Abstract
Mast cells play important roles in allergic inflammation by secreting various mediators. In the present study, based on the finding that the medium conditioned by activated RBL-2H3 mast cells enhanced the nerve growth factor (NGF)-induced neuritogenesis of PC12 cells, we attempted to isolate an active compound from the mast cell conditioned culture medium. Our experiment identified 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), one of the PGD2 metabolites, as a potential enhancer of neuritogenesis. 15d-PGJ2 strongly enhanced the neuritogenesis elicited by a low-concentration of NGF that alone was insufficient to induce the neuronal differentiation. This 15d-PGJ2 effect was exerted in a Ca2+-dependent manner, but independently of the NGF receptor TrkA. Importantly, 15d-PGJ2 activated the transient receptor potential vanilloid-type 1 (TRPV1), a non-selective cation channel, leading to the Ca2+ influx. In addition, we observed that (i) NGF promoted the insertion of TRPV1 into the cell surface membrane and (ii) 15d-PGJ2 covalently bound to TRPV1. These findings suggest that the NGF/15d-PGJ2-induced neuritogenesis may be regulated by two sets of mechanisms, one for the translocation of TRPV1 into the cell surface by NGF and one for the activation of TRPV1 by 15d-PGJ2. Thus, there is most likely a link between allergic inflammation and activation of the neuronal differentiation.
Highlights
Mast cells are some of the principal effector cells involved in the pathogenesis of allergic diseases and in certain host responses against infection
To find an active molecule providing a link between inflammation and the neuronal response, we examined the effect of the conditioned medium from the activated mast cells on the nerve growth factor (NGF)-induced neuritogenesis
The RBL-2H3 mast cells were stimulated with anti-DNP IgE/DNP-BSA, and the medium of the activated mast cells was examined for the NGF-induced neuritogenesis of rat pheochromocytoma PC12 cells
Summary
Mast cells are some of the principal effector cells involved in the pathogenesis of allergic diseases and in certain host responses against infection. PGD2 exerts its allergic inflammatory effects, including blood flow changes, influx of Th2 lymphocytes and eosinophils, and induction of Th2 cytokine production, through high affinity interactions with the G-protein coupled receptors DP1 and chemoattractant-homologous receptor expressed on T-helper type 2 cells (CRTH2) Both receptors act in concert to facilitate a variety of biological functions involved in the development and maintenance of the allergic response[6,7]. Unlike other classes of prostanoids, the J-series PGs have their own unique spectrum of biological effects, including anti-inflammatory effects[11,12] and an agonistic effect on the peroxisome proliferator-activated receptor γ (PPARγ )[13,14] Neurotrophins, such as the nerve growth factor (NGF), act as important regulators of the neuronal survival, growth, development, and functional maintenance in the central and peripheral nervous systems. We characterized the cellular events and established a possible mechanism, in which the PGD2 metabolite accelerates the NGF-mediated neuritogenesis via activation of a calcium ion channel
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