Transforming growth factor-beta induces nerve growth factor expression in pancreatic stellate cells by activation of the ALK-5 pathway.
Nerve growth factor (NGF), a survival factor for neurons enforces pain by sensitizing nociceptors. Also in the pancreas, NGF was associated with pain and it can stimulate the proliferation of pancreatic cancer cells. Hepatic stellate cells (HSC) respond to NGF with apoptosis. Transforming growth factor (TGF)-beta, one of the strongest pro-fibrogenic activators of pancreatic stellate cells (PSC) induced NGF and its two receptors in an immortalized human cell line (ihPSC) and primary rat PSC (prPSC) as determined by RT-PCR, western blot, and immunofluorescence. In contrast to HSC, PSC expressed both NGF receptors, although p75(NTR) expression was weak in prPSC. In contrast to ihPSC TGF-beta activated both Smad signaling cascades in prPSC. NGF secretion was diminished by the activin-like kinase (ALK)-5 inhibitor SB431542, indicating the predominant role of ALK5 in activating the NGF system in PSC. While NGF did not affect proliferation or survival of PSC it induced expression of Inhibitor of Differentiation-1. We conclude that under conditions of upregulated TGF-beta, like fibrosis, NGF levels will also increase in PSC which might contribute to pancreatic wound healing responses.
Haas
Stephan L
SL
Department of Medicine II, Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Fitzner
Brit
B
Jaster
Robert
R
Wiercinska
Eliza
E
Gaitantzi
Haristi
H
Jesnowski
Ralf
R
Jesenowski
Ralf
R
Löhr
J-Matthias
JM
Singer
Manfred V
MV
Dooley
Steven
S
Breitkopf
Katja
K
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020932:Nerve Growth Factor / Q000187:drug effects / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D051798:Inhibitor of Differentiation Protein 1; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D020932:Nerve Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat