Overview
The Interleukin‑28 receptor (IL‑28R) is a type III cytokine receptor complex that mediates cellular responses to the type III interferons, primarily interleukin‑28A (IFN‑λ2), interleukin‑28B (IFN‑λ3), and interleukin‑29 (IFN‑λ1). The receptor is a heterodimer composed of a ligand‑specific α‑chain (IL28RA, also termed IFNLR1) and a shared β‑chain (IL10RB, also termed IL‑10R2) that is common to several other cytokine receptors, including those for interleukin‑10, interleukin‑22, and interleukin‑26.
Molecular composition
| Subunit | Gene symbol | Protein name | Cellular location | Key features |
|---|---|---|---|---|
| α‑chain | IL28RA (IFNLR1) | Interleukin‑28 receptor α chain | Type I transmembrane protein; extracellular domain binds IFN‑λ ligands | Confers ligand specificity; contains a WSXWS motif typical of class II cytokine receptors |
| β‑chain | IL10RB | Interleukin‑10 receptor β chain | Type I transmembrane protein; shared among multiple cytokine receptors | Provides signal transduction capability via associated Janus kinases |
Signal transduction
Upon ligand binding, the heterodimeric receptor undergoes conformational changes that bring associated Janus kinases (JAK1 bound to IL28RA and TYK2 bound to IL10RB) into proximity. This results in phosphorylation of the receptor intracellular domains and subsequent recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins, principally STAT1 and STAT2, which form a heterodimer with IRF9 (the ISGF3 complex). The ISGF3 complex translocates to the nucleus and drives transcription of interferon‑stimulated genes (ISGs) that mediate antiviral, antiproliferative, and immunomodulatory effects.
Expression profile
IL28RA expression is tissue‑restricted, with high levels in epithelial cells of the respiratory and gastrointestinal tracts, hepatocytes, and certain immune cells (e.g., dendritic cells and NK cells). IL10RB is ubiquitously expressed, enabling the functional receptor complex to be assembled wherever IL28RA is present.
Physiological and clinical relevance
- Antiviral immunity: The IL‑28R pathway contributes to the innate defense against a broad range of viruses, including influenza, hepatitis C virus (HCV), and coronaviruses, by inducing ISGs that limit viral replication.
- Inflammatory diseases: Dysregulation of type III interferon signaling has been implicated in chronic inflammatory conditions such as inflammatory bowel disease and asthma, though the precise mechanisms remain under investigation.
- Therapeutic targeting: Recombinant IFN‑λ (e.g., pegylated interferon‑λ1) has been evaluated in clinical trials for HCV and more recently for SARS‑CoV‑2 infection, leveraging the tissue‑selective activity of the IL‑28R to achieve antiviral effects with reduced systemic inflammation compared with type I interferons.
Genetic variation
Polymorphisms in the IFNL4/IFNL3 locus, which influence the expression of IFN‑λ3 and IFN‑λ4, have been associated with differential outcomes in HCV infection and treatment response. Though these variants affect ligand availability rather than the receptor itself, they indirectly modulate IL‑28R signaling intensity.
References
- Kotenko, S. V., et al. “IFN‑λs: A New Type of Interferon.” Journal of Interferon & Cytokine Research 27.1 (2007): 75‑82.
- Sheppard, P., et al. “IFN‑λ (IL‑28/IL‑29) Receptor Complex: Functional Characterization.” Journal of Immunology 172.1 (2004): 597‑603.
- Galani, I., et al. “Type III Interferons in Antiviral Immunity.” Nature Reviews Immunology 20.2 (2020): 89‑101.
This entry reflects currently available peer‑reviewed literature as of July 2026.
