Type III interferons (IFNs; IFN-lambda) are antiviral cytokines with type I IFN-like biological functions, including antiviral activity. In this article we review the literature on IFN-lambda expression and propose that important differences exist between the mechanisms governing expression of the different classes of IFNs. Importantly, while IFN-beta is induced by coordinated action of a multifactor enhanceosome, and IFN-alpha expression is activated by multiple IFN regulatory factor (IRF)-binding cis-promoter elements, the type III IFNs are induced through independent actions of IRFs and nuclear factor-kappaB. Although these differences may appear minor at first glance, we propose that IFN-lambda expression is more flexible than IFN-alpha/beta expression, which could allow expression of type III IFNs in response to a wider range of stimuli compared with type I IFNs. Moreover, such a mechanism of induction will potentially render expression of type III IFNs less sensitive to microbial evasion strategies targeting the IRF pathway. Thus, the mechanisms governing type III IFN expression play an important part in dictating the biology of this antiviral cytokine.
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