Contribution of Interferon-β to the Murine Macrophage Response to the Toll-like Receptor 4 Agonist, Lipopolysaccharide

摘要: Interferon-beta (IFN-beta) has been identified as the signature cytokine induced via Toll-like receptor (TLR) 4, "MyD88-independent" signaling pathway in macrophages stimulated by Gram-negative bacterial lipopolysaccharide (LPS). In this study, we analyzed responses of derived from wild-type (IFN-beta(+/+)) mice or with a targeted mutation IFN-beta (IFN-beta(-/-)) to prototype TLR4 agonist, Escherichia coli LPS. A comparison basal and LPS-induced gene expression (by reverse transcription-PCR, real-time PCR, Affymetrix microarray analyses) resulted identification four distinct patterns affected deficiency. Analysis subset each group differentially regulated genes computer-assisted promoter analysis revealed putative IFN-responsive elements all examined. activation intracellular molecules, STAT1 Tyr-701, Ser-727, Akt, but not p38, JNK, ERK MAPK proteins, was significantly diminished IFN-beta(-/-) versus IFN-beta(+/+) macrophages. "Priming" exogenous recombinant increased levels for induction monocyte chemotactic protein 5, inducible nitric-oxide synthase, IP-10, IL-12 p40 mRNA, whereas no increase relatively small increases were observed IL-1beta, IL-6, 1, MyD88 mRNA. Finally, challenged vivo LPS exhibited survival when compared controls, indicating that contributes lethality; however, extent one observes more complete deficiencies (e.g. TLR4(-/-) TRIF(-/-) mice). Collectively, these findings reveal unanticipated regulatory roles response vitro vivo.