Journal
JOURNAL OF NEUROCHEMISTRY
Volume 96, Issue 1, Pages 65-77Publisher
WILEY
DOI: 10.1111/j.1471-4159.2005.03524.x
Keywords
calcitonin gene-related peptide; cytokine; migraine; mitogen-activated protein kinase; trigeminal; tumor necrosis factor-alpha
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Funding
- NATIONAL INSTITUTE OF DENTAL &CRANIOFACIAL RESEARCH [R01DE015385, R01DE016511] Funding Source: NIH RePORTER
- NHLBI NIH HHS [P01 HL014388, HL14388] Funding Source: Medline
- NIDCR NIH HHS [R01 DE016511, R01 DE015385, DE016511, DE015385] Funding Source: Medline
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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-kappa B, 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.
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