Details

Autor(en) / Beteiligte

• Hernandez, Pedro P.
• Mahlakoiv, Tanel
• Nguyen, Nam
• Staeheli, Peter
• Diefenbach, Andreas

Titel

119 : Interleukin-22 protects against intestinal viral infection through enhancement of interferon-λ signaling pathway

Ist Teil von

• Cytokine (Philadelphia, Pa.), 2013-09, Vol.63 (3), p.271-271

Ort / Verlag

Elsevier Ltd

Erscheinungsjahr

2013

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• The mucosal immune system has the challenge of being tolerant of the commensal microbiota while at the same time being able to mount an effective immune response to pathogens. It is now an emerging view that immunity against virus infection at barrier surfaces is orchestrated by a mucosal interferon (IFN) system distinct from the various type I IFNs (IFN-I). This is best documented for rotavirus infection, immunity to which is independent of IFN-I but instead is entirely dependent on IFN-λ and its receptor (IFN-λR1). IFN-λ is closely related to IL-22, a cytokine abundantly produced by innate lymphoid cells at mucosal surfaces. Interestingly, both the IL-22 and IFN-λ receptors are exclusively expressed by epithelial cells, allowing immune cells to control epithelial cell function and repair following infections. Given these similarities between the IL-22 and IFN-λ system, we investigated crosstalk between and interdependence of these pathways in epithelial cells. Following rotavirus infection, IFN-λ is required to up-regulate antiviral host defense genes (i.e., interferon stimulated genes, ISGs) in infected epithelial cells. Interestingly, mice genetically lacking IL-22 were highly susceptible to rotavirus infection similar to mice lacking IFN-λ signaling (IFN-λR1-deficient mice). Il22-/- mice had reduced expression of ISGs and we could demonstrate that IL-22 synergistically reinforces the activation of STAT1 after exposure to IFN-λ. Stimulation of epithelial cells with a combination of IL-22 and IFN-λ enhanced the phosphorylation of STAT1 thereby enhancing the induction of ISGs resulting in an improved antiviral response. Interestingly, this synergism is independent of STAT3 activation, which is essential for the IL-22-induced antibacterial function and regeneration of epithelial cells. Our data reveal a previously unappreciated interdependence of these two mucosal cytokine signaling pathways required for the protection against enteric virus infection.