Abstract
The activation of the platelet-activating factor receptor (PAFR) is associated to a suppressor phenotype in macrophages and dendritic cells (DCs). In the present study, we investigated mechanisms underlying the production of the interleukin 10 (IL-10) through PAFR activation in murine DCs. For this purpose, BALB/c mice bone marrow-derived DCs were differentiated by GM-CSF treatment and stimulated with LPS in the presence of the PAFR antagonist WEB2086. Signalling pathways downstream to TLR4 activation were investigated. We found that LPS stimulus induced PAFR ligands generation by DCs, but it did not affect the PAFR expression. The LPS-induced IL-10 production was found to be partially dependent of PAFR, since it was reduced in the presence of WEB2086. The IL-10 production through PAFR activation was independent on CREB and PPARγ, as the treatment with selective inhibitors of these pathways did not affect the IL-10 production. TLR4 adaptor molecules (MyD88 and TRIF) expression, MAPK, or NF-κB (p105/50 and p65 subunits) activation pathways were also excluded, since they were not affected by the treatment with WEB2086. The blockage of PAFR by WEB2086 downregulated the STAT3 (Tyr705) phosphorylation induced by LPS. Additionally, DCs treated with STAT3 inhibitor (S3I-201) showed reduced IL-10 production to the same levels observed in DCs treated with WEB2086. The requirement of STAT3 was confirmed in PAFR-KO DCs, since the STAT3 inhibition did not affect IL-10 production by these cells. Our data show an additional molecular mechanism whereby PAFR contributes to IL-10 production in DCs and support the importance of the PAFR activation in DCs phenotype and function.
Highlights
The interleukin 10 (IL-10) is an anti-inflammatory cytokine secreted by different immune cells that acts as an important regulator of the inflammatory and immune responses [1]
In order to explore the generation of platelet-activating factor receptor (PAFR) ligands, firstly we found that the LPS stimulus upregulated the gene expression for the inducible lyso-Platelet-activating factor (PAF) acetyltransferase (Lpcat2), an enzyme involved for PAF biosynthesis (Figure 1C)
Major findings from the present study demonstrate that PAFR activation enhance the IL-10 production induced by LPS stimulation in dendritic cells
Summary
The interleukin 10 (IL-10) is an anti-inflammatory cytokine secreted by different immune cells that acts as an important regulator of the inflammatory and immune responses [1]. In macrophages and myeloid dendritic cells (DCs), the IL-10 production is induced by different stimuli via pattern recognition receptors (PRRs) activation, which triggers an inflammatory response with the production of other cytokines, such as IL-1β, IL-12, IL-6, and so on [2]. We observed that vaccination of mice with dendritic cells (DCs) that had been previously treated with PAFR antagonists and stimulated with lipopolysaccharide (LPS) induced higher antigen-specific T cell proliferation, suggesting that the activation of this receptor in the site of immunization could adjust both innate and adaptive immunity responses [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
