Neurotrophic tyrosine kinase receptor 1 is a direct transcriptional and epigenetic target of IL-13 involved in allergic inflammation.
Although interleukin (IL)-13 and neurotrophins are functionally important for the pathogenesis of immune responses, the interaction of these pathways has not been explored. Herein, by interrogating IL-13-induced responses in human epithelial cells we show that neurotrophic tyrosine kinase receptor, type 1 (NTRK1), a cognate, high-affinity receptor for nerve growth factor (NGF), is an early transcriptional IL-13 target. Induction of NTRK1 was accompanied by accumulation of activating epigenetic marks in the promoter; transcriptional and epigenetic changes were signal transducer and activator of transcription 6 dependent. Using eosinophilic esophagitis as a model for human allergic inflammation, we found that NTRK1 was increased in inflamed tissue and dynamically expressed as a function of disease activity and that the downstream mediator of NTRK1 signaling early growth response 1 protein was elevated in allergic inflammatory tissue compared with control tissue. Unlike NTRK1, its ligand NGF was constitutively expressed in control and disease states, indicating that IL-13-stimulated NTRK1 induction is a limiting factor in pathway activation. In epithelial cells, NGF and IL-13 synergistically induced several target genes, including chemokine (C-C motif) ligand 26 (eotaxin-3). In summary, we have demonstrated that IL-13 confers epithelial cell responsiveness to NGF by regulating NTRK1 levels by a transcriptional and epigenetic mechanism and that this process likely contributes to allergic inflammation.
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
M
M
Rochman
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
A V
AV
Kartashov
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
J M
JM
Caldwell
Divisions of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
M H
MH
Collins
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
E M
EM
Stucke
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
K
K
Kc
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
J D
JD
Sherrill
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
J
J
Herren
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
A
A
Barski
Divisions of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
M E
ME
Rothenberg
D016000:Cluster Analysis; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D057765:Eosinophilic Esophagitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics* / Q000378:metabolism*; D018793:Interleukin-13 / Q000378:metabolism* / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology; D020917:Receptor, trkA / Q000235:genetics*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D051766:Early Growth Response Protein 1; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA