Human keratinocytes are vanilloid resistant.
BACKGROUND: Use of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca(2+)-cytotoxicity. Paradoxically, not only nociceptor...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2008-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2566593?pdf=render |
| _version_ | 1818292852728266752 |
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| author | László Pecze Kornélia Szabó Márta Széll Katalin Jósvay Krisztián Kaszás Erzsébet Kúsz Tamás Letoha János Prorok István Koncz András Tóth Lajos Kemény Csaba Vizler Zoltán Oláh |
| author_facet | László Pecze Kornélia Szabó Márta Széll Katalin Jósvay Krisztián Kaszás Erzsébet Kúsz Tamás Letoha János Prorok István Koncz András Tóth Lajos Kemény Csaba Vizler Zoltán Oláh |
| author_sort | László Pecze |
| collection | DOAJ |
| description | BACKGROUND: Use of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca(2+)-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular surgery have shown neither obvious behavioral, nor pathological side effects. METHODS: To address this paradox, we assessed the vanilloid sensitivity of the HaCaT human keratinocyte cell line and primary keratinocytes from skin biopsies. RESULTS: Although both cell types express TRPV1 mRNA, neither responded to vanilloids with Ca(2+)-cytotoxicity. Only ectopic overproduction of TRPV1 rendered HaCaT cells sensitive to low doses (1-50 nM) of vanilloids. The TRPV1-mediated and non-receptor specific Ca(2+)-cytotoxicity ([RTX]>15 microM) could clearly be distinguished, thus keratinocytes were indeed resistant to vanilloid-induced, TRPV1-mediated Ca(2+)-entry. Having a wider therapeutic window than capsaicin, RTX was effective in subnanomolar range, but even micromolar concentrations could not kill human keratinocytes. Keratinocytes showed orders of magnitudes lower TRPV1 mRNA level than sensory ganglions, the bona fide therapeutic targets in human pain management. In addition to TRPV1, TRPV1b, a dominant negative splice variant was also noted in keratinocytes. CONCLUSION: TRPV1B expression, together with low TRPV1 expression, may explain the vanilloid paradox: even genuinely TRPV1 mRNA positive cells can be spared with therapeutic (up to micromolar) doses of RTX. This additional safety information might be useful for planning future human clinical trials. |
| first_indexed | 2024-12-13T03:06:33Z |
| format | Article |
| id | doaj.art-52e58fa1720d48e69b6144ce633c6a70 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T03:06:33Z |
| publishDate | 2008-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-52e58fa1720d48e69b6144ce633c6a702022-12-22T00:01:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-01-01310e341910.1371/journal.pone.0003419Human keratinocytes are vanilloid resistant.László PeczeKornélia SzabóMárta SzéllKatalin JósvayKrisztián KaszásErzsébet KúszTamás LetohaJános ProrokIstván KonczAndrás TóthLajos KeményCsaba VizlerZoltán OláhBACKGROUND: Use of capsaicin or resiniferatoxin (RTX) as analgesics is an attractive therapeutic option. RTX opens the cation channel inflammatory pain/vanilloid receptor type 1 (TRPV1) permanently and selectively removes nociceptive neurons by Ca(2+)-cytotoxicity. Paradoxically, not only nociceptors, but non-neuronal cells, including keratinocytes express full length TRPV1 mRNA, while patient dogs and experimental animals that underwent topical treatment or anatomically targeted molecular surgery have shown neither obvious behavioral, nor pathological side effects. METHODS: To address this paradox, we assessed the vanilloid sensitivity of the HaCaT human keratinocyte cell line and primary keratinocytes from skin biopsies. RESULTS: Although both cell types express TRPV1 mRNA, neither responded to vanilloids with Ca(2+)-cytotoxicity. Only ectopic overproduction of TRPV1 rendered HaCaT cells sensitive to low doses (1-50 nM) of vanilloids. The TRPV1-mediated and non-receptor specific Ca(2+)-cytotoxicity ([RTX]>15 microM) could clearly be distinguished, thus keratinocytes were indeed resistant to vanilloid-induced, TRPV1-mediated Ca(2+)-entry. Having a wider therapeutic window than capsaicin, RTX was effective in subnanomolar range, but even micromolar concentrations could not kill human keratinocytes. Keratinocytes showed orders of magnitudes lower TRPV1 mRNA level than sensory ganglions, the bona fide therapeutic targets in human pain management. In addition to TRPV1, TRPV1b, a dominant negative splice variant was also noted in keratinocytes. CONCLUSION: TRPV1B expression, together with low TRPV1 expression, may explain the vanilloid paradox: even genuinely TRPV1 mRNA positive cells can be spared with therapeutic (up to micromolar) doses of RTX. This additional safety information might be useful for planning future human clinical trials.http://europepmc.org/articles/PMC2566593?pdf=render |
| spellingShingle | László Pecze Kornélia Szabó Márta Széll Katalin Jósvay Krisztián Kaszás Erzsébet Kúsz Tamás Letoha János Prorok István Koncz András Tóth Lajos Kemény Csaba Vizler Zoltán Oláh Human keratinocytes are vanilloid resistant. PLoS ONE |
| title | Human keratinocytes are vanilloid resistant. |
| title_full | Human keratinocytes are vanilloid resistant. |
| title_fullStr | Human keratinocytes are vanilloid resistant. |
| title_full_unstemmed | Human keratinocytes are vanilloid resistant. |
| title_short | Human keratinocytes are vanilloid resistant. |
| title_sort | human keratinocytes are vanilloid resistant |
| url | http://europepmc.org/articles/PMC2566593?pdf=render |
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