Interleukin 28

Interleukin-28 (IL-28) is a cytokine that comes in two isoforms, IL-28A and IL-28B, and plays a role in immune defense against viruses, including the induction of an "antiviral state" by turning on Mx proteins, 2',5'-oligoadenylate synthetase as well as ISGF3G (Interferon Stimulated Gene Factor 3).[1] IL-28A and IL-28B belong to the type III interferon family of cytokines and are highly similar (in amino acid sequence) to IL-29. Their classification as Interferons is due to their ability to induce an antiviral state, while their additional classification as cytokines is due to their chromosomal location as well as the fact that they are encoded by multiple exons, as opposed to a single exon, as most type-I IFNs are.

Interleukin 28A
Identifiers
SymbolIL28A
Alt. symbolsIFNL2
NCBI gene282616
HGNC18364
OMIM607401
RefSeqNM_172138
UniProtQ8IZJ0
Other data
LocusChr. 19 q13.13
Search for
StructuresSwiss-model
DomainsInterPro
Interleukin 28B
Identifiers
SymbolIL28B
Alt. symbolsIFNL3
NCBI gene282617
HGNC18365
OMIM607402
RefSeqNM_172139
UniProtQ8IZI9
Other data
LocusChr. 19 q13.13
Search for
StructuresSwiss-model
DomainsInterPro

Discovery

IL-28 was discovered in 2002 by Zymogenetics[2] using a genomic screening process in which the entire human genome was scanned for putative genes. Once these genes were found, a second scan was performed to look specifically for cytokines. Both IL-28 and IL-29 were found in humans using this type of analysis.

Structure

IL-28 genes are located near IL-29 on chromosome 19 in humans. The two isoforms of IL-28 (IL-28A and IL-28B) are 96% homologous. Differences in function between the two forms remains unclear.

The receptor for IL-28 is composed of a unique IL-28 Receptor Alpha chain which pairs with the IL-10 Receptor Beta chain, leading many to classify IL-28 as an IL-10-like family member.

Function

IL-28 has also been shown to play a role in the adaptive immune response, as its inclusion as an immunoadjuvant during small animal vaccination lead to augmented antigen-specific Interferon Gamma release as well as an increased cytotoxic potential in CD8+ T cells.[3]

Clinical significance

Addition of IL-28 to vaccination results in 100% protection from a lethal H1N1 Influenza challenge in a small animal model when it was paired with an Influenza vaccine that protected only 50% of the time without IL-28.[3]

Studies of IL-28B in non-human primate models of vaccination confirmed the small animal models, leading to an increase in Interferon Gamma production and CD8+ T cell activity in the form of cytotoxicity in an HIV vaccine study.[4] Scientists have credited this link to explain why some people infected with HSV-1 experience cold sores, while others do not.

A single nucleotide polymorphism (SNP) near the IL28B gene predicts response to hepatitis C treatment with interferon and ribavirin.[5][6] The SNP was identified in a genome-wide association study (GWAS) and is to date the best example of a successful GWAS hit that is clinically relevant.[7]

References
  1. Kempuraj D, Donelan J, Frydas S, Iezzi T, Conti F, Boucher W, et al. (2004). "Interleukin-28 and 29 (IL-28 and IL-29): new cytokines with anti-viral activities". International Journal of Immunopathology and Pharmacology. 17 (2): 103–6. doi:10.1177/039463200401700201. PMID 15171810. S2CID 43322911.
  2. Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. (January 2003). "IL-28, IL-29 and their class II cytokine receptor IL-28R". Nature Immunology. 4 (1): 63–8. doi:10.1038/ni873. PMID 12469119. S2CID 35764259.
  3. Morrow MP, Pankhong P, Laddy DJ, Schoenly KA, Yan J, Cisper N, Weiner DB (June 2009). "Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunity". Blood. 113 (23): 5868–77. doi:10.1182/blood-2008-11-190520. PMC 2700323. PMID 19304955.
  4. Morrow MP, Yan J, Pankhong P, Shedlock DJ, Lewis MG, Talbott K, et al. (September 2010). "IL-28B/IFN-lambda 3 drives granzyme B loading and significantly increases CTL killing activity in macaques". Molecular Therapy. 18 (9): 1714–23. doi:10.1038/mt.2010.118. PMC 2956930. PMID 20571540.
  5. PGxNews.Org (August 2009). "New biomarker predicts response to hepatitis C treatment". PGxNews.Org. Archived from the original on November 21, 2009. Retrieved 2009-08-17.
  6. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. (September 2009). "Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance". Nature. 461 (7262): 399–401. Bibcode:2009Natur.461..399G. doi:10.1038/nature08309. PMID 19684573. S2CID 1707096.
  7. Maxmen A (June 2011). "Pharmacogenomics: playing the odds". Nature. 474 (7350): S9-10. doi:10.1038/474S9a. PMID 21666735. S2CID 29585464.
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