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B Function1
*
Infectious Diseases and Microbiology, Charing Cross Campus, Imperial College, London, United Kingdom;
Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; and
Cytokine Biology and Signal Transduction Laboratory, Kennedy Institute of Rheumatology, London, United Kingdom
Buruli ulcer is a chronic and progressive necrotizing ulcer for
which there is no medical treatment. Historically, a soluble toxin
(factor) derived from the causative Mycobacterium
ulcerans was found to induce the massive necrosis of skin and
s.c. tissue seen in this condition. However, the persistence of the
disease is thought to be caused by a lack of any immune response. We
therefore investigated whether the factor was related to
immunosuppression. A protocol to partially purify the factor was
developed, and its effects on immune competent cells were tested. The
factor produced >95% inhibition of LPS-induced release of TNF and
IL-10 from human monocytes and caused a loss of adherence of these
cells without cell death. The factor also blocked the production of
IL-2 from activated T lymphocytes. The factor had no effect on
TNF-induced cytotoxicity, but abrogated TNF-induced NF-
B activation.
Surprisingly, a synergy was observed between the factor and phorbol
ester-directed NF-B activation. The factor had no effect on IL-1- or
LPS-induced NF-B activity, indicating selective activity of the
factor. The factor did not inhibit the degradation of IB
induced
by TNF, indicating that the target for its activity lies within an
undefined part of the TNF signaling mechanism. The data indicate that
the localized immunosuppression associated with Buruli ulcer relates to
the activity of the released factor, and this may provide a target for
future therapeutic strategies for this intractable
disease.
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