Interleukin 21
Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.[5][6][7]
Interleukin-21 is a
Gene
The human IL-21 gene is about 8.43kb, mapped to chromosome 4 and 180kb from IL-2 gene, and the mRNA product is 616 nucleotides long.[5][7]
Tissue and cell distribution
IL-21 is expressed in activated human
Interleukin-21 is also produced by
Receptor
The IL-21 receptor (IL-21R) is expressed on the surface of T, B and NK cells. IL-21r is similar in structure to the receptors for other type I cytokines like IL-2R[15] or IL-15 and requires dimerization with the common gamma chain (γc) in order to bind IL-21.[16][17] When bound to IL-21, the IL-21 receptor acts through the Jak/STAT pathway, utilizing Jak1 and Jak3 and a STAT3 homodimer to activate its target genes.[17]
Clinical relevance
Role in allergies
It has been shown that IL-21R knock-out mice express higher levels of IgE and lower levels of IgG1 than normal mice after antigen exposure. IgE levels decreased after mice were injected with IL-21. This has implications for the role of IL-21 in controlling allergic responses because of the role of IgE in hypersensitivity type 1 responses.[18] IL-21 has been tried as therapy for alleviating allergic responses. It was shown to be successful in decreasing pro-inflammatory cytokines produced by T cells in addition to decreasing IgE levels in a mouse model for rhinitis (nasal passage inflammation).[19] A study using mice with peanut allergies showed that systemic treatment of IL-21 was an effective means of mitigating the allergic response.[20] This has strong implications for the pharmacological development of IL-21 for controlling both localized and systemic allergies.
Role in cancer immunotherapy
A role for IL-21 in modulating the differentiation programming of human T cells was first reported by Li et al., where it was shown to enrich for a population of central memory-type CTL with a unique CD28+ CD127hi CD45RO+ phenotype with IL-2 producing capacity. Tumor-reactive antigen-specific CTL generated by priming in the presence of IL-21 led to a stable, 'helper-independent' phenotype.[21] IL-21 is also noted to have anti-tumour effects through continued and increased CD8+ cell response to achieve enduring tumor immunity.[22]
IL-21 was approved for Phase 1 clinical trials in metastatic
Role in viral infections
IL-21 may be a critical factor in the control of persistent viral infections. IL-21 (or IL-21R) knock-out mice infected with chronic LCMV (lymphocytic choriomeningitis virus) were not able to overcome chronic infection compared to normal mice. Besides, these mice with impaired IL-21 signaling had more dramatic exhaustion of LCMV-specific CD8+ T cells, suggesting that IL-21 produced by CD4+ T cells is required for sustained CD8+ T cell effector activity and then, for maintaining immunity to resolve persistent viral infection.[24] Thus, IL-21 may contribute to the mechanism by which CD4+ T helper cells orchestrate the immune system response to viral infections.
In HIV infected subjects, IL-21 has been reported to critically improve the HIV-specific cytotoxic T cell responses
Drug development
An antibody to IL-21 is in development for multiple inflammatory conditions (Clinicaltrials.gov entries).
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000138684 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027718 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ S2CID 4428126.
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- ^ a b "Entrez Gene: IL21 interleukin 21".
- S2CID 27480657.
- PMID 15210760.
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- PMID 17312126.
- PMID 18684866.
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- ^ PMID 12093291.
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Further reading
- Sivakumar PV, Foster DC, Clegg CH (June 2004). "Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumour responses". Immunology. 112 (2): 177–82. PMID 15147560.
- Leonard WJ, Spolski R (September 2005). "Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation". Nature Reviews. Immunology. 5 (9): 688–98. S2CID 12667905.
- Brandt K, Singh PB, Bulfone-Paus S, Rückert R (2007). "Interleukin-21: a new modulator of immunity, infection, and cancer". Cytokine & Growth Factor Reviews. 18 (3–4): 223–32. PMID 17509926.[verification needed]
- Flores I, Casaseca T, Martinez-A C, Kanoh H, Merida I (April 1996). "Phosphatidic acid generation through interleukin 2 (IL-2)-induced alpha-diacylglycerol kinase activation is an essential step in IL-2-mediated lymphocyte proliferation". The Journal of Biological Chemistry. 271 (17): 10334–40. PMID 8626603.
- Vosshenrich CA, Di Santo JP (March 2001). "Cytokines: IL-21 joins the gamma(c)-dependent network?". Current Biology. 11 (5): R175-7. S2CID 18207386.
- Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K (July 2001). "Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex". Journal of Immunology. 167 (1): 1–5. PMID 11418623.
- Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S (October 2002). "IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response". Journal of Immunology. 169 (7): 3600–5. PMID 12244150.
- Zhang JL, Foster D, Sebald W (January 2003). "Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain". Biochemical and Biophysical Research Communications. 300 (2): 291–6. PMID 12504082.
- Strengell M, Matikainen S, Sirén J, Lehtonen A, Foster D, Julkunen I, Sareneva T (June 2003). "IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells". Journal of Immunology. 170 (11): 5464–9. PMID 12759422.
- Brandt K, Bulfone-Paus S, Foster DC, Rückert R (December 2003). "Interleukin-21 inhibits dendritic cell activation and maturation". Blood. 102 (12): 4090–8. PMID 12893770.[verification needed]
- Sivori S, Cantoni C, Parolini S, Marcenaro E, Conte R, Moretta L, Moretta A (December 2003). "IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors". European Journal of Immunology. 33 (12): 3439–47. PMID 14635054.
- Pène J, Gauchat JF, Lécart S, Drouet E, Guglielmi P, Boulay V, Delwail A, Foster D, Lecron JC, Yssel H (May 2004). "Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells". Journal of Immunology. 172 (9): 5154–7. PMID 15100251.
- Strengell M, Julkunen I, Matikainen S (August 2004). "IFN-alpha regulates IL-21 and IL-21R expression in human NK and T cells". Journal of Leukocyte Biology. 76 (2): 416–22. S2CID 17666508.
- Zhang SQ, Chen B, Luo X, Xu CZ (July 2004). "[Cloning and expression of human interleukin-21 cDNA in E.coli]". Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal of Cellular and Molecular Immunology. 20 (4): 406–9. PMID 15207081.
- Ozaki K, Spolski R, Ettinger R, Kim HP, Wang G, Qi CF, Hwu P, Shaffer DJ, Akilesh S, Roopenian DC, Morse HC, Lipsky PE, Leonard WJ (November 2004). "Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6". Journal of Immunology. 173 (9): 5361–71. PMID 15494482.
- Mehta DS, Wurster AL, Weinmann AS, Grusby MJ (February 2005). "NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression". Proceedings of the National Academy of Sciences of the United States of America. 102 (6): 2016–21. PMID 15684054.