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. We investigated whether NGF 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 distribution of F-actin, which was completely blocked by pretreatment with Clostridium botulinum C(2) toxin, an actin-polymerization inhibitor. Because PMCs constitutively express the NGF high-affinity receptor (TrkA) with a tyrosine kinase domain, we focused on downstream effectors in signaling cascades following the TrkA. NGF rapidly activated both mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), and the addition of inhibitors specific for MAPK kinase and PI3K suppressed cell migration and these signals. In the coculture system with PMCs and fibroblasts, which produce biologically active NGF, directional migration of PMCs to fibroblasts was observed, and the addition of anti-NGF polyclonal antibodies significantly suppressed the migration of PMCs. These findings suggested that NGF initiated 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 inflammatory conditions. (Blood. 2000;95:2052-2058)
Sawada
J
J
Department of Veterinary Clinic, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
Itakura
A
A
Tanaka
A
A
Furusaka
T
T
Matsuda
H
H
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001905:Botulinum Toxins / Q000494:pharmacology; D002352:Carrier Proteins; D002465:Cell Movement; D002630:Chemotactic Factors / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018625:Microscopy, Atomic Force; D020932:Nerve Growth Factor / Q000502:physiology*; D010537:Peritoneum / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
D000199:Actins; D002352:Carrier Proteins; D002630:Chemotactic Factors; D004791:Enzyme Inhibitors; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; D001905:Botulinum Toxins; C096324:botulinum toxin type C