Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways

Despite being a well-characterized neurotrophic factor, nerve growth factor (NGF) influences survival, differentiation, and functions of mast cells. W e investigated whether PI3K was able to induce directional migration of rat peritoneal mast cells (PMCs), NGF clearly induced chemotactic movement of PMCs in a dose-dependent manner with the drastic morphological change and d istribution of F-actin, which was completely blocked by pretreatment with C lostridium botulinum Ca toxin, an actin-polymerization inhibitor, Because P MCs constitutively express the NGF high-affinity receptor (TrkA) with a tyr osine kinase domain, we focused on downstream effecters in signaling cascad es following the TrkA, NGF rapidly activated both mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), and the addition o f inhibitors specific for MAPK kinase and PI3K suppressed cell migration an d these signals, In the coculture system with PMCs and fibroblasts, which p roduce biologically active NGF, directional migration of PMCs to fibroblast s was observed, and the addition of anti-NGF polyclonal antibodies signific antly suppressed the migration of PMCs, These findings suggested that NGF i nitiated chemotactic movement of PMCs through both MAPK and PI3K signaling pathways following TrkA activation. Thus, locally produced NGF may play an important role In mast cell accumulation in allergic and nonallergic inflam matory conditions. (C) 2000 by The American Society of Hematology.