Regulation of platelet-activating factor-mediated interleukin-6 promoter activation by the 48 kDa but not the 45 kDa isoform of protein tyrosine phosphatase non-receptor type 2

Abstract

Background An underlying state of inflammation is thought to be an important cause of cardiovascular disease. Among cells involved in the early steps of atherosclerosis, monocyte-derived dendritic cells (Mo-DCs) respond to inflammatory stimuli, including platelet-activating factor (PAF), by the induction of various cytokines, such as interleukin 6 (IL-6). PAF is a potent phospholipid mediator involved in both the onset and progression of atherosclerosis. It mediates its effects by binding to its cognate G-protein coupled receptor, PAFR. Activation of PAFR-induced signaling pathways is tightly coordinated to ensure specific cell responses. Results Here, we report that PAF stimulated the phosphatase activity of both the 45 and 48 kDa isoforms of the protein tyrosine phosphatase non-receptor type 2 (PTPN2). However, we found that only the 48 kDa PTPN2 isoform has a role in PAFR-induced signal transduction, leading to activation of the IL-6 promoter. In luciferase reporter assays, expression of the 48 kDa, but not the 45 kDa, PTPN2 isoform increased human IL-6 (hIL-6) promoter activity by 40% after PAF stimulation of HEK-293 cells, stably transfected with PAFR (HEK-PAFR). Our results suggest that the differential localization of the PTPN2 isoforms and the differences in PAF-induced phosphatase activation may contribute to the divergent modulation of PAF-induced IL-6 promoter activation. The involvement of PTPN2 in PAF-induced IL-6 expression was confirmed in immature Mo-DCs (iMo-DCs), using siRNAs targeting the two isoforms of PTPN2, where siRNAs against the 48 kDa PTPN2 significantly inhibited PAF-stimulated IL-6 mRNA expression. Pharmacological inhibition of several signaling pathways suggested a role for PTPN2 in early signaling events. Results obtained by Western blot confirmed that PTPN2 increased the activation of the PI3K/Akt pathway via the modulation of protein kinase D (PKD) activity. WT PKD expression counteracted the effect of PTPN2 on PAF-induced IL-6 promoter transactivation and phosphorylation of Akt. Using siRNAs targeting the individual isoforms of PTPN2, we confirmed that these pathways were also active in iMo-DCs. Conclusion Taken together, our data suggest that PTPN2, in an isoform-specific manner, could be involved in the positive regulation of PI3K/Akt activation, via the modulation of PKD activity, allowing for the maximal induction of PAF-stimulated IL-6 mRNA expression. Electronic supplementary material The online version of this article (10.1186/s13578-019-0316-9) contains supplementary material, which is available to authorized users.

PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review

“…Second, they have different substrate specificity and modulatory mechanisms. Together with their tightly regulated localization, this supports the idea that each isoform has a different cellular function [ 21 ].…”

Role of PI3K in the Progression and Regression of Atherosclerosis

“…Apolipoprotein C3, promotes JAM-1 expression through the PI3K/IKK2/P65 signaling pathway and promotes inflammation during atherosclerosis ( Dai et al, 2019 ). Platelet-activating factor increases the enzymatic activity of phosphatase nonreceptor type 2 and mediates IL-6 mRNA expression through the PI3K/Akt pathways, which are involved in the inflammatory response ( Hamel-Cote et al, 2019 ).…”

PAF-R on activated T cells: Role in the IL-23/Th17 pathway and relevance to multiple sclerosis

“…We postulate that an inflammatory milieu containing PAF in addition to TGF- may skew the T cell development towards Th17 and away from Midgley et al Treg commitment. This argument is strengthened by the fact that PAF itself induces IL-6, a key element in the induction of Th17 cells and suppression of Treg cell development (Hamel-Cote, et al, 2019).…”