Interferon Lambda 3 Explained

Interferon lambda 3 (gene symbol: IFNL3) encodes the IFNL3 protein. IFNL3 was formerly named IL28B, but the Human Genome Organization Gene Nomenclature Committee renamed this gene in 2013 while assigning a name to the then newly discovered IFNL4 gene.^[1] Together with IFNL1 (formerly IL29) and IFNL2 (formerly IL28A), these genes lie in a cluster on chromosomal region 19q13. IFNL3 shares ~96% amino-acid identity with IFNL2, ~80% identity with IFNL1 and ~30% identity with IFNL4.

Interferon lambda genes encode cytokines classified as type III interferons, which are distantly related to type I interferons and the IL-10 family. Type III interferons are induced by viral infection and interact with a heterodimeric class II cytokine receptor that consists of interleukin 10 receptor, beta (IL10RB) and interferon lambda receptor 1 (IFNLR1) to signal via the JAK-STAT anti-viral pathway. [provided by [[RefSeq]], Jul 2008].

Hepatitis C

In 2009 (i.e., before the discovery of IFNL4), results from genome wide association studies (GWAS) indicated that single-nucleotide polymorphisms (SNPs) lying near IFNL3 (rs12979860, rs8099917 and others) were strongly associated with response to pegylated interferon-α and ribavirin treatment for chronic hepatitis C,^{[2] [3] [4] [5]} as well as spontaneous clearance of hepatitis C (HCV) infection.^{[6] [7] [8] [9]} The gene then known as IL28B (now IFNL3) was the closest known gene at the time, so these genetic variants were called “IL28B variants.” It was assumed that the observed associations reflected differences in the structure or regulation of that gene. However, discovery of IFNL4 revealed that the rs12979860 SNP is located within intron 1 of IFNL4, while rs8099917 lies in an intergenic region, but nearest to IFNL4.^[10]   The rs12979860 and rs8099917 SNPs are in high linkage disequilibrium with a variant of IFNL4 (IFNL4-ΔG/TT; rs368234815) that controls generation of the IFNL4 protein. IFNL4-ΔG/TT appears to be the functional polymorphism that accounts for GWAS associations of nearby SNPs with HCV clearance, and IFNL4-ΔG/TT was shown to have stronger statistical association with HCV clearance than that of rs12979860, especially in populations of African ancestry in which linkage disequilibrium between these variants is weaker than in other populations.^[11]

One possible functional variant in IFNL3 is the rs4803217 SNP, which lies in the 3’ untranslated regulatory region. Substitution of guanine for the ancestral thymine at this site increases IFNL3 mRNA expression by decreasing mRNA degradation and HCV-induced microRNA binding^[12] and changes the RNA structure.^[13] High linkage disequilibrium exists between rs4803217 and the IFNL4-ΔG/TT variant. rs4803217 has been shown to associate with HCV clearance, however, that association appears to stem from linkage disequilibrium with IFNL4-ΔG/TT rather than a direct functional effect of the rs4803217 SNP itself.

Further reading

• Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM . 6 . IL-28, IL-29 and their class II cytokine receptor IL-28R . Nature Immunology . 4 . 1 . 63–8 . January 2003 . 12469119 . 10.1038/ni873 . 35764259 .
• Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP . 6 . IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex . Nature Immunology . 4 . 1 . 69–77 . January 2003 . 12483210 . 10.1038/ni875 . 2734534 .
• Li M, He S . Purification and characterization of recombinant human interleukin-29 expressed in Escherichia coli . Journal of Biotechnology . 122 . 3 . 334–40 . April 2006 . 16413080 . 10.1016/j.jbiotec.2005.11.019 .
• Mennechet FJ, Uzé G . Interferon-lambda-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells . Blood . 107 . 11 . 4417–23 . June 2006 . 16478884 . 10.1182/blood-2005-10-4129 . free .
• Li MC, Wang HY, Wang HY, Li T, He SH . Liposome-mediated IL-28 and IL-29 expression in A549 cells and anti-viral effect of IL-28 and IL-29 on WISH cells . Acta Pharmacologica Sinica . 27 . 4 . 453–9 . April 2006 . 16539846 . 10.1111/j.1745-7254.2006.00292.x . free .
• Lasfar A, Lewis-Antes A, Smirnov SV, Anantha S, Abushahba W, Tian B, Reuhl K, Dickensheets H, Sheikh F, Donnelly RP, Raveche E, Kotenko SV . 6 . Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma . Cancer Research . 66 . 8 . 4468–77 . April 2006 . 16618774 . 10.1158/0008-5472.CAN-05-3653 . free .
• Dellgren C, Gad HH, Hamming OJ, Melchjorsen J, Hartmann R . Human interferon-lambda3 is a potent member of the type III interferon family . Genes and Immunity . 10 . 2 . 125–31 . March 2009 . 18987645 . 10.1038/gene.2008.87 . free .
• Li M, Liu X, Zhou Y, Su SB . Interferon-lambdas: the modulators of antivirus, antitumor, and immune responses . Journal of Leukocyte Biology . 86 . 1 . 23–32 . July 2009 . 19304895 . 10.1189/jlb.1208761 . 37741272 . free .
• Gad HH, Dellgren C, Hamming OJ, Vends S, Paludan SR, Hartmann R . Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family . The Journal of Biological Chemistry . 284 . 31 . 20869–75 . July 2009 . 19457860 . 2742852 . 10.1074/jbc.M109.002923 . free .
• Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB . 6 . Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance . Nature . 461 . 7262 . 399–401 . September 2009 . 19684573 . 10.1038/nature08309 . 2009Natur.461..399G . 1707096 .

Notes and References

1. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, Chen S, Brand N, Tarway M, Liu L, Sheikh F, Astemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O'Brien TR . 6 . A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus . Nature Genetics . 45 . 2 . 164–71 . February 2013 . 23291588 . 3793390 . 10.1038/ng.2521 .
2. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB . 6 . Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance . Nature . 461 . 7262 . 399–401 . September 2009 . 19684573 . 10.1038/nature08309 . 1707096 . 2009Natur.461..399G .
3. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Müller T, Bahlo M, Stewart GJ, Booth DR, George J . 6 . IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy . Nature Genetics . 41 . 10 . 1100–4 . October 2009 . 19749758 . 10.1038/ng.447 . 21619093 .
4. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M . 6 . Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C . Nature Genetics . 41 . 10 . 1105–9 . October 2009 . 19749757 . 10.1038/ng.449 . 20399078 .
5. Muir AJ, Gong L, Johnson SG, Lee MT, Williams MS, Klein TE, Caudle KE, Nelson DR . 6 . Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon-α-based regimens . Clinical Pharmacology and Therapeutics . 95 . 2 . 141–6 . February 2014 . 24096968 . 3904555 . 10.1038/clpt.2013.203 .
6. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M . 6 . Genetic variation in IL28B and spontaneous clearance of hepatitis C virus . Nature . 2009 . 461 . 7265 . 798–801 . 10.1038/nature08463 . 19759533 . 3172006 . 2009Natur.461..798T .
7. Salum GM, Dawood RM, Abd El-Meguid M, Ibrahim NE, Abdel Aziz AO, El Awady MK . Correlation between IL28B/TLR4 genetic variants and HCC development with/without DAAs treatment in chronic HCV patients . Genes & Diseases . 7 . 3 . 392–400 . September 2020 . 32884993 . 10.1016/j.gendis.2019.05.004. 7452484 . free .
8. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O'Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M . 6 . Genetic variation in IL28B and spontaneous clearance of hepatitis C virus . Nature . 461 . 7265 . 798–801 . October 2009 . 19759533 . 3172006 . 10.1038/nature08463 . 2009Natur.461..798T .
9. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, Bochud M, Battegay M, Bernasconi E, Borovicka J, Colombo S, Cerny A, Dufour JF, Furrer H, Günthard HF, Heim M, Hirschel B, Malinverni R, Moradpour D, Müllhaupt B, Witteck A, Beckmann JS, Berg T, Bergmann S, Negro F, Telenti A, Bochud PY . 6 . Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study . Gastroenterology . 138 . 4 . 1338–45, 1345.e1-7 . April 2010 . 20060832 . 10.1053/j.gastro.2009.12.056 . 25546833 .
10. Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, Chen S, Brand N, Tarway M, Liu L, Sheikh F, Astemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O'Brien TR . 6 . A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus . Nature Genetics . 45 . 2 . 164–71 . February 2013 . 23291588 . 3793390 . 10.1038/ng.2521 .
11. Lu YF, Goldstein DB, Urban TJ, Bradrick SS . Interferon-λ4 is a cell-autonomous type III interferon associated with pre-treatment hepatitis C virus burden . Virology . 476 . 334–340 . February 2015 . 25577150 . 4494652 . 10.1016/j.virol.2014.12.020 .
12. McFarland AP, Horner SM, Jarret A, Joslyn RC, Bindewald E, Shapiro BA, Delker DA, Hagedorn CH, Carrington M, Gale M, Savan R . 6 . The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs . Nature Immunology . 15 . 1 . 72–9 . January 2014 . 24241692 . 4183367 . 10.1038/ni.2758 .
13. Lu YF, Mauger DM, Goldstein DB, Urban TJ, Weeks KM, Bradrick SS . IFNL3 mRNA structure is remodeled by a functional non-coding polymorphism associated with hepatitis C virus clearance . Scientific Reports . 5 . 16037 . November 2015 . 26531896 . 10.1038/srep16037 . 4631997 . 2015NatSR...516037L . free .