title: The anti-inflammatory actions of IL-4 in human monocytes are not mediated by IL-10, RP105 or the kinase activity of RIPK2.
abstract: The anti-inflammatory actions of IL-4 in activated human monocytes may reflect transcriptional regulation of genes involved in TLR signaling pathways. Tailored gene arrays were conducted to profile the expression of 84 genes central to TLR-mediated signal transduction in human monocytes treated with the TLR4 ligand, LPS, with or without IL-4. In the first 3h, IL-4 down-regulated mRNA levels of LPS-induced inflammatory cytokines and chemokines, without altering mRNA levels of TLRs, TLR-related signaling molecules or multiple transcription factors. The down-regulation of inflammatory genes by IL-4 was preceded by an early up-regulation of IL-10 mRNA and protein and mRNA for receptor-interacting serine-threonine kinase 2 (RIPK2), the TLR homolog, RP105, and c-Maf, a transcription factor required for IL-10 gene expression. However, IL-4 still suppressed LPS-induced TNFα production in bone-marrow derived macrophages from IL10(-/-) mice, and in the presence of a neutralizing antibody to IL-10 in human monocytes. The up-regulation of RIPK2 and RP105 mRNA by IL-4 occurred independently of IL-10. IL-4 maintained the ability to suppress LPS-induced TNFα and enhance IL-10 production in the presence of RIPK2 kinase inhibitors. Further, IL-4 failed to up-regulate expression of RP105 at the cell surface. In conclusion, the anti-inflammatory actions of IL-4 occur independently of IL-10, RP105, and the kinase activity of RIPK2.
authors.affiliation: Inflammation Laboratory, Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, GPO Box 855, West Perth 6872, Australia.
authors.forename: Eleanor A
authors.initials: EA
authors.lastname: Woodward
authors.forename: Tatiana B
authors.initials: TB
authors.lastname: Kolesnik
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Prêle
authors.forename: Prue H
authors.initials: PH
authors.lastname: Hart
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D001483:Base Sequence; D017931:DNA Primers; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D051379:Mice; D009000:Monocytes / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000502:physiology*
chemical_list: D015703:Antigens, CD; C092722:CD180 protein, human; D017931:DNA Primers; D016753:Interleukin-10; D015847:Interleukin-4; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2