Abstract
Atherosclerosis is a pro-inflammatory condition underlying many cardiovascular diseases. Platelet-activating factor (PAF) and interleukin 6 (IL-6) are actively involved in the onset and progression of atherosclerotic plaques. The involvement of monocyte-derived macrophages is well characterized in the installation of inflammatory conditions in the plaque, but less is known about the contribution of monocyte-derived dendritic cells (Mo-DCs). In the same way, the involvement of calcium, phospholipase C and A2 in PAF-induced IL-6 production, in different cells types, has been shown; however, the importance of the Jak/STAT pathway and its regulation by protein-tyrosine phosphatases in this response have not been addressed. In this study, we report that PAF stimulates PTP1B activity via Jak2, thereby modulating PAF-induced IL-6 production. Using HEK 293 cells stably transfected with the PAF receptor in order to discriminate the pathway components, our results suggest that Jak2 modulates PAF-induced IL-6 production via both positive and negative pathways. Jak2 kinase activity was necessary for maximal transactivation of the IL-6 promoter, as seen by luciferase assays, whereas the same kinase also downregulated this promoter transactivation through the activation of a calcium/calpain/PTP1B pathway. The same pathways were operational in monocyte-derived dendritic cells, since PAF-induced PTP1B activation negatively regulated PAF-induced IL-6 mRNA production and, in addition, Jak2 activated calpain, one of the components involved in PAF-induced PTP1B activation. Results obtained in this study indicate that Jak2 activation is important for maximal IL-6 promoter transactivation by PAF and that PTP1B is involved in the negative regulation of this transactivation. However, PTP1B does not directly regulate Jak2 activation, but rather Jak2 regulates PAF-induced PTP1B activation.
Highlights
Platelet-activating factor (PAF) is a potent lipid mediator involved in different physiological processes, ranging from working memory [1], to pain [2] and inflammation [3]
Global representation of PAF-induced protein tyrosine phosphatases (PTPs) activation was studied by in-gel PTP assays. immature Mo-DCs (iMo-DCs) (Fig 1A) or HEK-PAFR (S1 Fig) were stimulated with PAF, for indicated times, and PTP activity was measured as described in Material and Methods
As we were interested in the modulation of the Jak/STAT pathway and PTP1B is a phosphatase associated with Jak2 modulation, we pursued this avenue
Summary
Platelet-activating factor (PAF) is a potent lipid mediator involved in different physiological processes, ranging from working memory [1], to pain [2] and inflammation [3]. Regulation of PAF-mediated PTP1B activation by a Jak2/calpain pathway atherosclerosis [7]. This lipid mediator is involved in both the onset and progression of atherosclerosis, in terms of cell migration, adhesion, in addition to cytokine and chemokine production [5]. It is involved in induction of metalloproteases which are known to destabilize the plaque [8]. Given that immature DCs are among the first cells found in arterial localizations susceptible to plaque development [12], that they respond to PAF, one of the first mediators produced by activated endothelium [5], and that PAF can induce IL-6 production [13], it is important to investigate the molecular mechanisms that regulate IL-6 production by DCs during the early stages of plaque formation
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