title: IFN-gamma downregulates interleukin-4 functional activity on monocytes by multiple mechanisms.
abstract: Interleukin-4 (IL-4) has potent anti-inflammatory properties on monocytes and suppresses lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) and IL-1beta production. Culture with interferon (IFN-gamma) alters human monocyte responses to IL-4 by multiple mechanisms. As previously published, IFN-gamma reduced IL-4-activated signal transducer and activator of transcription-6 (STAT-6). This correlated with an inability of IL-4 to suppress LPS-induced TNF-alpha but not IL-1beta production. A second mechanism, apparent some 48 h after exposure to IFN-gamma, involved a significant suppression of IL-4 receptor (IL-4R) expression at the cell surface, and this correlated with the loss of additional functional responses to IL-4, including IL-4-induced suppression of LPS-induced IL-1beta production. This study identified a further role of IFN-gamma on IL-4 responses, including reduced IL-4R surface expression by human monocytes. Increased release of soluble gammac from IFN-gamma-treated monocytes provides an additional mechanism by which IFN-gamma may control the functional activity of IL-4. This study characterizes further the opposing effects of the type 1 and type 2 cytokine regulatory systems.
authors.affiliation: Department of Microbiology and Infectious Diseases, School of Medicine, Flinders University, Adelaide, South Australia 5001.
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Bonder
authors.forename: Kate V L
authors.initials: KV
authors.lastname: Davies
authors.forename: Emma K
authors.initials: EK
authors.lastname: Hosszu
authors.forename: John J
authors.initials: JJ
authors.lastname: Finlay-Jones
authors.forename: Prue H
authors.initials: PH
authors.lastname: Hart
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019948:Receptors, Interleukin-4; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma