Molecular mechanism of LPS-induced TNF-α biosynthesis in polarized human macrophages

• Published in: Molecular immunology Vol. 93; pp. 206 - 215
• Main Authors: Schilling, Erik, Weiss, Ronald, Grahnert, Anja, Bitar, Michael, Sack, Ulrich, Hauschildt, Sunna
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2018
• Subjects: Adaptor Proteins, Vesicular Transport - physiology; Cells, Cultured; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Humans; Interferon-beta - pharmacology; Interleukin-10 - pharmacology; Lipopolysaccharides - pharmacology; LPS; Macrophage Activation - drug effects; Macrophage Colony-Stimulating Factor - pharmacology; Macrophage polarization; Macrophages - drug effects; Macrophages - metabolism; mRNA stability; Myeloid Differentiation Factor 88 - physiology; RNA Stability; RNA, Messenger - metabolism; Signal transduction; Signal Transduction - drug effects; TNF-α; Tristetraprolin - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Macrophage polarization; IFNAR; TRAM; ActD; MyD88; TIRAP; LPS; TTP; Signal transduction; IRF3; TNF-α; CSF; MΦ; TRIF; TLR4; mRNA stability
• ISSN: 0161-5890; 1872-9142
• DOI: 10.1016/j.molimm.2017.11.026

•M-MΦ are hallmarked by high TLR4 and CD14 expression and low TNF-α production.•LPS induced activation of signalling pathways differ slightly between GM-MΦ and M-MΦ.•M-MΦ favor the MyD88-dependent non-canonical pathway.•IL-10 but not IFN-β interferes with TNF-α production in M-MΦ.•TNF-α mRNA is markedly destabilized in M-MΦ. In response to environmental stimuli such as granulocyte-macrophage or macrophage colony stimulating factor (GM-CSF/M-CSF), macrophages (MΦ) can acquire distinct functional phenotypes that control inflammatory processes on the one hand and contribute to a broad spectrum of pathologies on the other. Potential intervention strategies will require an understanding of the signalling processes that are associated with macrophage polarization. In the present study, we show that M-MΦ produce more IFN-β and IL-10 and a lot less TNF-α than do GM-MΦ in response to LPS. To define the molecular mechanisms that underlie the biosynthesis of TNF-α we carried out a detailed investigation of the LPS-induced activation of the canonical and non-canonical myeloid differentiation primary response 88 (MyD88)-dependent signal transduction pathways as well as the TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent pathway. Our results show that all three pathways are activated in both cell types and that the activation is more pronounced in M-MΦ. While IL-10 was found to interfere with TNF-α production in M-MΦ, we exclude a decisive role for IFN-β in this respect. Furthermore, we demonstrate that TNF-α mRNA is markedly destabilized in M-MΦ and that expression of the mRNA destabilizing protein tristetraprolin is greatly enhanced in these cells. Collectively, our study suggests that differential effects of LPS on TNF-α mRNA turnover and on signal transduction pathways influence the amount of TNF-α finally produced by GM-MΦ and M-MΦ.