Abstract
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-1β expression 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.
Highlights
A unique subset of interleukin (IL)-17-producing CD4+ T helper (Th17) cells, distinct from the well-known Th1 and Th2 cells, was recently identified
An increased number of Th17 cells has been identified in the dermis and epidermis of psoriatic skin compared with normal skin [16], and these cells are activated based on increased IL-17A, IL-17C, IL-17F, and IL-22 expression
In order to assess the potential for plateletactivating factor (PAF) to modulate Th17 cell development, we initially exposed monocyte-derived Langerhans cells (LC) to graded concentrations of PAF and measured their capacity to express IL-23p19, IL-6, and IL-1β mRNA
Summary
A unique subset of interleukin (IL)-17-producing CD4+ T helper (Th17) cells, distinct from the well-known Th1 and Th2 cells, was recently identified. Th17 cells secrete a range of cytokines, including IL-17A, IL-17F, IL-21, IL-22, TNFα, and IL-6, which have both overlapping and distinct roles in host defense and inflammation [4, 6]. IL-17 appears to play essential roles in host defenses against various pathogens, and in the pathogenesis of chronic inflammatory disorders and in many autoimmune diseases, including multiple sclerosis, inflammatory bowel disease, asthma, and psoriasis [9,10,11,12,13,14,15]. IL-23 was reported to be highly expressed in lesional psoriatic skin and to be produced by keratinocytes, Langerhans cells (LC), dermal dendritic cells and macrophages [18, 19]. Resolution of psoriatic lesions has been achieved with the use of several kinds of immune modulators that block the IL-23/Th17 [20]
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