title: 17(R)-Resolvin D1 differentially regulates TLR4-mediated responses of primary human macrophages to purified LPS and live E. coli.
abstract: Detection and clearance of bacterial infection require balanced effector and resolution signals to avoid chronic inflammation. Detection of GNB LPS by TLR4 on m induces inflammatory responses, contributing to chronic inflammation and tissue injury. LXs and Rvs are endogenous lipid mediators that enhance resolution of inflammation, and their actions on primary human m responses toward GNB are largely uncharacterized. Here, we report that LXA(4), LXB(4), and RvD1, tested at 0.1-1 μM, inhibited LPS-induced TNF production from primary human m, with ATL and 17(R)-RvD1, demonstrating potent inhibition at 0.1 μM. In addition, 17(R)-RvD1 inhibited LPS-induced primary human m production of IL-7, IL-12p70, GM-CSF, IL-8, CCL2, and MIP-1α without reducing that of IL-6 or IL-10. Remarkably, when stimulated with live Escherichia coli, m treated with 17(R)-RvD1 demonstrated increased TNF production and enhanced internalization and killing of the bacteria. 17(R)-RvD1-enhanced TNF, internalization, and killing were not evident for an lpxM mutant of E. coli expressing hypoacylated LPS with reduced inflammatory activity. Furthermore, 17(R)-RvD1-enhanced, E. coli-induced TNF production was evident in WT but not TLR4-deficient murine m. Thus, Rvs differentially modulate primary human m responses to E. coli in an LPS- and TLR4-dependent manner, such that this Rv could promote resolution of GNB/LPS-driven inflammation by reducing m proinflammatory responses to isolated LPS and increasing m responses important for clearance of infection.
authors.affiliation: Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Palmer
authors.forename: Christy J
authors.initials: CJ
authors.lastname: Mancuso
authors.forename: Jerrold P
authors.initials: JP
authors.lastname: Weiss
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Eva C
authors.initials: EC
authors.lastname: Guinan
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D018836:Inflammation Mediators; C112251:LPXN protein, human; D008070:Lipopolysaccharides; D010750:Phosphoproteins; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; C518399:resolvin D1; D004281:Docosahexaenoic Acids