title: Manumycin A downregulates release of proinflammatory cytokines from TNF alpha stimulated human monocytes.
abstract: 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.
authors.affiliation: Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Cecrdlova
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Petrickova
authors.affiliation: Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Kolesar
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Petricek
authors.affiliation: Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Sekerkova
authors.affiliation: Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Svachova
authors.affiliation: Department of Clinical and Transplant Immunology, Institute for Clinical and Experimental Medicine, Videnska 1958, 14021 Prague, Czech Republic. Electronic address: ilja.striz@ikem.cz.
authors.forename: Ilja
authors.initials: I
authors.lastname: Striz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D011090:Polyenes / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D011090:Polyenes; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; C054474:manumycin
keywords: Cytokines; Immunomodulation; Manumycin A; Monocytes; THP-1 cells