Lipid IVa incompletely activates MyD88-independent Toll-like receptor 4 signaling in mouse macrophage cell lines

• Published in: Pathogens and disease Vol. 67; no. 3; pp. 199 - 205
• Main Authors: Ogura, Norihiko, Muroi, Masashi, Sugiura, Yuka, Tanamoto, Ken-ichi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.04.2013; Oxford University Press
• Subjects: Animals; Biotechnology; Cell Line; Cell lines; Cytokines; Cytokines - biosynthesis; E coli; Escherichia coli - immunology; Gene Expression Profiling; Glycolipids - immunology; IL-1β; innate immunity; Interferon regulatory factor 3; Kinases; Lipid A; Lipid A - analogs & derivatives; Lipid A - immunology; Lipids; lipopolysaccharide; Macrophages; Macrophages - drug effects; Mice; Monophosphoryl lipid A; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; NF-κB protein; Phosphorylation; Protein Processing, Post-Translational; RANTES; Salmonella; Salmonella - immunology; Signal Transduction; Signaling; Stimulation; TLR4 protein; Toll-Like Receptor 4 - agonists; Toll-like receptors; TRIF; β-Interferon; innate immunity; lipopolysaccharide; TRIF
• DOI: 10.1111/2049-632X.12031
• ISSN: 2049-632X

Abstract We investigated the difference in the effect of synthetic lipid A compounds on MyD88-dependent and -independent Toll-like receptor 4 (TLR4) signaling in mouse macrophage cells. At higher concentrations, Escherichia coli -type hexa-acylated lipid A 506, Salmonella -type hepta-acylated lipid A 516, the lipid A precursor lipid IVa and monophosphoryl lipid A induced similar levels of production of the MyD88-dependent cytokine IL-1β although their potencies varied, whereas the maximum production of the MyD88-independent cytokine RANTES induced by lipid IVa was less than 50% that of other lipid A compounds. A maximum level of NF-κB activation, which is involved in IL-1β gene transcription, was also induced to a similar level by these four lipid A compounds, while the maximum level of IFN-β promoter activity induced during MyD88-independent signaling was also less than 50% for lipid IVa stimulation compared with other lipid A compounds. Early IκBα phosphorylation activated by MyD88-dependent signaling was similarly induced by 506 and lipid IVa, whereas lipid IVa barely stimulated the phosphorylation of IRF3, a MyD88-independent transcription factor, although efficient phosphorylation was observed with 506 stimulation. These results indicate that lipid IVa has limited activity toward MyD88-independent signaling of TLR4, in macrophage cell lines, despite having efficient activity in the MyD88-dependent pathway. The manuscript contains interesting novel observation that lipid IVa preferentially stimulates MyD88-associated NFkB signaling in mouse macrophage cell-lines. This information will be useful to those who investigate mechanisms of differential signaling adapter usage by the TLR4/MD2 LPS receptor.