Abstract
BackgroundPolyketide-derived antibiotics including macrolides are known to exert potent anti-inflammatory and immunomodulatory effects beyond their purely antibacterial action. The mechanisms of their biological activities are still being investigated but the effect on signalling pathways of transcription factors which regulate a number of pro-inflammatory and/or pro-fibrotic genes might be preferentially involved. The aim of our study was to assess the effect of manumycin and structurally related compounds asukamycin and collabomycin on a release of proinflammatory cytokines IL-1beta and IL-18 from THP-1 monocyte/macrophage cell line. Furthermore, the level of mRNA expression of multiple genes associated with immune regulation has been studied.MethodsThe THP-1 cells were cultured in RPMI1640 with 5% fetal calf serum and then stimulated with TNF alpha (20 ng/mL) under serum free conditions in the presence or absence of manumycin and asukamycin (both at 0.3 μg/mL). The concentrations of cytokines in culture supernatants were measured by ELISA (IL-18, MBL) or Luminex (IL-1 beta, R&D). Quantitative RT-PCR (SABiosciences) was used for the evaluation of 84 different gene expressions in TNF alpha and manumycin stimulated cultures.ResultsIL-1 beta was not detectable in culture supernatants of unstimulated THP-1 cells but appeared in response to TNF alpha (4.96 + 0.59 pg/mL). Both manumycin (0.34 + 0.48 pg/mL) and asukamycin (1.06 + 0.81) inhibited IL-1 beta release induced by TNF alpha. IL-18 was found to be constitutively produced (14.68 + 7.83 pg/mL) and the release was doubled by TNF alpha (30.98 + 2.21 pg/mL) and inhibited to basal values by both manumycin (18.04 + 10.21 pg/mL) and asukamycin (12.96 + 2.32 pg/mL). Manumycin inhibited mRNA expression of several genes associated with proinflammatory responses including IL-1 beta, IL-6, and TLR8. Among the genes upregulated in response to manumycin, HMOX1, gene for heme oxigenase 1, showed the highest mRNA induction.ConclusionsWe assume from our study that manumycin and asukamycin represent potent inhibitors of IL-1 beta and IL-18 release from human macrophages. Some of the potentially proinflammatory genes are regulated on the level of transcription.
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