Macrophage Derived Platelet Activating Factor Implicated in the Resolution Phase of Gouty Inflammation

Human blood derivedin vitrodifferentiated monocytes or macrophages are a population of cells which have been investigated over the years to determine the role these cells play in the resolution phase of gout. Macrophages are able to phagocytose monosodium urate monohydrate (MSU) crystals without releasing inflammatory factors. This study analysed macrophage platelet activating factor secretion and its possible role in the pathway of gout resolution. Analysis of sunatants fromin vitrodifferentiated macrophages stimulated with MSU crystals revealed the secretion of platelet activating factor (PAF) 1.54±0.10mean ± SEM; ng/mL per 106cells. This secretion was absent in immature monocytes treated similarly. When these monocytes were pretreated with recombinant human PAF-acetylhydrolase (rhuPAF-AH) and MSU crystals resulted in TNFαsuppression. Addition of WEB2086, a platelet activating factor (PAF) antagonist, to differentiated macrophages with MSU crystals unmasked TNFαsecretion0.7±0.06mean ± SEM; ng/mL per 106cells. This study identifies a role for PAF and the PAF receptor antagonist in the pathway by which macrophages ingest MSU crystals and resolve the concomitant inflammation.

THERAPEUTIC EFFICACY OF A POLY-FUNCTIONAL ANTIALLERGIC DRUG - RUPATADINE

Rupatadine is a new poly-functional agent (selective histamine H 1-receptor and PAF-receptor antagonist with additional anti-inflammatory potency) for the management of patients with allergic rhinitis and chronic urticaria. It has a rapid onset of action, and its long-lasting effect permits once-daily dosing. It has been shown that rupatadine is effective, well-tolerated and safe in relieving symptoms in patients with seasonal and perennial/ intermittent and persistent allergic rhinitis and chronic urticaria.

Platelet-Activating Factor Induces Th17 Cell Differentiation

Th17 cells have been implicated in a number of inflammatory and autoimmune diseases. The phospholipid mediator platelet-activating factor (PAF) is found in increased concentrations in inflammatory lesions and has been shown to induce IL-6 production. We investigated whether PAF could affect the development of Th17 cells. Picomolar concentrations of PAF induced IL-23, IL-6, and IL-1βexpression in monocyte-derived Langerhans cells (LCs) and in keratinocytes. Moreover, when LC were pretreated with PAF and then cocultured with anti-CD3- and anti-CD28-activated T cells, the latter developed a Th17 phenotype, with a significant increase in the expression of the transcriptional regulator RORγt and enhanced expression of IL-17, IL-21, and IL-22. PAF-induced Th17 development was prevented by the PAF receptor antagonist WEB2086 and by neutralizing antibodies to IL-23 and IL-6R. This may constitute a previously unknown stimulus for the development and persistence of inflammatory processes that could be amenable to pharmacologic intervention.