Abstract
In response to pathogen recognition by Toll-like receptors (TLRs) on their cell surface, macrophages release lipid mediators and cytokines that are widely distributed throughout the body and play essential roles in host responses. Granulocyte macrophage colony-stimulating factor (GM-CSF) is important for the immune response during infections to improve the clearance of microorganisms. In this study, we examined the release of mediators in response to TLR2 ligands by bone marrow-derived macrophages (BMDMs) primed with GM-CSF. We demonstrated that when stimulated with TLR2 ligands, non-primed BMDMs preferentially produced PGE2 in greater amounts than LTB4. However, GM-CSF priming shifted the release of lipid mediators by BMDMs, resulting in a significant decrease of PGE2 production in response to the same stimuli. The decrease of PGE2 production from primed BMDMs was accompanied by a decrease in PGE-synthase mRNA expression and an increase in TNF-α and nitric oxide (NO) production. Moreover, some GM-CSF effects were potentiated by the addition of IFN-γ. Using a variety of TLR2 ligands, we established that PGE2 release by GM-CSF-primed BMDMs was dependent on TLR2 co-receptors (TLR1, TLR6), CD14, MyD88 and the nuclear translocation of NFκB but was not dependent on peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. Indeed, GM-CSF priming enhanced TLR2, TLR4 and MyD88 mRNA expression and phospho-IκBα formation. These findings demonstrate that GM-CSF drives BMDMs to present a profile relevant to the host during infections.
Highlights
The innate immune response is initiated by microbe recognition, phagocytosis and activation of numerous cells; macrophages seem to be at the focal point of this scenario
Considering that lipid-activated nuclear receptors may play an important role in macrophage differentiation and in the inflammatory response, we examined the influence of peroxisome proliferator-activated receptor-c (PPAR-c) inhibition on TNF-a and PGE2 production by Toll-like receptors (TLRs)-stimulated macrophages primed with Granulocyte macrophage colony-stimulating factor (GM-CSF) using a specific Peroxisome proliferator activated receptors (PPARs)-c antagonist (GW9662)
We analyzed the mechanisms governing TLRmediated eicosanoid production by bone marrow-derived macrophages (BMDMs) primed with GMCSF
Summary
The innate immune response is initiated by microbe recognition, phagocytosis and activation of numerous cells; macrophages seem to be at the focal point of this scenario. Through the production of inflammatory mediators macrophages exert a broad variety of functions [1]. Murine macrophages have been used as an important primary cell model for the investigation of the release and function of pro-inflammatory mediators. The activation of TLR2 pathways by bacterial and yeast cell wall components is enhanced by GM-CSF [4]. The increased release of LT results from GM-CSF priming through increase of arachidonic acid (AA) release, enhancement of 5-Lipoxygenase (5-LO) activation [6,7] and rapid augmentation of mRNA translation to increase 5-LO protein levels [8]. Likewise, when alveolar macrophages (AM) are stimulated with GM-CSF, the production of LT is increased [9], validating its role as a primary stimulator of different cell populations
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