y., Shin-Ya, M., Asada, H., Kuriyama, H., Sugai, M., Shimizu, A., Yokota, Y., Hama, T., Imanishi, J., Hisa, Y., Mazda, O. J. Immunol. (2007) [Pubmed]
  7. IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21R.Fc reduces disease progression. Herber, D., Brown, T.P., Liang, S., Young, D.A., Collins, M., Dunussi-Joannopoulos, K. J. Immunol. (2007) [Pubmed]
  8. Cutting edge: IL-21 is not essential for Th17 differentiation or experimental autoimmune encephalomyelitis. Coquet, J.M., Chakravarti, S., Smyth, M.J., Godfrey, D.I. J. Immunol. (2008) [Pubmed]
  9. Driven to autoimmunity: the nod mouse. Gallegos, A.M., Bevan, M.J. Cell (2004) [Pubmed]
  10. IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Kasaian, M.T., Whitters, M.J., Carter, L.L., Lowe, L.D., Jussif, J.M., Deng, B., Johnson, K.A., Witek, J.S., Senices, M., Konz, R.F., Wurster, A.L., Donaldson, D.D., Collins, M., Young, D.A., Grusby, M.J. Immunity (2002) [Pubmed]
  11. Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery. Bolesta, E., Kowalczyk, A., Wierzbicki, A., Eppolito, C., Kaneko, Y., Takiguchi, M., Stamatatos, L., Shrikant, P.A., Kozbor, D. J. Immunol. (2006) [Pubmed]
  12. IL-21 enhances tumor rejection through a NKG2D-dependent mechanism. Takaki, R., Hayakawa, Y., Nelson, A., Sivakumar, P.V., Hughes, S., Smyth, M.J., Lanier, L.L. J. Immunol. (2005) [Pubmed]
  13. Redundant and unique regulation of activated mouse B lymphocytes by IL-4 and IL-21. Jin, H., Malek, T.R. J. Leukoc. Biol. (2006) [Pubmed]
  14. IL-21 induces the apoptosis of resting and activated primary B cells. Mehta, D.S., Wurster, A.L., Whitters, M.J., Young, D.A., Collins, M., Grusby, M.J. J. Immunol. (2003) [Pubmed]
  15. Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. Parrish-Novak, J., Foster, D.C., Holly, R.D., Clegg, C.H. J. Leukoc. Biol. (2002) [Pubmed]
  16. Differential effects of IL-15 and IL-21 in myeloid (CD11b+) and lymphoid (CD11b-) bone marrow cells. Pelletier, M., Girard, D. J. Immunol. (2006) [Pubmed]
  17. Interleukin 21 prevents antigen-induced IgE production by inhibiting germ line C(epsilon) transcription of IL-4-stimulated B cells. Suto, A., Nakajima, H., Hirose, K., Suzuki, K., Kagami, S., Seto, Y., Hoshimoto, A., Saito, Y., Foster, D.C., Iwamoto, I. Blood (2002) [Pubmed]
  18. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. Wei, L., Laurence, A., Elias, K.M., O'Shea, J.J. J. Biol. Chem. (2007) [Pubmed]
  19. Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. Jin, H., Carrio, R., Yu, A., Malek, T.R. J. Immunol. (2004) [Pubmed]
  20. IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice. Di Carlo, E., Comes, A., Orengo, A.M., Rosso, O., Meazza, R., Musiani, P., Colombo, M.P., Ferrini, S. J. Immunol. (2004) [Pubmed]
  21. IL-21 induces the functional maturation of murine NK cells. Brady, J., Hayakawa, Y., Smyth, M.J., Nutt, S.L. J. Immunol. (2004) [Pubmed]
  22. Cytokine requirements for the growth and development of mouse NK cells in vitro. Toomey, J.A., Gays, F., Foster, D., Brooks, C.G. J. Leukoc. Biol. (2003) [Pubmed]
  23. Preliminary study on mouse interleukin-21 application in tumor gene therapy. Dou, J., Chen, G., Wang, J., Zhao, F., Chen, J., Fang, X., Tang, Q., Chu, L. Cell. Mol. Immunol. (2004) [Pubmed]
  24. IL-21-induced B{varepsilon} cell apoptosis mediated by natural killer T cells suppresses IgE responses. Harada, M., Magara-Koyanagi, K., Watarai, H., Nagata, Y., Ishii, Y., Kojo, S., Horiguchi, S., Okamoto, Y., Nakayama, T., Suzuki, N., Yeh, W.C., Akira, S., Kitamura, H., Ohara, O., Seino, K., Taniguchi, M. J. Exp. Med. (2006) [Pubmed]
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