Cytokines play a critical role in modulating the innate and adaptive immune systems. Here, we have identified from the human genomic sequence a family of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric class II cytokine receptor that consisted of IL-10 receptor β (IL-10Rβ) and an orphan class II receptor chain, designated IL-28Rα. This newly described cytokine family may serve as an alternative to type I IFNs in providing immunity to viral infection.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Pestka, S., Langer, J.A., Zoon, K.C. & Samuel, C.E. Interferons and their actions. Annu. Rev. Biochem. 56, 727–777 (1987).
Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).
Kotenko, S.V. The family of IL-10-related cytokines and their receptors: related, but to what extent? Cytok. Growth Factor Rev. 13, 223–240 (2002).
Biron, C.A. Role of early cytokines, including alpha and beta interferons (IFN-α/β), in innate and adaptive immune responses to viral infections. Semin. Immunol. 10, 383–390 (1998).
Fellous, M. et al. Interferon-dependent induction of mRNA for the major histocompatibility antigens in human fibroblasts and lymphoblastoid cells. Proc. Natl. Acad. Sci. USA 79, 3082–3086 (1982).
Marrack, P., Kappler, J. & Mitchell, T. Type I interferons keep activated T cells alive. J. Exp. Med. 189, 521–530 (1999).
Buelens, C. et al. Interleukin-3 and interferon β cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties. Blood 99, 993–998 (2002).
Oritani, K. et al. Limitin: An interferon-like cytokine that preferentially influences B-lymphocyte precursors. Nat. Med. 6, 659–666 (2000).
LaFleur, D.W. et al. Interferon-κ, a novel type I interferon expressed in human keratinocytes. J. Biol. Chem. 276, 39765–39771 (2001).
Novick, D., Cohen, B. & Rubinstein, M. The human interferon α/β receptor: characterization and molecular cloning. Cell 77, 391–400 (1994).
Uze, G., Lutfalla, G. & Gresser, I. Genetic transfer of a functional human interferon α receptor into mouse cells: cloning and expression of its cDNA. Cell 60, 225–234. (1990).
Stark, G.R., Kerr, I.M., Williams, B.R., Silverman, R.H. & Schreiber, R.D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).
Dumoutier, L., Van Roost, E., Colau, D. & Renauld, J.C. Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc. Natl. Acad. Sci. USA 97, 10144–10149 (2000).
de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C.G. & de Vries, J.E. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174, 1209–1220 (1991).
Fiorentino, D.F., Zlotnik, A., Mosmann, T.R., Howard, M. & O'Garra, A. IL-10 inhibits cytokine production by activated macrophages. J. Immunol. 147, 3815–3822 (1991).
Kotenko, S.V. et al. Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J. 16, 5894–5903 (1997).
Xie, M.H. et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J. Biol. Chem. 275, 31335–31339 (2000).
Kotenko, S.V. et al. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rβ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J. Biol. Chem. 276, 2725–2732 (2001).
Liu, Y., Wei, S.H., Ho, A.S., de Waal Malefyt, R. & Moore, K.W. Expression cloning and characterization of a human IL-10 receptor. J. Immunol. 152, 1821–1829 (1994).
Xu, W. et al. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc. Natl. Acad. Sci. USA 98, 9511–9516 (2001).
Weber-Nordt, R.M. et al. Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J. Biol. Chem. 271, 27954–27961 (1996).
Hubbard, T. et al. The Ensembl genome database project. Nucleic Acids Res. 30, 38–41 (2002).
Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).
Raj, N.B. & Pitha, P.M. Two levels of regulation of β-interferon gene expression in human cells. Proc. Natl. Acad. Sci. USA 80, 3923–3927 (1983).
Bazan, J.F. Structural design and molecular evolution of a cytokine receptor superfamily. Proc. Natl. Acad. Sci. USA 87, 6934–6938 (1990).
Dondi, E. et al. Down-modulation of type 1 interferon responses by receptor cross-competition for a shared Jak kinase. J. Biol. Chem. 276, 47004–47012 (2001).
Gutterman, J.U. Cytokine therapeutics: lessons from interferon alpha. Proc. Natl. Acad. Sci. USA 91, 1198–1205 (1994).
Dusheiko, G. Side effects of α interferon in chronic hepatitis C. Hepatology 26 (Suppl.) 112–121 (1997).
Burge, C. & Karlin, S. Prediction of complete gene structures in human genomic DNA. J. Mol. Biol. 268, 78–94 (1997).
von Heijne, G., Marrack, P., Kappler, J. & Mitchell, T. Patterns of amino acids near signal-sequence cleavage sites. Eur. J. Biochem. 133, 17–21 (1983).
Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19 (2001).
Zdanov, A. et al. Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon γ. Structure 3, 591–601 (1995).
Radhakrishnan, R. et al. Zinc mediated dimer of human interferon-α2 revealed by X-ray crystallography. Structure 4, 1453–1463 (1996).
Familletti, P.C., Rubinstein, S. & Pestka, S. A convenient and rapid cytopathic effect inhibition assay for interferon. Meth. Enzymol. 78, 387–394 (1981).
Berg, K., Hansen, M.B. & Nielsen, S.E. A new sensitive bioassay for precise quantification of interferon activity as measured via the mitochondrial dehydrogenase function in cells (MTT-method). Apmis 98, 156–162 (1990).
We thank P. O'Hara, R. Adams and D. Sawislak for project advice.
About this article
Nasal commensal Staphylococcus epidermidis enhances interferon-λ-dependent immunity against influenza virus
Anti-H7N9 avian influenza A virus activity of interferon in pseudostratified human airway epithelium cell cultures
Virology Journal (2019)
Nature Microbiology (2019)
Cellular & Molecular Immunology (2019)
Genes & Immunity (2019)