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TLR4 and NLRP3 inflammasome activation in monocytes by N-propionyl cysteaminylphenol-maleimide-dextran (NPCMD).
- Source :
-
Journal of dermatological science [J Dermatol Sci] 2014 Mar; Vol. 73 (3), pp. 209-15. Date of Electronic Publication: 2013 Nov 14. - Publication Year :
- 2014
-
Abstract
- Background: N-propionyl cysteaminylphenol-maleimide-dextran (NPCMD) is a toxic tyrosinase substrate developed to treat melanoma.<br />Objective: We investigated the effect of NPCMD on innate immune responses in monocytes.<br />Methods: CD14⁺ monocytes and a monocytic cell line, THP-1, were stimulated with NPCMD in vitro. Cytokines in the culture supernatants were determined by ELISA and flow cytometry.<br />Results: NPCMD stimulated CD14⁺ monocytes and THP-1 cells to secrete TNFα, IL-6 and IL-8, but not IL-10 or IL-12. TNFα secretion from THP-1 cells stimulated with NPCMD was inhibited by addition of an anti-TLR4 mAb in culture. Moreover, NPCMD stimulated production of pro-IL-1β in CD14⁺ monocytes and monocytic cell line THP-1 cells and activated the NLRP3-inflammasome, resulting in production of mature IL-1β. Use of ASC and NLRP3-deficient THP-1 cell lines established involvement of the NLRP3 inflammasome in an IL-1β secretion in treatment with NPCMD. Inhibition of IL-1β secretion by an endocytosis inhibitor, cytochalasin B, and a lysosomal enzyme cathepsin B inhibitor, CA-074 Me, suggested the involvement of lysosomal rupture and leakage of cathepsin B into the cytosol in NLRP3 activation by NPCMD.<br />Conclusion: The immunopotentiating effect of NPCMD mediated by TLR4 and NLRP3 inflammasome activation could be useful for eliciting effective adaptive immune responses against melanoma and other tumors.<br /> (Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)
- Subjects :
- Cell Line, Tumor
Cystamine pharmacology
Humans
Interleukin-1beta metabolism
Monocytes drug effects
NLR Family, Pyrin Domain-Containing 3 Protein
Carrier Proteins physiology
Cystamine analogs & derivatives
Dextrans pharmacology
Inflammasomes physiology
Maleimides pharmacology
Monocytes physiology
Phenols pharmacology
Toll-Like Receptor 4 physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-569X
- Volume :
- 73
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of dermatological science
- Publication Type :
- Academic Journal
- Accession number :
- 24315204
- Full Text :
- https://doi.org/10.1016/j.jdermsci.2013.11.006