Interferon-λs: Special Immunomodulatory Agents and Potential Therapeutic Targets

Interferon (IFN)-λs are a new addition to the old IFN family and share many similarities, such as antiviral and antiproliferative characteristics, with type I IFNs. IFN-λs also exhibit unique characteristics in immunomodulation. Accumulating studies have indicated the interactions between IFN-λs and immune cells, which lead to the regulation of the latter. IFN-λs can influence dendritic cells (DCs) and their product, IFN-λs-DCs, can then regulate the function of T cells. On the other hand, IFN-λs can also directly affect T cells through inhibition of the T helper 2 cell (Th2) responses. IFN-λs have varying immunomodulatory functions under different physiological conditions or in different organs and can inhibit tumor growth via regulation of the immune system. Diseases associated with IFN-λs include asthma, allergy, and systemic lupus erythematosus. In this review, we summarize the current knowledge of the biology of IFN-λs and their immunomodulatory function in relevant human diseases.

[1]  L. Enjuanes,et al.  Combined action of type I and type III interferon restricts initial replication of severe acute respiratory syndrome coronavirus in the lung but fails to inhibit systemic virus spread. , 2012, The Journal of general virology.

[2]  A. Urbańska,et al.  IL28B CC genotype is associated with higher all-cause mortality in antiretroviral-treated HIV-infected patients. , 2012, AIDS research and human retroviruses.

[3]  D. Yuan,et al.  IFN type I and type II independent enhancement of B cell TLR7 expression by natural killer cells , 2012, Journal of leukocyte biology.

[4]  A. Lewis-Antes,et al.  Type III IFNs Are Produced by and Stimulate Human Plasmacytoid Dendritic Cells , 2012, The Journal of Immunology.

[5]  A. Boonstra,et al.  Type I and III interferons enhance IL‐10R expression on human monocytes and macrophages, resulting in IL‐10‐mediated suppression of TLR‐induced IL‐12 , 2012, European journal of immunology.

[6]  K. Eriksson,et al.  HHV-6B Induces IFN-Lambda1 Responses in Cord Plasmacytoid Dendritic Cells through TLR9 , 2012, PloS one.

[7]  Zhi-Gang Liu,et al.  Eosinophil-derived interferon-lambda contributes to initiation of allergen-related inflammation in the intestine. , 2012, Cytokine.

[8]  A. Rauch,et al.  Genetic Variations in IL28B and Allergic Disease in Children , 2012, PloS one.

[9]  R. Rabin,et al.  Expression profiles of human interferon-alpha and interferon-lambda subtypes are ligand- and cell-dependent , 2012, Immunology and cell biology.

[10]  S. Johnston,et al.  Impaired type I and type III interferon induction and rhinovirus control in human cystic fibrosis airway epithelial cells , 2012, Thorax.

[11]  Shih-Chang Lin,et al.  Profiling the expression of interleukin (IL)‐28 and IL‐28 receptor α in systemic lupus erythematosus patients , 2012, European journal of clinical investigation.

[12]  Hong Chen,et al.  Antitumor activities of recombinant human interferon (IFN)-λ1 in vitro and in xenograft models in vivo for colon cancer. , 2011, Cancer letters.

[13]  A. Lasfar,et al.  Interferon Lambda: A New Sword in Cancer Immunotherapy , 2011, Clinical & developmental immunology.

[14]  G. Gallagher,et al.  Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells , 2011, The Journal of Immunology.

[15]  Takashi Suzuki,et al.  Antitumor activity of type III interferon alone or in combination with type I interferon against human non‐small cell lung cancer , 2011, Cancer science.

[16]  M. Tagawa,et al.  Adenoviruses-mediated transduction of human oesophageal carcinoma cells with the interferon-λ genes produced anti-tumour effects , 2011, British Journal of Cancer.

[17]  Zhiqiang Liu,et al.  Interferon-λ mediates oral tolerance and inhibits antigen-specific, T-helper 2 cell-mediated inflammation in mouse intestine. , 2011, Gastroenterology.

[18]  E. Lourenço,et al.  Interferon-lambda1 induces peripheral blood mononuclear cell-derived chemokines secretion in patients with systemic lupus erythematosus: its correlation with disease activity , 2011, Arthritis research & therapy.

[19]  M. Neurath,et al.  IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease , 2011, EMBO molecular medicine.

[20]  S. Johnston,et al.  Interferon-lambda as a new approach for treatment of allergic asthma? , 2011, EMBO molecular medicine.

[21]  J. Nattermann,et al.  Interferon-lambda serum levels in hepatitis C. , 2011, Journal of hepatology.

[22]  M. Hornef,et al.  IFN-λ determines the intestinal epithelial antiviral host defense , 2011, Proceedings of the National Academy of Sciences.

[23]  R. Schreiber,et al.  Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion , 2011, Science.

[24]  A. Boonstra,et al.  IL-29 and IFNα differ in their ability to modulate IL-12 production by TLR-activated human macrophages and exhibit differential regulation of the IFNγ receptor expression. , 2011, Blood.

[25]  Eleanor Barnes,et al.  Interferon lambdas: the next cytokine storm , 2011, Gut.

[26]  C. Zhao,et al.  CD14+ cell–derived IL‐29 modulates proinflammatory cytokine production in patients with allergic airway inflammation , 2011, Allergy.

[27]  Y. Nakanishi,et al.  IL-13 suppresses double-stranded RNA-induced IFN-λ production in lung cells. , 2011, Biochemical and biophysical research communications.

[28]  R. Bartenschlager,et al.  Comparative Analysis of the Lambda-Interferons IL-28A and IL-29 regarding Their Transcriptome and Their Antiviral Properties against Hepatitis C Virus , 2010, PloS one.

[29]  Jacques Fellay,et al.  IL28B genotype is associated with differential expression of intrahepatic interferon‐stimulated genes in patients with chronic hepatitis C , 2010, Hepatology.

[30]  Christian A. Luber,et al.  Mouse CD8α+ DCs and human BDCA3+ DCs are major producers of IFN-λ in response to poly IC , 2010, The Journal of experimental medicine.

[31]  M. Busch,et al.  Host genetic basis for hepatitis C virus clearance: a role for blood collection centers , 2010, Current opinion in hematology.

[32]  A. Zdanov.  Structural analysis of cytokines comprising the IL-10 family. , 2010, Cytokine & growth factor reviews.

[33]  Y. Chen,et al.  Expression and release of IL‐29 by mast cells and modulation of mast cell behavior by IL‐29 , 2010, Allergy.

[34]  S. Kotenko,et al.  Interferon-lambda: a new addition to an old family. , 2010, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[35]  M. Robek,et al.  Interferon-lambda in the immune response to hepatitis B virus and hepatitis C virus. , 2010, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[36]  H. Steen,et al.  Interferon-lambda as a potential therapeutic agent in cancer treatment. , 2010, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[37]  G. Gallagher,et al.  The lambda interferons: guardians of the immune-epithelial interface and the T-helper 2 response. , 2010, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[38]  S. Paludan,et al.  Mechanisms of type III interferon expression. , 2010, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[39]  N. Sardesai,et al.  IL-28B/IFN-λ3 Drives Granzyme B Loading and Significantly Increases CTL Killing Activity in Macaques. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[40]  R. Sabat,et al.  IL-28A, IL-28B, and IL-29: promising cytokines with type I interferon-like properties. , 2010, Cytokine & growth factor reviews.

[41]  M. Robek,et al.  Interferon-λ in HCV Infection and Therapy , 2010, Viruses.

[42]  G. Kochs,et al.  Temporal and Spatial Resolution of Type I and III Interferon Responses In Vivo , 2010, Journal of Virology.

[43]  A. Melcher,et al.  Type III IFN interleukin-28 mediates the antitumor efficacy of oncolytic virus VSV in immune-competent mouse models of cancer. , 2010, Cancer research.

[44]  J. McCarthy,et al.  Interferon‐lambda genotype and low serum low‐density lipoprotein cholesterol levels in patients with chronic hepatitis C infection , 2010, Hepatology.

[45]  G. Gallagher,et al.  IL-4 enhances IFN-lambda1 (IL-29) production by plasmacytoid DCs via monocyte secretion of IL-1Ra. , 2010, Blood.

[46]  F. Belardelli,et al.  Recent advances on the immunomodulatory effects of IFN-α: Implications for cancer immunotherapy and autoimmunity , 2010, Autoimmunity.

[47]  Sven Bergmann,et al.  Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. , 2010, Gastroenterology.

[48]  S. Günther,et al.  Lambda Interferon Renders Epithelial Cells of the Respiratory and Gastrointestinal Tracts Resistant to Viral Infections , 2010, Journal of Virology.

[49]  A. D. Torre,et al.  Antitumor activity of Type I and Type III interferons in BNL hepatoma model , 2010, Cancer Immunology, Immunotherapy.

[50]  S. Paludan,et al.  Expression of Type III Interferon (IFN) in the Vaginal Mucosa Is Mediated Primarily by Dendritic Cells and Displays Stronger Dependence on NF-κB than Type I IFNs , 2010, Journal of Virology.

[51]  G. Nuovo,et al.  Interleukin-29 Binds to Melanoma Cells Inducing Jak-STAT Signal Transduction and Apoptosis , 2010, Molecular Cancer Therapeutics.

[52]  A. C. Looman,et al.  Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines , 2009, Genes and Immunity.

[53]  G. Gallagher,et al.  Modulation of human plasmacytoid DC function by IFN‐λ1 (IL‐29) , 2009, Journal of leukocyte biology.

[54]  Jacques Fellay,et al.  Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance , 2009, Nature.

[55]  S. Su,et al.  Interferon‐λs: the modulators of antivirus, antitumor, and immune responses , 2009, Journal of leukocyte biology.

[56]  G. Gallagher,et al.  IFN-lambda1 (IL-29) inhibits GATA3 expression and suppresses Th2 responses in human naive and memory T cells. , 2009, Blood.

[57]  D. Weiner,et al.  Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunity. , 2009, Blood.

[58]  S. Johnston,et al.  Respiratory virus induction of alpha‐, beta‐ and lambda‐interferons in bronchial epithelial cells and peripheral blood mononuclear cells , 2009, Allergy.

[59]  J. Melchjorsen,et al.  Human interferon-λ3 is a potent member of the type III interferon family , 2009, Genes and Immunity.

[60]  K. Hartshorn,et al.  Differentiated Human Alveolar Type II Cells Secrete Antiviral IL-29 (IFN-λ1) in Response to Influenza A Infection1 , 2009, The Journal of Immunology.

[61]  G. Gallagher,et al.  Interferon‐λ1 (interleukin‐29) preferentially down‐regulates interleukin‐13 over other T helper type 2 cytokine responses in vitro , 2008, Immunology.

[62]  S. Ansell,et al.  A role for IFN-λ1 in multiple myeloma B cell growth , 2008, Leukemia.

[63]  J. Ceuppens,et al.  Type III IFN‐λ mRNA expression in sputum of adult and school‐aged asthmatics , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[64]  S. Maher,et al.  IFN-α and IFN-λ differ in their antiproliferative effects and duration of JAK/STAT signaling activity , 2008 .

[65]  K. Asadullah,et al.  Maturing dendritic cells are an important source of IL‐29 and IL‐20 that may cooperatively increase the innate immunity of keratinocytes , 2008, Journal of leukocyte biology.

[66]  T. Michiels,et al.  IFN-Lambda (IFN-λ) Is Expressed in a Tissue-Dependent Fashion and Primarily Acts on Epithelial Cells In Vivo , 2008, PLoS pathogens.

[67]  U. Jensen,et al.  An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity1 , 2008, The Journal of Immunology.

[68]  S. Kotenko,et al.  IFN Regulatory Factor Family Members Differentially Regulate the Expression of Type III IFN (IFN-λ) Genes1 , 2007, The Journal of Immunology.

[69]  A. Nielsen,et al.  Type III Interferon (IFN) Induces a Type I IFN-Like Response in a Restricted Subset of Cells through Signaling Pathways Involving both the Jak-STAT Pathway and the Mitogen-Activated Protein Kinases , 2007, Journal of Virology.

[70]  Takashi Suzuki,et al.  IL-28 Elicits Antitumor Responses against Murine Fibrosarcoma , 2007, The Journal of Immunology.

[71]  G. Gallagher,et al.  Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response , 2007, Genes and Immunity.

[72]  S. Akira,et al.  Viral Infections Activate Types I and III Interferon Genes through a Common Mechanism* , 2007, Journal of Biological Chemistry.

[73]  G. Gallagher,et al.  Interferon lambda-1 (IFN-λ1/IL-29) induces ELR− CXC chemokine mRNA in human peripheral blood mononuclear cells, in an IFN-γ-independent manner , 2007, Genes and Immunity.

[74]  Stephen T Holgate,et al.  Role of deficient type III interferon-λ production in asthma exacerbations , 2006, Nature Medicine.

[75]  S. Brand,et al.  Novel interferon-λs induce antiproliferative effects in neuroendocrine tumor cells , 2006 .

[76]  M. Ohtsuki,et al.  Antitumor Activity of IFN-λ in Murine Tumor Models1 , 2006, The Journal of Immunology.

[77]  S. Paludan,et al.  IFN-λ: Novel Antiviral Cytokines , 2006 .

[78]  S. Paludan,et al.  Lambda Interferon (IFN-λ), a Type III IFN, Is Induced by Viruses and IFNs and Displays Potent Antiviral Activity against Select Virus Infections In Vivo , 2006, Journal of Virology.

[79]  S. Smirnov,et al.  Characterization of the mouse IFN-λ ligand-receptor system: IFN-λs exhibit antitumor activity against B16 melanoma , 2006 .

[80]  S. Brand,et al.  IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[81]  S. Kotenko,et al.  The expanded family of class II cytokines that share the IL‐10 receptor‐2 (IL‐10R2) chain , 2004, Journal of leukocyte biology.

[82]  J. Renauld,et al.  Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling. , 2004, The Journal of biological chemistry.

[83]  G. Sabatino,et al.  Interleukin-28 and 29 (IL-28 and IL-29): New Cytokines with Anti-Viral Activities , 2004, International journal of immunopathology and pharmacology.

[84]  S. Kotenko,et al.  Full house: 12 receptors for 27 cytokines. , 2004, International immunopharmacology.

[85]  E. Coccia,et al.  Viral infection and Toll‐like receptor agonists induce a differential expression of type I and λ interferons in human plasmacytoid and monocyte‐derived dendritic cells , 2004, European journal of immunology.

[86]  C. Herrick,et al.  To respond or not to respond: T cells in allergic asthma , 2003, Nature Reviews Immunology.

[87]  F. Belardelli,et al.  Cytokines as a link between innate and adaptive antitumor immunity. , 2002, Trends in immunology.

[88]  T. Bieber,et al.  Evidence for a pathophysiological role of keratinocyte-derived type III interferon (IFNλ) in cutaneous lupus erythematosus. , 2011, The Journal of investigative dermatology.

[89]  M. Tagawa,et al.  Interferon-lambda induces G1 phase arrest or apoptosis in oesophageal carcinoma cells and produces anti-tumour effects in combination with anti-cancer agents. , 2010, European journal of cancer.

[90]  M. Neurath,et al.  IL-28A is a key regulator of T-cell-mediated liver injury via the T-box transcription factor T-bet. , 2007, Gastroenterology.

[91]  M. Boniotto,et al.  Modulation of the human cytokine response by interferon lambda-1 (IFN-λ1/IL-29) , 2007, Genes and Immunity.

[92]  A. Lewis-Antes,et al.  IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex , 2003, Nature Immunology.

[93]  Scott R. Presnell,et al.  IL-28, IL-29 and their class II cytokine receptor IL-28R , 2002, Nature Immunology.