Platelet-Activation Factor Receptor Induces Interleukin 10 Production through STAT3 Activation in Dendritic Cells

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 marrowderived 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.

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“…Zymosan recruits CREB to the IL10 promoter via PGE 2 and cyclic AMP, while LPS activates STAT3 via TLR4 receptors and IFNb. Although it has been suggested that PAF contributes to the activation of STAT3 (Koga et al, 2017), experiments did not confirm this mechanism. (F) Effect of Ptafr deletion on Y705-STAT3 phosphorylation in BMDCs stimulated with 1 mg/mL zymosan and 10 mg/mL LPS.…”

“…Notably, patients with low levels of the enzyme PAF acetylhydrolase show an increased risk for lethal anaphylaxis (Vadas et al, 2008). Recently, the list of PAF effects has been enlarged by the report of its involvement in a feedforward autocrine signaling mechanism that enhances the production of IL-10 ( Koga et al, 2013Koga et al, , 2017 and IL-23 (Rodríguez et al, 2016).…”

Platelet activating factor receptor antagonists improve the efficacy of experimental chemo- and radiotherapy

“…The PAF/PAFR axis can also suppress the immune response by inducing tolerogenic dendritic cells 41 and proliferation of myeloid-derived suppressor cells 42 . In these cells, PAFR-mediated suppression involves IL10 and prostaglandin production 43 . PAFR-dependent immunosuppression was suggested to occur via activation of regulatory T cells (Tregs) 44 - 46 .…”

Immune Cells Govern Cancer, Inflammation and Infections

“…Using an in vitro system, Lin and Lin [8] investigated the effects of different natural polysaccharides on the chemokine mediated immune therapy of human breast cancer. Move from cancer to inflammation, Koga et al [9] presented a platelet-activating factor receptor (PAFR) and signal transducer and activator of transcription 3 (STAT3) dependent signal pathway of IL-10 production by dendritic cells (DCs) during LPSstimulation. To understanding DCs better, Lin and Wang [10] briefly reviewed the roles of cytoskeletal actin and its regulators in the function of DCs, especially during the viral infections.…”