title: Lipid IVa incompletely activates MyD88-independent Toll-like receptor 4 signaling in mouse macrophage cell lines.
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.
authors.affiliation: Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.
authors.forename: Norihiko
authors.initials: N
authors.lastname: Ogura
authors.forename: Masashi
authors.initials: M
authors.lastname: Muroi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sugiura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Tanamoto
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004926:Escherichia coli / Q000276:immunology; D020869:Gene Expression Profiling; D006017:Glycolipids / Q000276:immunology*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012475:Salmonella / Q000276:immunology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D016207:Cytokines; D006017:Glycolipids; D008050:Lipid A; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C040142:lipid A precursors, bacterial