Manumycin A downregulates release of proinflammatory cytokines from TNF alpha stimulated human monocytes
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26602157
DOI
10.1016/j.imlet.2015.11.010
PII: S0165-2478(15)30068-7
Knihovny.cz E-resources
- Keywords
- Cytokines, Immunomodulation, Manumycin A, Monocytes, THP-1 cells,
- MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Anti-Inflammatory Agents pharmacology MeSH
- Cell Line MeSH
- Cytokines genetics metabolism MeSH
- Immunomodulation MeSH
- Humans MeSH
- RNA, Messenger genetics MeSH
- Monocytes drug effects immunology MeSH
- Polyenes pharmacology MeSH
- Polyunsaturated Alkamides pharmacology MeSH
- Early Growth Response Protein 1 genetics metabolism MeSH
- Receptors, Interleukin-1 genetics metabolism MeSH
- Gene Expression Regulation drug effects MeSH
- Tumor Necrosis Factor-alpha metabolism MeSH
- Toll-Like Receptor 8 genetics metabolism MeSH
- Inflammation drug therapy immunology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Anti-Bacterial Agents MeSH
- Anti-Inflammatory Agents MeSH
- Cytokines MeSH
- EGR1 protein, human MeSH Browser
- manumycin MeSH Browser
- RNA, Messenger MeSH
- Polyenes MeSH
- Polyunsaturated Alkamides MeSH
- Early Growth Response Protein 1 MeSH
- Receptors, Interleukin-1 MeSH
- Tumor Necrosis Factor-alpha MeSH
- Toll-Like Receptor 8 MeSH
Macrolide antibiotics such as azithromycin or clarithromycin are known to have potent anti-inflammatory and immunomodulatory effects but these properties cannot be widely used due to a risk of bacterial resistance. We studied another polyketide antibiotic, structurally related manumycin A known as a streptomycete derived farnesyltransferase inhibitor with limited antibacterial effects, with respect to its potential regulation of mRNA expression of several genes associated with proinflammatory responses. Downregulation of mRNA for IL-6, TLR-8, IL-1 beta and IL-10 was found in THP-1 cells after 4h stimulation with TNF alpha in the presence of manumycin A and downregulated TLR-8 and EGR-1 genes were observed after 8h. Among the genes upregulated in response to manumycin were HMOX-1, TNFRSF10A, IL-1R1, TICAM2, NLRP12 after 4h and only IL-1R1 after 8h. Furthermore, manumycin A was found to inhibit IL-1beta, IL-6, and IL-8 production in TNF alpha stimulated THP-1 cells and peripheral blood monocytes in a dose dependent manner (0.25-1 μM of manumycin A) without affecting cell viability. Cell viability of blood monocytes decreased by about 30% at manumycin A doses of 2-5 μM. Manumycin A also inhibited IL-18 release from THP-1 cells, while in cultures of blood monocytes, this cytokine was not detectable. That manumycin A mediated downregulation of proinflammatory genes in human monocytes confirmed by a measurement of cytokine levels in culture supernatants, together with a very limited effect on cell viability, might suggest potential anti-inflammatory properties of this polyketide antibiotic.
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