Tumor necrosis factor-α stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons
Article first published online: 8 NOV 2005
Journal of Neurochemistry
Volume 96, Issue 1, pages 65–77, January 2006
How to Cite
Bowen, E. J., Schmidt, T. W., Firm, C. S., Russo, A. F. and Durham, P. L. (2006), Tumor necrosis factor-α stimulation of calcitonin gene-related peptide expression and secretion from rat trigeminal ganglion neurons. Journal of Neurochemistry, 96: 65–77. doi: 10.1111/j.1471-4159.2005.03524.x
- Issue published online: 8 NOV 2005
- Article first published online: 8 NOV 2005
- Received May 21, 2005; revised manuscript received August 22, 2005; accepted August 23, 2005.
- calcitonin gene-related peptide;
- mitogen-activated protein kinase;
- tumor necrosis factor-α
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-α (TNF-α). TNFR1 receptors were found on the majority of CGRP-containing rat trigeminal ganglion neurons. Treatment of cultures with TNF-α stimulated CGRP secretion. In addition, the intracellular signaling intermediate from the TNFR1 receptor, ceramide, caused a similar increase in CGRP release. TNF-α caused a coordinate increase in CGRP promoter activity. TNF-α treatment activated the transcription factor NF-κB, as well as the Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways. The importance of TNF-α 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.