Abstract
Activation of NF-κB and 5-lipoxygenase-mediated (5-LO-mediated) biosynthesis of the lipid mediator leukotriene B4 (LTB4) are pivotal components of host defense and inflammatory responses. However, the role of LTB4 in mediating innate immune responses elicited by specific TLR ligands and cytokines is unknown. Here we have shown that responses dependent on MyD88 (an adaptor protein that mediates signaling through all of the known TLRs, except TLR3, as well as IL-1β and IL-18) are reduced in mice lacking either 5-LO or the LTB4 receptor BTL1, and that macrophages from these mice are impaired in MyD88-dependent activation of NF-κB. This macrophage defect was associated with lower basal and inducible expression of MyD88 and reflected impaired activation of STAT1 and overexpression of the STAT1 inhibitor SOCS1. Expression of MyD88 and responsiveness to the TLR4 ligand LPS were decreased by Stat1 siRNA silencing in WT macrophages and restored by Socs1 siRNA in 5-LO-deficient macrophages. These results uncover a pivotal role in macrophages for the GPCR BLT1 in regulating activation of NF-κB through Stat1-dependent expression of MyD88.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Arachidonate 5-Lipoxygenase / immunology
-
Chemokine CCL5 / immunology
-
Female
-
Gene Silencing
-
Immunity, Innate / immunology
-
Interleukin-6 / immunology
-
Janus Kinase 2 / metabolism
-
Leukotriene B4 / immunology*
-
Lipopolysaccharides / immunology
-
Macrophages / cytology
-
Macrophages / immunology*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Myeloid Differentiation Factor 88 / genetics
-
Myeloid Differentiation Factor 88 / immunology*
-
NF-kappa B / immunology*
-
RNA Interference
-
STAT1 Transcription Factor / genetics
-
STAT1 Transcription Factor / immunology
-
Signal Transduction / immunology
-
Suppressor of Cytokine Signaling 1 Protein
-
Suppressor of Cytokine Signaling Proteins / genetics
-
Suppressor of Cytokine Signaling Proteins / immunology*
Substances
-
Chemokine CCL5
-
Interleukin-6
-
Lipopolysaccharides
-
Myeloid Differentiation Factor 88
-
NF-kappa B
-
STAT1 Transcription Factor
-
Socs1 protein, mouse
-
Stat1 protein, mouse
-
Suppressor of Cytokine Signaling 1 Protein
-
Suppressor of Cytokine Signaling Proteins
-
Leukotriene B4
-
Arachidonate 5-Lipoxygenase
-
Jak2 protein, mouse
-
Janus Kinase 2