Mast cells differentially express and release active high molecular weight neurotrophins.
Nerve growth factor (NGF), a target-derived factor for survival and maintenance of peripheral and central neurons, has been implicated in inflammatory processes. Mast cells are the principal effector cells in IgE-dependent hypersensitivity reactions, and also play a role in diseases characterised by inflammation, including those of the nervous system like multiple sclerosis. Mast cells are capable of synthesising and responding to NGF, although the occurrence of other members of the NGF family of neurotrophins and their protein forms have not been described. Immunoblot analysis with highly selective neurotrophin antibodies has now been used to show that rat peritoneal mast cells express a higher molecular weight form (73 kDa) of NGF, but not the monomeric (13 kDa) NGF polypeptide. Mast cells also expressed 73 kDa forms of neurotrophin-4 and neurotrophin-3; brain-derived neurotrophic factor was not detected. Medium conditioned by degranulating peritoneal mast cells contained similar high molecular weight forms of NGF and neurotrophin-4 on Western blots, but no neurotrophin-3. Mast cell-derived neurotrophin immunoreactivities were inhibited by the respective peptide antigen, further demonstrating the specificity of the mast cell-derived neurotrophic protein. Mast cell-released proteins supported the survival of cultured chicken embryonic neural crest- and placode-derived sensory neurons; neurotrophic activities were inhibited by neutralising antibodies for NGF and neurotrophin-4, respectively. High molecular isoforms of neurotrophins have been reported to occur in experimental colitis and in the inflamed gut of patients with Crohn's disease and ulcerative colitis, tissue sites rich in mast cells. The data suggest an important role for neurotrophins in the pathophysiology of inflammatory disease.
Skaper
S D
SD
Neurology Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. stephen_skaper-1@gsk.com
Pollock
M
M
Facci
L
L
D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000032:analysis / Q000096:biosynthesis / Q000737:chemistry; D015550:Cell Degranulation; D002470:Cell Survival; D008297:Male; D008407:Mast Cells / Q000737:chemistry / Q000378:metabolism*; D008970:Molecular Weight; D020932:Nerve Growth Factor / Q000032:analysis / Q000737:chemistry; D009414:Nerve Growth Factors / Q000032:analysis / Q000096:biosynthesis* / Q000737:chemistry; D009475:Neurons, Afferent / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D020933:Neurotrophin 3 / Q000032:analysis / Q000096:biosynthesis / Q000737:chemistry; D009620:Nodose Ganglion / Q000166:cytology; D010529:Peritoneal Cavity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000032:analysis / Q000737:chemistry; D012701:Serotonin / Q000378:metabolism; D014316:Tritium
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D011994:Recombinant Proteins; D014316:Tritium; D012701:Serotonin; D020932:Nerve Growth Factor; C073922:neurotrophin 4