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

Abstract

Background Platelet-activating factor (PAF) is a potent lipid mediator whose involvement in the onset and progression of atherosclerosis is mediated by, among others, the modulation of cytokine expression patterns. The presence of multiple potential protein-tyrosine phosphatase (PTP) 1B substrates in PAF receptor signaling pathways brought us to investigate its involvement in PAF-induced cytokine expression in monocyte-derived dendritic cells (Mo-DCs) and to study the pathways involved in this modulation. Methods We used in-vitro-matured human dendritic cells and the HEK-293 cell line in our studies. PTP1B inhibition was though siRNAs and a selective inhibitor. Cytokine expression was studied with RT-PCR, luciferase assays and ELISA. Phosphorylation status of kinases and transcription factors was studied with western blotting. Results Here, we report that PTP1B was involved in the modulation of cytokine expression in PAF-stimulated Mo-DCs. A study of the down-regulation of PAF-induced IL-8 expression, by PTP1B, showed modulation of PAF-induced transactivation of the IL-8 promoter which was dependent on the presence of the C/EBPß -binding site. Results also suggested that PTP1B decreased PAF-induced IL-8 production by a glycogen synthase kinase (GSK)-3-dependent pathway via activation of the Src family kinases (SFK). These kinases activated an unidentified pathway at early stimulation times and the PI3K/Akt signaling pathway in a later phase. This change in GSK-3 activity decreased the C/EBPß phosphorylation levels of the threonine 235, a residue whose phosphorylation is known to increase C/EBPß transactivation potential, and consequently modified IL-8 expression. Conclusion The negative regulation of GSK-3 activity by PTP1B and the consequent decrease in phosphorylation of the C/EBPß transactivation domain could be an important negative feedback loop by which cells control their cytokine production after PAF stimulation. Electronic supplementary material The online version of this article (10.1186/s12964-019-0334-6) contains supplementary material, which is available to authorized users.

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

“…Further, MAPK-phosphorylated Thr188 may act as a priming site for GSK3β-mediated phosphorylation of Ser184 and Ser179, i.e., phospho-residues favoring dimerization due to conformational changes and enhancing both DNA binding and transactivation activity [40,258]. Decreased C/EBPβ-Thr235 phosphorylation due to GSK3 inactivation was detected in TNF long-term-incubated monocytic cells in the presence of kenpaullone [259] as well as human monocyte-derived DC in response to platelet-activating factor [260]. In contrast, in IL-17-stimulated murine ST2 stromal cells, ERK-mediated priming phosphorylation at Thr188 and subsequent phosphorylation at Ser179 by GSK3 have been described as being repressive for certain C/EBP-dependent genes [261].…”

Bovine Respiratory Syncytial Virus Enhances the Adherence of Pasteurella multocida to Bovine Lower Respiratory Tract Epithelial Cells by Upregulating the Platelet-Activating Factor Receptor

“…Infection of cells by human rhinovirus, HRSV, coronavirus, or influenza A virus is known to increase the PAFR expression level and enhance the adhesion of Staphylococcus aureus , S. pneumoniae , and H. influenzae to lower respiratory epithelial cells ( Avadhanula et al, 2006 ; Hendaus et al, 2015 ). Previous work has shown that PAFR expression is induced by several inflammatory factors, including interleukins-1 and -6 and tumor-necrosis factor alpha, resulting in increases in the levels of both normal cell surface-displayed and PAFR ( Ishizuka et al, 2003 ; Garcia et al, 2010 ; Hamel-Côté et al, 2019 ). These reports suggested that regulation of bacterial adhesion-related cellular receptors is associated with the severity of pneumoniae ( Wang et al, 2009 ; Sacco et al, 2014 ; Hendaus et al, 2015 ).…”

Role of Ginkgolides in the Inflammatory Immune Response of Neurological Diseases: A Review of Current Literatures

“…Kinases and phospholipases whose activation is induced by PAF include MAPK, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), protein tyrosine kinases, G-protein-coupled receptor kinase, and multiple intracellular signal transducers (Ishii and Shimizu, 2000 ). In addition, PAF regulates the expressions of interleukin (IL)-1, IL-6, IL-8, and pleiotropic cytokines (Hamel-Côté et al, 2019a , b ). As an inflammatory factor, PAF plays an important role in many pathological conditions.…”