Regulation of platelet-activating factor-mediated protein tyrosine phosphatase 1B activation by a Janus kinase 2/calpain pathway

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.

Regulation of platelet-activating factor-induced interleukin-8 expression by protein tyrosine phosphatase 1B

“…We had shown that PAF induces the activation of PTP1B via a pathway involving Jak2 and calpain [63]. In this report, we investigated the role of this phosphatase in the signaling pathways of PAF-induced cytokine production, focusing on IL-8 in immature monocyte-derived DCs (iMo-DCs).…”

“…We had established, previously, that the activation and maturation of the cells were not changed by the siRNA transfection and that the use of the PTP1B inhibitor gave the same results as the specific siRNAs [63]. In addition, we had demonstrated that siCTRL did not affect the expression of PTP1B compared to untransfected iMo-DCs, whereas siPTP1B down-regulated PTP1B mRNA and protein expression without affecting the expression of the highly related TC-PTP [63] or cell survival (Additional file 1: Figure S1A). Using real-time PCR, we examined cytokine mRNA expression from PAF-stimulated iMo-DCs transfected with siCTRL (siCTRL-MoDCs) or siPTP1B (siPTP1B-MoDCs).…”

“…The p-NF-κB-luc reporter plasmid was kindly provided by Dr. Patrick McDonald (Université de Sherbrooke) [66]. The WT PTP1B construction and its dominant negative form (D181A) are described elsewhere [63].…”

“…Little is known about PAF-induced Mo-DCs cellular responses, but among possible modulators of the PAF-induced signaling pathways involved in cytokine production, the protein tyrosine phosphatase PTP1B is of interest as it modulates several kinases and some transcription factors mentioned above such as Jak2, Tyk2, Src or the MAP kinase p38 [48, 56–62]. Moreover, we have previously shown that PAF activates PTP1B, which is involved in PAFR signal transduction leading to the production of IL-6, an atherogenic cytokine [63]. Therefore, we investigated the involvement of this PTP in PAF-induced signal transduction and its impact in PAF-induced cytokine expression patterns, focusing on IL-8 expression in Mo-DCs.…”

Body fluid from the parasitic worm Ascaris suum inhibits broad‐acting pro‐inflammatory programs in dendritic cells

“…Interleukin-15Ra is important for the Type 1 response, as IL-15Ra can enhance the anti-tumor properties of natural killer or CD8 + T cells through trans-presentation when bound to IL-15. 53 Similarly, helminth PCF treatment down-regulated expression of PTAFR, encoding the receptor of platelet-activating factor, which can promote Th17 immune responses via IL-6 induction in moDCs, 54 indicating that helminth PCF-treated moDCs might evade further activation by platelet-activating factor.…”