HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Simmonds, R. E. Articles by Foxwell, B. M. Search for Related Content PubMed PubMed Citation Articles by Simmonds, R. E. Articles by Foxwell, B. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

Mycolactone Inhibits Monocyte Cytokine Production by a Posttranscriptional Mechanism¹

Rachel E. Simmonds^2,3,*, Ferdinand V. Lali^2,, Tim Smallie^*, Pamela L. C. Small and Brian M. Foxwell^4,*

^* Cytokine and Signal Transduction Laboratory, Kennedy Institute of Rheumatology Division, London, United Kingdom; Department of Biochemistry, Makerere University, Kampala, Uganda; and Department of Microbiology, University of Tennessee, Knoxville, TN 37996

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-1β, IL-6, IL-10, and IFN--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-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Arthritis Research Council, Kennedy Institute of Rheumatology Trustees, and Union Bank of Switzerland Optimus Foundation, and also the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the World Health Organization.

² R.E.S. and F.V.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Rachel E. Simmonds, Cytokine and Signal Transduction Laboratory, Kennedy Institute of Rheumatology Division, Arthritis Research Council Building, Charing Cross Campus, Imperial College London, 65 Aspenlea Road, London W6 8LH. E-mail address: r.simmonds{at}imperial.ac.uk

⁴ Deceased.

⁵ Abbreviations used in this paper: BU, Buruli ulcer; ActD, actinomycin D; CHX, cycloheximide; Cox, cyclooxygenase; Ct, cycle threshold; eIF, eukaryotic initiation factor; EtOH, ethanol; FWB, FACS wash buffer; IP-10, IFN--inducible protein-10; Met/Cys, methionine and cysteine; mTORC1, mammalian target of rapamycin complex 1; poly(I:C), polyinosinic-polycytidylic acid; PSI, proteasome inhibitor; qRT-PCR, quantitative RT-PCR.