Interleukin-21

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Interleukin-21
Interleukin-21
Ribbon model of human interleukin-21 (from two sides), according to PDB  2OPQ
Properties of human protein
Mass / length primary structure 133 amino acids
Precursor (155 aa)
Isoforms IL-21, IL-21iso
Identifier
Gene name IL21
External IDs
Occurrence
Parent taxon Vertebrates

Interleukin-21 (IL21) is an interleukin that in humans by the IL21 - gene is encoded.

Interleukin-21 is a cytokine with important regulatory effects on cells of the immune system , including natural killer cells ( NK cells ), B cells and cytotoxic T cells that can be infected with viruses or destroy cancer cells . This cytokine induces cell division and growth in its target cells.

gene

The human IL-21 gene is approximately 8.43 kb in size and is  linked to chromosome 4 and 180 kb of the IL-2 gene. The mRNA product is 616 nucleotides long.

Distribution in tissues and cells

IL-21 is found in activated human CD4 + T cells , but not in most other tissues. In addition, IL-21 is the main cytokine for T follicular helper cells and has important effects in B cell proliferation, antibody induction and maturation. Furthermore, IL-21 is produced in natural killer T cells ( NK T cells ) and regulates their function.

Interleukin-21 is also produced by Hodgkin's lymphoma (HL) cancer cells . This observation could explain much of the behavior of classical Hodgkin lymphoma, including the accumulation of other immune cells around HL cells in cell cultures. IL-21 is therefore the focus of research into potential treatment approaches or at least the development of a test for HL.

Clinical significance

Allergies

IL-21R knockout mice show higher levels of IgE and lower levels of IgG1 than wild-type mice after exposure to the antigen. IgE levels decreased after injection of IL-21. This is significant to the role IL-21 plays in controlling allergic reactions because of the role of IgE in type 1 hypersensitivity reactions. Therapeutic attempts have been carried out with IL-21 to reduce allergic reactions. It was shown that proinflammatory cytokines, which are produced by T cells, could be reduced, and IgE levels could also be reduced in mice suffering from allergic rhinitis (allergic rhinitis). A study in mice with peanut allergy showed that systemic treatment with IL-21 effectively counteracted the allergic reaction. This is of great importance for the pharmacological development of IL-21-based drugs against local and systemic allergies.

Immunotherapy for cancer

IL-21 has been approved for Phase 1 clinical trials in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC). It was presented to the authorities as safe enough with only flu-like side effects. Dose-limiting toxicity was determined on the basis of small numbers of lymphocytes, neutrophils and platelets and on the basis of liver values. According to the criteria for treatment effects in solid tumors (Response Evaluation Criteria in Solid Tumors, RECIST) , 2 of 47 MM patients and 4 of 19 RCC patients showed comprehensive or partial effects. In addition, increases in perforin , granzyme B , IFN-γ and CXCR3 mRNA were found in peripheral NK cells and CD8 + T cells . This suggests that IL-21 promotes CD8 + effector functions and thereby leads to an anti-tumor response. Phase 2 clinical trials were then carried out with IL-21, where it was administered alone or in combination with drugs such as sorafinib and rituximab .

Viral infections

IL-21 may be a critical factor in controlling persistent viral infections. IL-21 (or IL-21R) knockout mice infected with chronic lymphocytic choriomenginitis virus (LCM virus, LCMV) were unable to get rid of it, in contrast to wild-type mice. In addition, these knockout mice with a damaged IL-21 signaling pathway showed much more dramatic releases of LCMV-specific, cytotoxic T cells , which suggests that IL-21 produced by CD4 + T helper cells is necessary for sustained CD8 + effector activity of the T cells is. It is therefore likely that IL-21 is involved in the mechanism by which helper CD4 + T cells orchestrate the immune system's response to viral infections.

Of HIV -infected has been reported that IL-21 enhances HIV-specific cytotoxic response of T-cells. and NK cell functions. It has also been shown that HIV-specific CD4 T cells from long-term stable (rare cases in which AIDS does not develop even though they are not treated) are able to produce significantly more IL-21 than the majority of people. In addition, IL-21-producing, virus-specific CD8 T cells were found more frequently in the long-term stable patients. These data and the fact that IL-21-stimulated CD8 or NK cells were able to prevent virus replication of HIV in vitro indicate that this cytokine can potentially be used for anti-HIV therapeutics.

Individual evidence

  1. ↑ a b c d Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Speaker C, Gross JA, Johnston J, Madden K, Xu W, West J, Schrader S, Burkhead S, Heipel M, Brandt C, Kuijper JL, Kramer J, Conklin D, Presnell SR, Berry J, Shiota F, Bort S, Hambly K, Mudri S, Clegg C, Moore M, Grant FJ, Lofton-Day C, Gilbert T, Rayond F, Ching A, Yao L, Smith D, Webster P, Whitmore T, Maurer M, Kaushansky K , Holly RD, Foster D: Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function . In: Nature . 408, No. 6808, November 2000, pp. 57-63. doi : 10.1038 / 35040504 . PMID 11081504 .
  2. ↑ Cake S, Robbins R, Sims GP, Sheng C, Phillips TM, Lipsky PE, Ettinger R: Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4 + T cell-B cell collaboration . In: J Immunol . 179, No. 9, October 2007, pp. 5886-96. PMID 17947662 .
  3. ↑ a b Entrez Gene: IL21 interleukin 21 . Retrieved May 23, 2012.
  4. ↑ Parrish-Novak J, Foster DC, Holly RD, Clegg CH: Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses Archived from the original on January 8, 2009. In: J Leukoc Biol . . 72, No. 5, 2002, pp. 856-63. PMID 12429707 .
  5. ↑ Chtanova T, Tangye SG, Newton R, Frank N, Hodge MR, Rolph MS, Mackay CR: T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1 / Th2 effector cells that provide help for B cells. . In: J Immunol . 173, No. 1, 2004, pp. 68-78. PMID 15210760 .
  6. ^ Wei L, Laurence A, Elias KM, O'Shea JJ ,: IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. . In: J Biol Chem . 282, No. 48, 2007, pp. 34605-10. doi : 10.1074 / jbc.M705100200 . PMID 17884812 . PMC 2323680 (free full text).
  7. ^ Wurster AL, Rodgers VL, Satoskar AR, Whitters MJ, Young DA, Collins M, Grusby MJ: Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells . . In: J Exp Med . 196, No. 7, 2002, pp. 969-77. doi : 10.1084 / jem.20020620 . PMID 12370258 . PMC 2194031 (free full text).
  8. ↑ Coquet JM, Kyparissoudis K, Pellicci, DG, Besra G, Berzins, SP, Smyth, MJ, Godfrey DI: IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production . In: J Immunol . 178, No. 5, 2007, pp. 2827-2834. PMID 17312126 .
  9. ↑ Lamprecht B, Kreher S, Anagnostopoulos, I, Johrens k, Monteleone G, Junt F, Stein H, Janz M, Dorken B, Mathas S: Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts Treg cells via regulation of MIP-3a . In: Blood . 112, No. Oct 2008, 2008, pp. 3339-3347. doi : 10.1182 / blood-2008-01-134783 . PMID 18684866 .
  10. ↑ Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, Morse HC 3rd, Liu C, Schwartzberg PL, Leonard WJ .: A critical role for IL-21 in regulating immunoglobulin production . In: Science . 298, No. 5598, November 2002, pp. 1630-4. doi : 10.1126 / science.1077002 . PMID 12446913 .
  11. ↑ Hiromura Y, Kishida T, Nakano H, Hama T, Imanishi J, Hisa Y, Mazda O .: IL-21 administration into the nostril alleviates murine allergic rhinitis . In: Journal of Immunology . 179, No. 10, November 2007, pp. 7157-65. PMID 17982108 .
  12. ↑ 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 ..: IL-21 induces inhibitor of differentiation 2 and leads to complete abrogation of anaphylaxis in mice . In: Journal of Immunology . 179, No. 12, December 2007, pp. 8554-61. PMID 18056403 .
  13. ↑ Søndergaard H, Skak K: IL-21: roles in immunopathology and cancer therapy . In: Tissue Antigens . 74, No. 6, October 2009, pp. 467-79. doi : 10.1111 / j.1399-0039.2009.01382.x . PMID 19845910 .
  14. ^ LDS Johnson and SC Jameson: A Chronic Need for IL-21 . In: Science . 324, No. 5934, 2009, pp. 1525-1526. doi : 10.1126 / science.1176487 . PMID 19541985 .
  15. ↑ White L., Krishnan S., Strbo N., Liu H., Kolber MA, Lichtenheld MG, Pahwa RN, Pahwa S .: Differential effects of IL-21 and IL-15 on perforin expression, lysosomal degranulation, and proliferation in CD8 T cells of patients with human immunodeficiency virus-1 (HIV) . In: Blood . 109, No. 9, 2007, pp. 3873-80. doi : 10.1182 / blood-2006-09-045278 . PMID 17192392 . PMC 1874576 (free full text).
  16. ↑ a b c Chevalier MF, Julg B., Pyo A., Flanders M., Ranasinghe S., Soghoian DZ, Kwon DS, Rychert J., Lian J., Muller MI, Cutler S., McAndrew E., Jessen H. ., Pereyra F., Rosenberg ES, Altfeld M., Walker BD, Streeck H: HIV-1-Specific Interleukin-21 + CD4 + T Cell Responses Contribute to Durable Viral Control through the Modulation of HIV-Specific CD8 + T Cell Function . In: Journal of Virology . 85, No. 2, 2010, pp. 733-41. doi : 10.1128 / JVI.02030-10 . PMID 21047960 . PMC 3020027 (free full text).
  17. ↑ a b Iannello A, Boulassel MR, Samarani S, Tremblay C, Toma E, Routy JP, Ahmad A .: IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication . In: J Leukoc Biol . 87, No. 5, 2010, pp. 857-67. doi : 10.1189 / jlb.1009701 . PMID 20103765 .
  18. ^ Williams LD, Bansal A., Sabbaj S., Heath SL, Song W., Tang J., Zajac AJ, Goepfert PA: Interleukin-21-producing HIV-1-specific CD8 T cells are Preferentially Seen in Elite Controllers . In: Journal of Virology . 85, No. 5, 2010, pp. 2316-2324. doi : 10.1128 / JVI.01476-10 . PMID 21159862 . PMC 3067790 (free full text).

Further literature

  • Sivakumar PV, Foster DC, Clegg CH: Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumor responses . In: Immunology . 112, No. 2, 2004, pp. 177-82. doi : 10.1111 / j.1365-2567.2004.01886.x . PMID 15147560 . PMC 1782493 (free full text).
  • Leonard WJ, Spolski R: Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation . In: Nat. Rev. Immunol. . 5, No. 9, 2005, pp. 688-98. doi : 10.1038 / nri1688 . PMID 16138102 .
  • Brandt K, Singh PB, Bulfone-Paus S, Rückert R: Interleukin-21: a new modulator of immunity, infection, and cancer . In: Cytokine Growth Factor Rev. . 18, No. 3-4, 2007, pp. 223-32. doi : 10.1016 / j.cytogfr.2007.04.003 . PMID 17509926 .
  • Flores I, Casaseca T, Martinez-AC, et al. : Phosphatidic acid generation through interleukin 2 (IL-2) -induced alpha-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation . In: J. Biol. Chem. . 271, No. 17, 1996, pp. 10334-40. doi : 10.1074 / jbc.271.17.10334 . PMID 8626603 .
  • Vosshenrich CA, Di Santo JP: Cytokines: IL-21 joins the gamma (c) -dependent network? . In: Curr. Biol . 11, No. 5, 2001, pp. R175-7. doi : 10.1016 / S0960-9822 (01) 00087-2 . PMID 11267886 .
  • Asao H, Okuyama C, Kumaki S, et al. : Cutting edge: the common gamma chain is an indispensable subunit of the IL-21 receptor complex . In: J. Immunol. . 167, No. 1, 2001, pp. 1-5. PMID 11418623 .
  • Strengell M, Sareneva T, Foster D, et al. : IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response . In: J. Immunol. . 169, No. 7, 2002, pp. 3600-5. PMID 12244150 .
  • Strausberg RL, Feingold EA, Grouse LH, et al. : Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . In: Proc. Natl. Acad. Sci. USA . 99, No. 26, 2003, pp. 16899-903. doi : 10.1073 / pnas.242603899 . PMID 12477932 . PMC 139241 (free full text).
  • Zhang JL, Foster D, Sebald W: Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain . In: Biochem. Biophys. Res. Commun. . 300, No. 2, 2003, pp. 291-6. doi : 10.1016 / S0006-291X (02) 02836-X . PMID 12504082 .
  • Strengell M, Matikainen S, Sirén J, et al. : IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells . In: J. Immunol. . 170, No. 11, 2003, pp. 5464-9. PMID 12759422 .
  • Brandt K, Bulfone-Paus S, Foster DC, Rückert R: Interleukin-21 inhibits dendritic cell activation and maturation . In: Blood . 102, No. 12, 2004, pp. 4090-8. doi : 10.1182 / blood-2003-03-0669 . PMID 12893770 .
  • Sivori S, Cantoni C, Parolini S, et al. : IL-21 induces both rapid maturation of human CD34 + cell precursors towards NK cells and acquisition of surface killer Ig-like receptors . In: Eur. J. Immunol. . 33, No. 12, 2004, pp. 3439-47. doi : 10.1002 / eji.200324533 . PMID 14635054 .
  • Pène J, Gauchat JF, Lécart S, et al. : Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells . In: J. Immunol. . 172, No. 9, 2004, pp. 5154-7. PMID 15100251 .
  • Strengell M, Julkunen I, Matikainen S: IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells . In: J. Leukoc. Biol . 76, No. 2, 2004, pp. 416-22. doi : 10.1189 / jlb.1003488 . PMID 15178704 .
  • Zhang SQ, Chen B, Luo X, Xu CZ: [Cloning and expression of human interleukin-21 cDNA in E. coli] . In: Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi . 20, No. 4, 2005, pp. 406-9. PMID 15207081 .
  • Gerhard DS, Wagner L, Feingold EA, et al. : The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC) . In: Genome Res. . 14, No. 10B, 2004, pp. 2121-7. doi : 10.1101 / gr.2596504 . PMID 15489334 . PMC 528928 (free full text).
  • Ozaki K, Spolski R, Ettinger R, et al. : Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6 . In: J. Immunol. . 173, No. 9, 2004, pp. 5361-71. PMID 15494482 .
  • Mehta DS, Wurster AL, Weinmann AS, Grusby MJ: NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression . In: Proc. Natl. Acad. Sci. USA . 102, No. 6, 2005, pp. 2016-2021. doi : 10.1073 / pnas.0409512102 . PMID 15684054 . PMC 548571 (free full text).