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Modulation of the human cytokine response by interferon lambda-1 (IFN-λ1/IL-29)

Abstract

The interferon lambda family (IFN-λ1/2/3) is a newly described group of cytokines that are related to both the type-1 interferons and IL-10 family members. These novel cytokines are induced during viral infection and, like type-1 interferons, display significant anti-viral activity. In order to understand their function in more depth, we have examined the ability of IFN-λ1/IL-29 to regulate cytokine production by human immune cells. Whole peripheral blood mononuclear cells (PBMC) exposed to IFN-λ1 specifically upregulated IL-6, -8 and -10 but there were no visible effects on TNF or IL-1. This response was produced in a dose-dependant fashion and was inhibited by IL-10. Examination of purified cell populations isolated from PBMC demonstrated that monocytes, rather than lymphocytes, were the major IFN-λ1-responsive cellular subset, producing IL-6, -8 and -10 in response to IFN-λ1. Monocyte responses induced by low-level LPS stimulation were also synergistically enhanced by the presence of IFN-λ1. Human macrophages were also shown to react to IFN-λ1 similarly to monocytes, by producing the cytokines IL-6, -8 and -10. In conclusion, we have shown that IFN-λ1, a cytokine produced in response to viral infection, activates both monocytes and macrophages producing a restricted panel of cytokines and may therefore be important in activating innate immune responses at the site of viral infection.

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References

  1. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 2003; 4: 69–77.

    Article  CAS  Google Scholar 

  2. Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 2003; 4: 63–68.

    Article  CAS  Google Scholar 

  3. Donnelly RP, Sheikh F, Kotenko SV, Dickensheets H . The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. J Leukoc Biol 2004; 76: 314–321.

    Article  CAS  Google Scholar 

  4. Dumoutier L, Lejeune D, Hor S, Fickenscher H, Renauld JC . Cloning of a new type II cytokine receptor activating signal transducer and activator of transcription (STAT)1, STAT2 and STAT3. Biochem J 2003; 370 (Part 2): 391–396.

    Article  CAS  Google Scholar 

  5. Nadeau OW, Domanski P, Usacheva A, Uddin S, Platanias LC, Pitha P et al. The proximal tyrosines of the cytoplasmic domain of the beta chain of the type I interferon receptor are essential for signal transducer and activator of transcription (Stat) 2 activation. Evidence that two Stat2 sites are required to reach a threshold of interferon alpha-induced Stat2 tyrosine phosphorylation that allows normal formation of interferon-stimulated gene factor 3. J Biol Chem 1999; 274: 4045–4052.

    Article  CAS  Google Scholar 

  6. Renauld JC . Class II cytokine receptors and their ligands: key antiviral and inflammatory modulators. Nat Rev Immunol 2003; 3: 667–676.

    Article  CAS  Google Scholar 

  7. Meager A, Visvalingam K, Dilger P, Bryan D, Wadhwa M . Biological activity of interleukins-28 and -29: comparison with type I interferons. Cytokine 2005; 31: 109–118.

    Article  CAS  Google Scholar 

  8. Igietseme JU, Ananaba GA, Bolier J, Bowers S, Moore T, Belay T et al. Suppression of endogenous IL-10 gene expression in dendritic cells enhances antigen presentation for specific Th1 induction: potential for cellular vaccine development. J Immunol 2000; 164: 4212–4219.

    Article  CAS  Google Scholar 

  9. de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE . Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991; 174: 1209–1220.

    Article  CAS  Google Scholar 

  10. de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C et al. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 1991; 174: 915–924.

    Article  CAS  Google Scholar 

  11. de Waal Malefyt R, Yssel H, de Vries JE . Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 1993; 150: 4754–4765.

    CAS  PubMed  Google Scholar 

  12. Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S . Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 1993; 150: 353–360.

    CAS  Google Scholar 

  13. Kadowaki N, Liu YJ . Natural type I interferon-producing cells as a link between innate and adaptive immunity. Hum Immunol 2002; 63: 1126–1132.

    Article  CAS  Google Scholar 

  14. Le Bon A, Tough DF . Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 2002; 14: 432–436.

    Article  CAS  Google Scholar 

  15. Kadowaki N, Antonenko S, Lau JY, Liu YJ . Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J Exp Med 2000; 192: 219–226.

    Article  CAS  Google Scholar 

  16. Simovic MO, Bonham MJ, Abu-Zidan FM, Windsor JA . Anti-inflammatory cytokine response and clinical outcome in acute pancreatitis. Crit Care Med 1999; 27: 2662–2665.

    Article  CAS  Google Scholar 

  17. Taniguchi T, Koido Y, Aiboshi J, Yamashita T, Suzaki S, Kurokawa A . The ratio of interleukin-6 to interleukin-10 correlates with severity in patients with chest and abdominal trauma. Am J Emerg Med 1999; 17: 548–551.

    Article  CAS  Google Scholar 

  18. Taniguchi T, Koido Y, Aiboshi J, Yamashita T, Suzaki S, Kurokawa A . Change in the ratio of interleukin-6 to interleukin-10 predicts a poor outcome in patients with systemic inflammatory response syndrome. Crit Care Med 1999; 27: 1262–1264.

    Article  CAS  Google Scholar 

  19. Gallagher G, Dickensheets H, Eskdale J, Izotova LS, Mirochnitchenko OV, Peat JD et al. Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun 2000; 1: 442–450.

    Article  CAS  Google Scholar 

  20. Gallagher G, Eskdale J, Jordan W, Peat J, Campbell J, Boniotto M et al. Human interleukin-19 and its receptor: a potential role in the induction of Th2 responses. Int Immunopharmacol 2004; 4: 615–626.

    Article  CAS  Google Scholar 

  21. Liao SC, Cheng YC, Wang YC, Wang CW, Yang SM, Yu CK et al. IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J Immunol 2004; 173: 6712–6718.

    Article  CAS  Google Scholar 

  22. Oral HB, Kotenko SV, Yilmaz M, Mani O, Zumkehr J, Blaser K et al. Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26. Eur J Immunol 2006; 36: 380–388.

    Article  CAS  Google Scholar 

  23. Jordan WJ, Eskdale J, Boniotto M, Lennon GP, Peat J, Campbell JD et al. Human IL-19 regulates immunity through auto-induction of IL-19 and production of IL-10. Eur J Immunol 2005; 35: 1576–1582.

    Article  CAS  Google Scholar 

  24. Le Bon A, Etchart N, Rossmann C, Ashton M, Hou S, Gewert D et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol 2003; 4: 1009–1015.

    Article  CAS  Google Scholar 

  25. Le Bon A, Schiavoni G, D'Agostino G, Gresser I, Belardelli F, Tough DF . Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 2001; 14: 461–470.

    Article  CAS  Google Scholar 

  26. Durand V, Wong SY, Tough DF, Le Bon A . Shaping of adaptive immune responses to soluble proteins by TLR agonists: a role for IFN-alpha/beta. Immunol Cell Biol 2004; 82: 596–602.

    Article  CAS  Google Scholar 

  27. Lopez CB, Moltedo B, Alexopoulou L, Bonifaz L, Flavell RA, Moran TM . TLR-independent induction of dendritic cell maturation and adaptive immunity by negative-strand RNA viruses. J Immunol 2004; 173: 6882–6889.

    Article  CAS  Google Scholar 

  28. Uematsu S, Sato S, Yamamoto M, Hirotani T, Kato H, Takeshita F et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-med. J Exp Med 2005; 201: 915–923.

    Article  CAS  Google Scholar 

  29. Hertzog PJ, O'Neill LA, Hamilton JA . The interferon in TLR signaling: more than just antiviral. Trends Immunol 2003; 24: 534–539.

    Article  CAS  Google Scholar 

  30. Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, Visintin A, Latz E et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med 2003; 198: 1043–1055.

    Article  CAS  Google Scholar 

  31. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT et al. IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 2003; 4: 491–496.

    Article  CAS  Google Scholar 

  32. Sheppard P, Presnell SR, Fox B, Gilbert T, Haldeman B, Grant FJ . Interferon-like protein, Zcyto21. United States Patent Application no. 002003963 April 4, 2002; 2002.

  33. Radich JP, Mao M, Stepaniants S, Biery M, Castle J, Ward T et al. Individual-specific variation of gene expression in peripheral blood leukocytes. Genomics 2004; 83: 980–988.

    Article  CAS  Google Scholar 

  34. Riedemann NC, Guo RF, Hollmann TJ, Gao H, Neff TA, Reuben JS et al. Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis. FASEB J 2004; 18: 320–322.

    Article  Google Scholar 

  35. Gabay C . Interleukin-6 and chronic inflammation. Arthritis Res Ther 2006; 8 (Suppl 2): S3.

    Article  Google Scholar 

  36. Cassatella MA, Tamassia N, Crepaldi L, McDonald PP, Ear T, Calzetti F et al. Lipopolysaccharide primes neutrophils for a rapid response to IL-10. Eur J Immunol 2005; 35: 1877–1885.

    Article  CAS  Google Scholar 

  37. Dang PM, Elbim C, Marie JC, Chiandotto M, Gougerot-Pocidalo MA, El-Benna J . Anti-inflammatory effect of IL-10 on neutrophil respiratory burst involves inhibition of GM-CSF produced p47PHOX phospohrylation through a decrease in ERK1/2 activity. FASEB J 2006; 20: 1504–1506.

    Article  CAS  Google Scholar 

  38. McLoughlin RM, Jenkins BJ, Grail D, Williams AS, Fielding CA, Parker CR et al. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci USA 2005; 102: 9589–9594.

    Article  CAS  Google Scholar 

  39. Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C . IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol 2003; 24: 25–29.

    Article  CAS  Google Scholar 

  40. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A . Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683–765.

    Article  CAS  Google Scholar 

  41. Beebe AM, Cua DJ, de Waal Malefyt R . The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine Growth Factor Rev 2002; 13: 403–412.

    Article  CAS  Google Scholar 

  42. Itoh K, Hirohata S . The role of IL-10 in human B cell activation, proliferation, and differentiation. J Immunol 1995; 154: 4341–4350.

    CAS  PubMed  Google Scholar 

  43. Levy Y, Brouet JC . Interleukin-10 prevents spontaneous death of germinal center B cells by induction of the bcl-2 protein. J Clin Invest 1994; 93: 424–428.

    Article  CAS  Google Scholar 

  44. Rousset F, Garcia E, Defrance T, Peronne C, Vezzio N, Hsu DH et al. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci USA 1992; 89: 1890–1893.

    Article  CAS  Google Scholar 

  45. Defrance T, Vanbervliet B, Briere F, Durand I, Rousset F, Banchereau J . Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med 1992; 175: 671–682.

    Article  CAS  Google Scholar 

  46. Curotto de Lafaille MA, Lafaille JJ . CD4(+) regulatory T cells in autoimmunity and allergy. Curr Opin Immunol 2002; 14: 771–778.

    Article  CAS  Google Scholar 

  47. Levings MK, Bacchetta R, Schulz U, Roncarolo MG . The role of IL-10 and TGF-beta in the differentiation and effector function of T regulatory cells. Int Arch Allergy Immunol 2002; 129: 263–276.

    Article  CAS  Google Scholar 

  48. Wolk K, Witte E, Reineke U, Witte K, Friedrich M, Sterry W et al. Is there an interaction between interleukin-10 and interleukin-22? Genes Immun 2005; 6: 8–18.

    Article  CAS  Google Scholar 

  49. Koks S, Kingo K, Ratsep R, Karelson M, Silm H, Vasar E . Combined haplotype analysis of the interleukin-19 and -20 genes: relationship to plaque-type psoriasis. Genes Immun 2004; 5: 662–667.

    Article  CAS  Google Scholar 

  50. Li HH, Lin YC, Chen PJ, Hsiao CH, Lee JY, Chen WC et al. Interleukin-19 upregulates keratinocyte growth factor and is associated with psoriasis. Br J Dermatol 2005; 153: 591–595.

    Article  CAS  Google Scholar 

  51. Otkjaer K, Kragballe K, Funding AT, Clausen JT, Noerby PL, Steiniche T et al. The dynamics of gene expression of interleukin-19 and interleukin-20 and their receptors in psoriasis. Br J Dermatol 2005; 153: 911–918.

    Article  CAS  Google Scholar 

  52. Jordan WJ, Ritter MA . Optimal analysis of composite cytokine responses during alloreactivity. J Immunol Methods 2002; 260: 1–14.

    Article  CAS  Google Scholar 

  53. Langenkamp A, Messi M, Lanzavecchia A, Sallusto F . Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 2000; 1: 311–316.

    Article  CAS  Google Scholar 

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Acknowledgements

WJ Jordan was supported by a grant from the National Institute of Dental and Craniofacial Research, Health Disparities Program, No. R1DE14997A. J Eskdale was supported by the New Jersey Dental School. M Boniotto was supported by the Department of Defense. When this work was conducted, JE, MB and GG were employed at New Jersey Dental School.

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Correspondence to G Gallagher.

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Jordan, W., Eskdale, J., Boniotto, M. et al. Modulation of the human cytokine response by interferon lambda-1 (IFN-λ1/IL-29). Genes Immun 8, 13–20 (2007). https://doi.org/10.1038/sj.gene.6364348

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