Journal article
Cooperative and redundant signaling of leukotriene B4 and leukotriene D4 in human monocytes
Allergy (Copenhagen), Vol.66(10), pp.1304-1311
2011
DOI: 10.1111/j.1398-9995.2011.02647.x
PMCID: PMC3170431
PMID: 21605126
Abstract
Background: Leukotriene B4 (LTB4) and cysteinyl leukotrienes (cysLTs) are important immune mediators, often found concomitantly at sites of inflammation. Although some of the leukotriene-mediated actions are distinctive (e.g., bronchial constriction for cysLTs), many activities such as leukocyte recruitment to tissues and amplification of inflammatory responses are shared by both classes of leukotrienes.
Objective: We used human monocytes to characterize leukotriene-specific signaling, gene expression signatures, and functions and to identify interactions between LTB4- and cysLTs-induced pathways.
Methods: Responsiveness to leukotrienes was assessed using oligonucleotide microarrays, real-time PCR, calcium mobilization, kinase activation, and chemotaxis assays.
Results: Human monocytes were found to express mRNA for high- and low-affinity LTB4 receptors, BLT1 and BLT2, but signal predominantly through BLT1 in response to LTB4 stimulation as shown using selective agonists, inhibitors, and gene knock down experiments. LTB4 acting through BLT1 coupled to G-protein α inhibitory subunit activated calcium signaling, p44/42 mitogen-activated protein kinase, gene expression, and chemotaxis. Twenty-seven genes, including immediate early genes (IEG), transcription factors, cytokines, and membrane receptors were significantly up-regulated by LTB4. LTB4 and LTD4 had similar effects on signaling, gene expression, and chemotaxis indicating redundant cell activation pathways but costimulation with both lipid mediators was additive for many monocyte functions.
Conclusion: Leukotriene B4 and LTD4 display both redundant and cooperative effects on intracellular signaling, gene expression, and chemotaxis in human monocytes. These findings suggest that therapies targeting either leukotriene alone may be less effective than approaches directed at both.
Details
- Title: Subtitle
- Cooperative and redundant signaling of leukotriene B4 and leukotriene D4 in human monocytes
- Creators
- L. Y CHEN - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesM EBERLEIN - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesY LIU - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesG WOSZCZEK - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesS ALSAATY - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesA MARTINEZ-ANTON - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesJ BARB - Division of Computational Bioscience, Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesP. J MUNSON - Division of Computational Bioscience, Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesR. L DANNER - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesC LOGUN - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United StatesJ. H SHELHAMER - Critical Care Medicine Department, Clinical Center, National Institutes of Health, Center for Information Technology, National Institutes of Health, Bethesda, MD, United States
- Resource Type
- Journal article
- Publication Details
- Allergy (Copenhagen), Vol.66(10), pp.1304-1311
- DOI
- 10.1111/j.1398-9995.2011.02647.x
- PMID
- 21605126
- PMCID
- PMC3170431
- NLM abbreviation
- Allergy
- ISSN
- 0105-4538
- eISSN
- 1398-9995
- Publisher
- Blackwell
- Language
- English
- Date published
- 2011
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
- Record Identifier
- 9984094670202771
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