Differential activation of dendritic cells by nerve growth factor and brain-derived neurotrophic factor.
BACKGROUND
Neurotrophins are involved in inflammatory reactions influencing several cells in health and disease including allergy and asthma. Dendritic cells (DCs) play a major role in the induction of inflammatory processes with an increasing role in allergic diseases as well.


OBJECTIVE
The aim of this study was to investigate the influence of neurotrophins on DC function.


METHODS
Monocyte-derived dendritic cells were generated from allergic and non-allergic donors. Neurotrophin receptors were demonstrated by western blotting, flow cytometry and fluorescence microscopy. Activation of small GTPases was evaluated by pull-down assays. DCs were incubated with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and supernatants were collected for measurement of IL-4, IL-6, IL-10, IL-12p70, TNF-alpha and TGF-beta.


RESULTS
Receptor proteins were detectable by western blot, fluorescence activated cell sorting analysis and fluorescence microscopy. Signalling after neurotrophin stimulation occurred in a ligand-specific pattern. NGF led to decreased RhoA and increased Rac activation, while BDNF affected RhoA and Rac activity in a reciprocal fashion. Cells of allergics released a significantly increased amount of IL-6, while for healthy subjects a significantly higher amount of IL-10 was found.


CONCLUSIONS
These data indicate that DCs are activated by the neurotrophins NGF and BDNF by different pathways in a receptor-dependant manner. These cells then may initiate inflammatory responses based on allergic sensitization releasing preferred cytokines inducing tolerance or a T-helper type 2 response.
Noga
O
O
Department of Infectious and Respiratory Diseases; Charité, Universitätsmedizin Berlin, Berlin, Germany. oliver.noga@charite.de
Peiser
M
M
Altenähr
M
M
Knieling
H
H
Wanner
R
R
Hanf
G
G
Grosse
R
R
Suttorp
N
N
D015703:Antigens, CD / Q000378:metabolism; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D023201:CD40 Ligand / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000097:blood; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology*; D011070:Poly I-C / Q000494:pharmacology; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D015703:Antigens, CD; D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016753:Interleukin-10; D023201:CD40 Ligand; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D011070:Poly I-C