Basophil priming by neurotrophic factors. Activation through the trk receptor.
There is increasing evidence that nerve growth factor (NGF) acts on cells of the immune system, apart from its neurotrophic effects. In human basophils, NGF potentiates mediator release and primes the cells to produce leukotriene C4 in response to C5a. It is, however, unknown whether other homologous neurotrophins also act outside the nervous system, and whether activation of basophils by NGF requires interaction with trk tyrosine kinase receptors, the low affinity NGF receptor (LNGFR), or both. A triple mutant NGF designed to interrupt binding to the LNGFR was found to activate basophils with equal efficacy as wild-type NGF, demonstrating that the LNGFR is not necessary. Despite a 10 times lower potency of mutant NGF, no LNGFR expression was detected by FACS analysis. Brain-derived neurotrophic factor, which interacts with trkB, was inactive at concentrations up to 1000 ng/ml (> 30,000-fold lower potency than NGF), while neurotrophin-3, which is thought to interact with trkC, trkB, and more weakly with trk, induced a threshold effect at 300 ng/ml (approximately 10,000-fold lower potency), demonstrating that 1) the LNGFR cannot deliver a direct signal; and 2) basophils do not express functional trkB and trkC receptors. In agreement with the functional data, basophils (in contrast to other granulocyte types) expressed mRNA for trk, but not trkB or trkC, and no or minimal mRNA for LNGFR. These data demonstrate that human blood basophils express functional trk receptors that do not require the participation of LNGFR, and that, among the neurotrophin family, NGF is unique in priming basophils.
Bürgi
B
B
Institute of Immunology and Allergology, Inselspital, Bern, Switzerland.
Otten
U H
UH
Ochensberger
B
B
Rihs
S
S
Heese
K
K
Ehrhard
P B
PB
Ibanez
C F
CF
Dahinden
C A
CA
D001491:Basophils / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D015870:Gene Expression; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D015289:Leukotrienes / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D020917:Receptor, trkA; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D015289:Leukotrienes; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020812:Receptor, trkC