The anti-inflammatory actions of IL-4 in human monocytes are not mediated by IL-10, RP105 or the kinase activity of RIPK2

• Published in: Cytokine (Philadelphia, Pa.) Vol. 58; no. 3; pp. 415 - 423
• Main Authors: Woodward, Eleanor A., Kolesnik, Tatiana B., Nicholson, Sandra E., Prêle, Cecilia M., Hart, Prue H.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2012
• Subjects: Animals; Antibodies; Antigens, CD - physiology; Base Sequence; Bone marrow; c-Maf protein; Cell surface; Chemokines; DNA Primers; Flow Cytometry; Gene expression; gene expression regulation; Gene regulation; genes; Humans; Inflammation; Inflammation - prevention & control; Interleukin 1; Interleukin 10; Interleukin 4; Interleukin-10 - genetics; Interleukin-10 - physiology; Interleukin-4 - physiology; Lipopolysaccharides; Macrophages; Mice; Monocytes; Monocytes - physiology; Monocytes/macrophages; neutralizing antibodies; Protein-serine/threonine kinase; Real-Time Polymerase Chain Reaction; Receptor-Interacting Protein Serine-Threonine Kinase 2 - physiology; RP105; Signal transduction; TLR4 protein; Toll-like receptor signaling; Toll-like receptors; Transcription; transcription (genetics); Transcription factors; Tumor necrosis factor- alpha; Interleukin-4; Toll-like receptor signaling; BMM; M-CSF; Interleukin-10; RIPK2; UBE2D2; Monocytes/macrophages; IRS; MAPK; PBMC; PPARγ; RP105; MFI; SOCS1; GM-CSF; TLR
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2012.03.009

► IL-4 down-regulates mRNA levels of LPS-induced inflammatory cytokines and chemokines. ► IL-4 causes an early up-regulation of IL-10, RIPK2, RP105 and c-Maf mRNA. ► IL-4 suppresses LPS-induced TNFα production independently of IL-4-induced IL-10. ► The anti-inflammatory actions of IL-4 are independent of the kinase activity of RIPK2. ► IL-4 fails to up-regulate cell surface expression of the RP105 receptor in monocytes. 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.