Human keratinocytes are vanilloid resistant

Lśzló Pecze, Kornélia Szabó, M. Széll, Katalin Jósvay, Krisztián Kaszás, E. Kúsz, Tamás Letoha, János Prorok, István Koncz, A. Tóth, L. Kemény, C. Vízler, Zoltán Oláh

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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 Ca2+-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 Ca2+-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 Ca2+-cytotoxity ([RTX]>15 μM) could clearly be distinguished, thus keratinocytes were indeed resistant to vanilloid-induced, TRPV1-mediated Ca2+-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.

Original languageEnglish
Article numbere3419
JournalPLoS One
Volume3
Issue number10
DOIs
Publication statusPublished - Oct 14 2008

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keratinocytes
Keratinocytes
Nociceptors
calcium
therapeutics
Messenger RNA
capsaicin
Capsaicin
Cytotoxicity
cytotoxicity
pain
Cells
cells
Sensory Ganglia
Therapeutics
TRPV Cation Channels
Biopsy
analgesics
Pain Management
dosage

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Pecze, L., Szabó, K., Széll, M., Jósvay, K., Kaszás, K., Kúsz, E., ... Oláh, Z. (2008). Human keratinocytes are vanilloid resistant. PLoS One, 3(10), [e3419]. https://doi.org/10.1371/journal.pone.0003419

Human keratinocytes are vanilloid resistant. / Pecze, Lśzló; Szabó, Kornélia; Széll, M.; Jósvay, Katalin; Kaszás, Krisztián; Kúsz, E.; Letoha, Tamás; Prorok, János; Koncz, István; Tóth, A.; Kemény, L.; Vízler, C.; Oláh, Zoltán.

In: PLoS One, Vol. 3, No. 10, e3419, 14.10.2008.

Research output: Contribution to journalArticle

Pecze, L, Szabó, K, Széll, M, Jósvay, K, Kaszás, K, Kúsz, E, Letoha, T, Prorok, J, Koncz, I, Tóth, A, Kemény, L, Vízler, C & Oláh, Z 2008, 'Human keratinocytes are vanilloid resistant', PLoS One, vol. 3, no. 10, e3419. https://doi.org/10.1371/journal.pone.0003419
Pecze L, Szabó K, Széll M, Jósvay K, Kaszás K, Kúsz E et al. Human keratinocytes are vanilloid resistant. PLoS One. 2008 Oct 14;3(10). e3419. https://doi.org/10.1371/journal.pone.0003419
Pecze, Lśzló ; Szabó, Kornélia ; Széll, M. ; Jósvay, Katalin ; Kaszás, Krisztián ; Kúsz, E. ; Letoha, Tamás ; Prorok, János ; Koncz, István ; Tóth, A. ; Kemény, L. ; Vízler, C. ; Oláh, Zoltán. / Human keratinocytes are vanilloid resistant. In: PLoS One. 2008 ; Vol. 3, No. 10.
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