title: An essential role for IFN-β in the induction of IFN-stimulated gene expression by LPS in macrophages.
abstract: TLR agonists such as LPS and poly(I:C) induce expression of type I IFNs, such as IFN-α and -β, by macrophages. To examine the role of IFN-β in the induction of ISGs by LPS, we compared the ability of LPS to induce ISGF3 activity and ISG expression in bone marrow-derived macrophages from WT and Ifnb1(-/-) mice. We found that LPS treatment activated ISGF3 and induced expression of ISGs such as Oas1, Mx1, Ddx58 (RIG-I), and Ifih1 (MDA5) in WT macrophages, but not in macrophages derived from Ifnb1(-/-) mice or Ifnar1(-/-) mice. The inability of LPS to induce activation of ISGF3 and ISG expression in Ifnb1(-/-) macrophages correlated with the failure of LPS to induce activation of STAT1 and -2 in these cells. Consistent with these findings, LPS treatment also failed to induce ISG expression in bone marrow-derived macrophages from Stat2 KO mice. Although activation of ISGF3 and induction of ISG expression by LPS was abrogated in Ifnb1(-/-) and Ifnar1(-/-) macrophages, activation of NF-κB and induction of NF-κB-responsive genes, such as Tnf (TNF-α) and Il1b (IL-1β), were not affected by deletion of either the IFN-β or IFN-αR1 genes. These findings demonstrate that induction of ISGF3 activity and ISG expression by LPS is critically dependent on intermediate production of IFN-β and autocrine signaling through type I IFN receptors.
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD, USA;
authors.forename: Faruk
authors.initials: F
authors.lastname: Sheikh
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD, USA;
authors.forename: Harold
authors.initials: H
authors.lastname: Dickensheets
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA; and.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gamero
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.affiliation: Division of Therapeutic Proteins, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD, USA; raymond.donnelly@fda.hhs.gov.
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Donnelly
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C522693:ISG56 protein, mouse; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D051193:Toll-Like Receptors; D014157:Transcription Factors; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta
keywords: ISGF3; NF-κB; STAT; TLR4; endotoxin