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Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression
Carlos H. Serezani, … , Sonia Jancar, Marc Peters-Golden
Carlos H. Serezani, … , Sonia Jancar, Marc Peters-Golden
Published January 4, 2011
Citation Information: J Clin Invest. 2011;121(2):671-682. https://doi.org/10.1172/JCI43302.
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Research Article Inflammation

Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression

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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.

Authors

Carlos H. Serezani, Casey Lewis, Sonia Jancar, Marc Peters-Golden

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Figure 8

SOCS1 silencing restores MyD88 expression and responsiveness in 5-LO–/– macrophages.

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SOCS1 silencing restores MyD88 expression and responsiveness in 5-LO–/– ...
(A) WT and 5-LO–/– macrophages were treated for 48 hours in the absence (control) or presence of Socs1 siRNA or scrambled siRNA (control siRNA), and the expression of Socs1 mRNA was determined by real-time RT-PCR and expressed relative to values in untreated WT cells (dashed line). (B) Myd88 mRNA and (C) MyD88 protein expression in WT and 5-LO–/– macrophages treated with Socs1 and control siRNA, as determined by real-time RT-PCR and immunoblotting, respectively; mRNA levels are expressed relative to those in untreated WT cells (dashed line). Immunoblot is representative of 3 independent experiments. (D) WT macrophages were treated for 48 hours in the presence of scrambled control and Socs3 siRNAs, and the expression of Socs3, Myd88, and Socs1 mRNA was determined by real-time RT-PCR and expressed relative to values in control siRNA cells. (E) NO, (F) RANTES, and (G) IL-6 secretion in Socs1-silenced WT and 5-LO–/– macrophages incubated with or without LPS. (H) Proposed model of LTB4/BLT1 regulation of SOCS1 and MyD88 expression and enhancement of MyD88-dependent NF-κB activation. Data are mean ± SEM from 3 individual experiments, each performed in triplicate. *P < 0.05 versus control; #P < 0.05 versus WT or 5-LO–/– control siRNA; &P < 0.05 versus LPS-challenged control siRNA.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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