Abstract
Platelet-activating factor (PAF) is a potent inflammatory phospholipid mediator that is known to play a role in early-phase responses in asthma and other diseases. Through its high affinity receptor, PAFR, PAF is known to activate multiple signalling pathways contributing to its proinflammatory effects. Of these pathways, the mitogen-activated protein kinase (MAPK) cascade is initiated upon PAF stimulation, leading to the activation of the conventional MAPKs ERK1/2, p38 and JNK. Since dual-specificity phosphatases (DUSP) downregulated MAPK activity, we postulated that PAF could also enhance DUSP expression and thus induced an autoregulatory loop. In this report, we studied the effect of PAF on DUSP mRNA expression in human monocytes. Our results demonstrate that PAF induces DUSP1 and DUSP5 gene expression in a time- and concentration-dependent manner, with maximal effects at PAF 100 nM and at 20 - 30 min of stimulation. In contrast, DUSP2 and DUSP6 gene expression was not enhanced by PAF. Moreover, leukotriene D4, another lipid mediator of inflammation, was unable to modulate DUSP expression. PAF-induced DUSP expression was prevented by the PAFR antagonist WEB2170 and by pretreatment with the transcriptional inhibitor Actinomycin D. Moreover, enhanced DUSP5, but not DUSP1 expression was prevented by pretreatment with the ERK inhibitor PD98059 or the PI3K inhibitor Wortmannin. Taken together, our results indicate that PAF selectively enhances DUSP1 and DUSP5 gene expressions through PAFR activation, and suggest that PAF may have an active role in the resolution of inflammation by its ability to upregulate the two DUSPs and thus provide a negative auto-regulatory signalling mechanism.
Highlights
Platelet activating factor (PAF)1 is a potent phospholipid mediator that has a role in an array of inflammatory diseases [1]
Unstimulated human monocytes mainly expressed DUSP1 and DUSP5 as compared to DUSP2 and DUSP6 (Figure 1). Both DUSP1 and DUSP5 have been implicated in inflammation [12] [15] and DUSP1 expression was shown to be upregulated in airway smooth muscle cells and in monocytes/macrophages in response to inflammatory stimuli [19] [20]
We proceeded to study the potential effect of PAF on DUSP1 and DUSP5 gene expression
Summary
Platelet activating factor (PAF) is a potent phospholipid mediator that has a role in an array of inflammatory diseases [1]. It is secreted by a wide variety of cells including leukocytes and endothelial cells [2]. PAF-induced effects are mediated through activation of its high-affinity, widely expressed receptor, PAFR, a G-protein-coupled receptor. PAF is known to induce the activation of multiple signalling pathways leading to expression of a number of cytokines and chemokines, contributing to the proinflammatory effects of the lipid. The mitogen-activated protein kinase (MAPK) cascade is initiated early upon PAF stimulation [3]-[5] leading to the activation of the conventional MAPKs ERK1/2, p38 and JNK [6]-[8]. ERK1 and ERK2 are mainly implicated in the proliferation and differentiation processes, whereas p38 is associated with pro-inflammatory cytokine production and JNK, with regulation of extracellular matrix [9]
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