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IL-1β Stimulates COX-2 Dependent PGE(2) Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells
OBJECTIVE: Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D recepto...
Autores principales: | , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048859/ https://www.ncbi.nlm.nih.gov/pubmed/21394197 http://dx.doi.org/10.1371/journal.pone.0017360 |
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author | Neeb, Lars Hellen, Peter Boehnke, Carsten Hoffmann, Jan Schuh-Hofer, Sigrid Dirnagl, Ulrich Reuter, Uwe |
author_facet | Neeb, Lars Hellen, Peter Boehnke, Carsten Hoffmann, Jan Schuh-Hofer, Sigrid Dirnagl, Ulrich Reuter, Uwe |
author_sort | Neeb, Lars |
collection | PubMed |
description | OBJECTIVE: Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. METHODS AND RESULTS: 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE(2)) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE(2) and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. CONCLUSION: We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE(2) (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine. |
format | Text |
id | pubmed-3048859 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-30488592011-03-10 IL-1β Stimulates COX-2 Dependent PGE(2) Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells Neeb, Lars Hellen, Peter Boehnke, Carsten Hoffmann, Jan Schuh-Hofer, Sigrid Dirnagl, Ulrich Reuter, Uwe PLoS One Research Article OBJECTIVE: Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. METHODS AND RESULTS: 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE(2)) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE(2) and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. CONCLUSION: We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE(2) (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the mechanism of action of COX-2 inhibitors in migraine. Public Library of Science 2011-03-04 /pmc/articles/PMC3048859/ /pubmed/21394197 http://dx.doi.org/10.1371/journal.pone.0017360 Text en Neeb et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Neeb, Lars Hellen, Peter Boehnke, Carsten Hoffmann, Jan Schuh-Hofer, Sigrid Dirnagl, Ulrich Reuter, Uwe IL-1β Stimulates COX-2 Dependent PGE(2) Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells |
title | IL-1β Stimulates COX-2 Dependent PGE(2) Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells |
title_full | IL-1β Stimulates COX-2 Dependent PGE(2) Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells |
title_fullStr | IL-1β Stimulates COX-2 Dependent PGE(2) Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells |
title_full_unstemmed | IL-1β Stimulates COX-2 Dependent PGE(2) Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells |
title_short | IL-1β Stimulates COX-2 Dependent PGE(2) Synthesis and CGRP Release in Rat Trigeminal Ganglia Cells |
title_sort | il-1β stimulates cox-2 dependent pge(2) synthesis and cgrp release in rat trigeminal ganglia cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048859/ https://www.ncbi.nlm.nih.gov/pubmed/21394197 http://dx.doi.org/10.1371/journal.pone.0017360 |
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