Mycolactone Inhibits Monocyte Cytokine Production by a Posttranscriptional Mechanism

The virulence and immunosuppressive activity of Mycobacterium ulcerans is attributed to mycolactone, a macrolide toxin synthesized by the bacteria. We have explored the consequence and mechanism of mycolactone pretreatment of primary human monocytes activated by a wide range of TLR ligands. The prod...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2009-02, Vol.182 (4), p.2194-2202
Main Authors: Simmonds, Rachel E, Lali, Ferdinand V, Smallie, Tim, Small, Pamela L. C, Foxwell, Brian M
Format: Article
Language:English
Subjects:
Bacterial Toxins - metabolism
Blotting, Western
Buruli Ulcer - immunology
Cytokines - biosynthesis
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Humans
Lipopolysaccharides - immunology
Macrolides
Monocytes - immunology
Protein Biosynthesis - physiology
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction - physiology
Toll-Like Receptors - immunology
Toll-Like Receptors - metabolism
Transcription, Genetic
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Summary:The virulence and immunosuppressive activity of Mycobacterium ulcerans is attributed to mycolactone, a macrolide toxin synthesized by the bacteria. We have explored the consequence and mechanism of mycolactone pretreatment of primary human monocytes activated by a wide range of TLR ligands. The production of cytokines (TNF, IL-1beta, IL-6, IL-10, and IFN-gamma-inducible protein-10), chemokines (IL-8), and intracellular effector molecules (exemplified by cyclooxygenase-2) was found to be powerfully and dose dependently inhibited by mycolactone, irrespective of the stimulating ligand. However, mycolactone had no effect on the activation of signaling pathways that are known to be important in inducing these genes, including the MAPK and NF-kappaB pathways. Unexpectedly, LPS-dependent transcription of TNF, IL-6, and cyclooxygenase-2 mRNA was found not to be inhibited, implying that mycolactone has a novel mechanism of action and must function posttranscriptionally. We propose that mycolactone mediates its effects by inhibiting the translation of a specific subset of proteins in primary human monocytes. This mechanism is distinct from rapamycin, another naturally occurring immunosuppressive lactone. The current findings also suggest that monocyte-derived cytokine transcript and protein levels may not correlate in Buruli ulcer lesions, and urge caution in the interpretation of RT-PCR data obtained from patient biopsy samples.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0802294