Effects of mammalian target of rapamycin inhibitors on cytokine production and differentiation in keratinocytes
Risk factors for the development of cutaneous squamous cell carcinoma (cSCC) include ultraviolet radiation and immunosuppression. In particular, solid organ transplant recipients show a high incidence of cSCC, depending on the immunosuppressive regimen. While azathioprine or calcineurin inhibitors i...
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| Published in | Experimental dermatology Vol. 25; no. 10; pp. 775 - 782 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Denmark
Blackwell Publishing Ltd
01.10.2016
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0906-6705 1600-0625 |
| DOI | 10.1111/exd.13079 |
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| Abstract | Risk factors for the development of cutaneous squamous cell carcinoma (cSCC) include ultraviolet radiation and immunosuppression. In particular, solid organ transplant recipients show a high incidence of cSCC, depending on the immunosuppressive regimen. While azathioprine or calcineurin inhibitors increase the risk of cSCC development, mammalian target of rapamycin (mTOR) inhibitors decreases this risk. At the moment, the mechanisms behind this protective effect of mTOR inhibitors are not fully understood. We evaluated effects of the mTOR inhibitors sirolimus and everolimus on keratinocytes, cSCC cell lines and an organotypic skin model in vitro in regard to proliferation, cytokine secretion and differentiation. We show that mTOR inhibitors block keratinocyte proliferation and alter cytokine and cytokeratin production: in particular, mTOR inhibition leads to upregulation of interleukin‐6 and downregulation of cytokeratin 10. Therefore, mTOR inhibitors have effects on keratinocytes, which could play a role in the pathogenesis of cSCC. |
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| AbstractList | Risk factors for the development of cutaneous squamous cell carcinoma (cSCC) include ultraviolet radiation and immunosuppression. In particular, solid organ transplant recipients show a high incidence of cSCC, depending on the immunosuppressive regimen. While azathioprine or calcineurin inhibitors increase the risk of cSCC development, mammalian target of rapamycin (mTOR) inhibitors decreases this risk. At the moment, the mechanisms behind this protective effect of mTOR inhibitors are not fully understood. We evaluated effects of the mTOR inhibitors sirolimus and everolimus on keratinocytes, cSCC cell lines and an organotypic skin model in vitro in regard to proliferation, cytokine secretion and differentiation. We show that mTOR inhibitors block keratinocyte proliferation and alter cytokine and cytokeratin production: in particular, mTOR inhibition leads to upregulation of interleukin-6 and downregulation of cytokeratin 10. Therefore, mTOR inhibitors have effects on keratinocytes, which could play a role in the pathogenesis of cSCC. Risk factors for the development of cutaneous squamous cell carcinoma (c SCC ) include ultraviolet radiation and immunosuppression. In particular, solid organ transplant recipients show a high incidence of c SCC , depending on the immunosuppressive regimen. While azathioprine or calcineurin inhibitors increase the risk of c SCC development, mammalian target of rapamycin (m TOR ) inhibitors decreases this risk. At the moment, the mechanisms behind this protective effect of m TOR inhibitors are not fully understood. We evaluated effects of the m TOR inhibitors sirolimus and everolimus on keratinocytes, c SCC cell lines and an organotypic skin model in vitro in regard to proliferation, cytokine secretion and differentiation. We show that m TOR inhibitors block keratinocyte proliferation and alter cytokine and cytokeratin production: in particular, m TOR inhibition leads to upregulation of interleukin‐6 and downregulation of cytokeratin 10. Therefore, m TOR inhibitors have effects on keratinocytes, which could play a role in the pathogenesis of c SCC . |
| Author | DeTemple, Viola Walter, Antje Gutzmer, Ralf Schaper, Katrin Satzger, Imke |
| Author_xml | – sequence: 1 givenname: Viola surname: DeTemple fullname: DeTemple, Viola email: v.detemple@kabelmail.de, v.detemple@kabelmail.de organization: Department for Dermatology, Allergology and Venerology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany – sequence: 2 givenname: Imke surname: Satzger fullname: Satzger, Imke organization: Department for Dermatology, Allergology and Venerology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany – sequence: 3 givenname: Antje surname: Walter fullname: Walter, Antje organization: Department for Dermatology, Allergology and Venerology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany – sequence: 4 givenname: Katrin surname: Schaper fullname: Schaper, Katrin organization: Department for Dermatology, Allergology and Venerology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany – sequence: 5 givenname: Ralf surname: Gutzmer fullname: Gutzmer, Ralf organization: Department for Dermatology, Allergology and Venerology, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27194247$$D View this record in MEDLINE/PubMed |
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| Keywords | mTOR inhibition keratinocytes cytokeratin 10 interleukin-6 |
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| References_xml | – reference: O'Donovan P, Perrett CM, Zhang X, et al. Science. 2005;309:1871-1874. – reference: Dowling RJ, Topisirovic I, Alain T, et al. Science. 2010;328:1172-1176. – reference: Hoogendijk-van den Akker JM, Harden PN, Hoitsma AJ, et al. J Clin Oncol. 2013;31:1317-1323. – reference: Reichelt J, Furstenberger G, Magin TM. J Invest Dermatol. 2004;123:973-981. – reference: Thoms K, Kuschal C, Oetjen E, et al. Exp Dermatol. 2011;20:232-236. – reference: He TY, Tsai LH, Huang CC, et al. Ann Surg Oncol. 2014;21(Suppl 4):S703-S710. – reference: Salgo R, Gossmann J, Schöfer H, et al. Am J Transplant. 2010;10:1385-1393. – reference: Sodhi A, Chaisuparat R, Hu J, et al. Cancer Cell. 2006;10:133-143. – reference: Lederle W, Depner S, Schnur S, et al. Int J Cancer. 2011;128:2803-2814. – reference: Balasoiu M, Turculeanu A, Margaritescu C, et al. Rom J Morphol Embryol. 2008;49:211-214. – reference: Carr TD, DiGiovanni J, Lynch CJ, et al. 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| SubjectTerms | Cell Differentiation Cell Line, Tumor Cell Proliferation - drug effects cytokeratin 10 Cytokines - secretion Humans interleukin-6 keratinocytes Keratinocytes - cytology Keratinocytes - drug effects Keratinocytes - secretion mTOR inhibition TOR Serine-Threonine Kinases - antagonists & inhibitors |
| Title | Effects of mammalian target of rapamycin inhibitors on cytokine production and differentiation in keratinocytes |
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