IFN-beta-mediated inhibition of IL-8 expression requires the ISGF3 components Stat1, Stat2, and IRF-9.
Interleukin-8 (IL-8) is a key component of the innate immune response because of its ability to recruit inflammatory cells to sites of inflammation. Although the effects of IL-8 are largely beneficial, aberrant expression of IL-8 is known to contribute to a number of pathologic states. Interferon-beta (IFN-beta), an antiviral cytokine, is known to inhibit the expression of IL-8, although the exact mechanism by which this occurs has yet to be elucidated. In this study, we dissect the role of each member of the IFN-stimulated gene factor 3 (ISGF3) signaling complex in contributing to IFN-beta inhibition of IL-8 gene expression. To date, no IFN-stimulated response element (ISRE) (the DNA binding target for ISGF3) has been identified within the promoter region of the IL-8 gene. We conclude, through use of cell lines deficient for ISGF3 components, that all three members of this complex, Stat1, Stat2, and IFN regulatory factor-9 (IRF-9), are required for IFN-beta-mediated inhibition of IL-8 expression. In contrast to positive signaling by ISGF3 to activate gene expression, we find that the transactivation domains of Stat1 and Stat2 are not essential to IFN-beta inhibition of IL-8. Taken together, these data define the role of the ISGF3 members in IFN-beta inhibitory signaling.
Laver
Travis
T
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
Nozell
Susan E
SE
Benveniste
Etty N
EN
D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism*; D016899:Interferon-beta / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016209:Interleukin-8; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; D016899:Interferon-beta; D013755:Tetradecanoylphorbol Acetate