Open AccessInterferon‐α synergistically enhances induction of interleukin‐6 by double stranded RNA in HeLa cells
Author(s) -
Harcourt Jennifer L.,
Offermann Margaret K.
Publication year - 2000
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.2000.01300.x
Subject(s) - rna silencing , biology , creb , microbiology and biotechnology , interferon , messenger rna , protein kinase r , transcription (linguistics) , cytokine , rna , transcription factor , rna interference , virology , phosphorylation , protein kinase a , gene , immunology , biochemistry , cyclin dependent kinase 2 , linguistics , philosophy
Double stranded RNA (dsRNA), an intermediate that is common during viral infection, directly induces much higher levels of expression of interleukin‐6 (IL‐6) mRNA than does the cytokine IL‐1β. Interferon α (IFNα) by itself does not induce expression of IL‐6; nonetheless, IFNα pretreatment dramatically enhances IL‐6 induction by dsRNA but not by IL‐1β. Mutation of either the activating transcription factor/cyclic AMP response element binding protein (ATF/CREB) or the NF‐IL‐6 binding element within the IL‐6 promoter eliminates most responsiveness of CAT reporter constructs to either dsRNA or to IL‐1β. IFNα pretreatment partially restores responsiveness to dsRNA but not to IL‐1β when either the ATF/CREB site or the NF‐IL‐6 site is mutated, but at least one of these sites must be intact for responsiveness to be restored. Mutation of the κB binding site in the IL‐6 promoter eliminates responsiveness to either IL‐1β or to dsRNA, and pretreatment with IFNα does not restore any responsiveness. Incubation with dsRNA leads to a decrease in protein translation, especially in cells that have been pretreated with IFNα. Nonetheless, IFNα pretreatment followed by dsRNA leads to very high IL‐6 protein levels. These studies demonstrate that major differences exist in the induction of IL‐6 at both the mRNA and protein levels by dsRNA compared to cytokines and that IFNα pretreatment selectively enhances IL‐6 induction by dsRNA but not by IL‐1β. The high levels of IL‐6 expression that result when cells encounter class I IFN prior to dsRNA suggest a mechanism for a heightened host response to viral infection with heightened production of this pleotropic cytokine.