Tumor necrosis factor-alpha stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons.
Expression of the neuropeptide calcitonin gene-related peptide (CGRP) in trigeminal ganglion is implicated in neurovascular headaches and temporomandibular joint disorders. Elevation of cytokines contributes to the pathology of these diseases. However, a connection between cytokines and CGRP gene expression in trigeminal ganglion nerves has not been established. We have focused on the effects of the cytokine tumor necrosis factor-alpha (TNF-alpha). TNFR1 receptors were found on the majority of CGRP-containing rat trigeminal ganglion neurons. Treatment of cultures with TNF-alpha stimulated CGRP secretion. In addition, the intracellular signaling intermediate from the TNFR1 receptor, ceramide, caused a similar increase in CGRP release. TNF-alpha caused a coordinate increase in CGRP promoter activity. TNF-alpha treatment activated the transcription factor NF-kappaB, as well as the Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways. The importance of TNF-alpha induction of MAP kinase pathways was demonstrated by inhibiting MAP kinases with pharmacological reagents and gene transfer with an adenoviral vector encoding MAP kinase phosphatase-1 (MKP-1). We propose that selective and regulated inhibition of MAP kinases in trigeminal neurons may be therapeutically beneficial for inflammatory disorders involving elevated CGRP levels.
Bowen
Elizabeth J
EJ
Department of Biology, Missouri State University, Springfield, Missouri 65897, USA.
Schmidt
Thomas W
TW
Firm
Christina S
CS
Russo
Andrew F
AF
Durham
Paul L
PL
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001485:Basement Membrane / Q000187:drug effects*; D001672:Biocompatible Materials; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007797:Laminin; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D011509:Proteoglycans; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D001672:Biocompatible Materials; D004338:Drug Combinations; D016326:Extracellular Matrix Proteins; D007797:Laminin; D010446:Peptide Fragments; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases