Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 670, Issue 1, Pages 272-279Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2011.08.046
Keywords
Thalidomide; NF-kappa B; TNF-alpha; M. leprae; Leprosy
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Funding
- IOC/FIOCRUZ
- CNPq
- CNPq, Brazil
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It is widely accepted that tumor necrosis factor alpha (TNF-alpha) plays a critical role in the development of tissue and nerve damage in leprosy and during the reactional episodes of acute inflammation. Thalidomide (N-alpha-phthalimidoglutarimide), a drug used to treat leprosy reaction, modulates immune response, inhibits inflammation and NF-kappa B activity. Here we investigated whether thalidomide inhibits NF-kappa B activation induced by Mycobacterium leprae, p38 and ERK1/2 MAPK activation. EMSA and supershift assays were performed to investigate NF-kappa B activation in response to M. leprae and its modulation following in vitro treatment with thalidomide. Luciferase assay was assayed in transfected THP-1 cells to determine NF-kappa B transcriptional activity. Flow cytometry and immunofluorescence were used to investigate p65 accumulation in the nucleus. Immunoblotting was used to investigate p38 and ERK1/2 phosphorylation. Following activation of PBMC and monocytes with M. leprae, the formation and nuclear localization of NF-kappa B complexes composed mainly of p65/p50 and p50/p50 dimers was observed. Induction of NF-kappa B activation and DNA binding activity was inhibited by thalidomide. The drug also reduced M. leprae-induced TNF-alpha production and inhibited p38 and ERK1/2 activation. Definition of the activation mechanisms in cells stimulated with M. leprae can lead to the development of new therapy applications to modulate NF-kappa B activation and to control the inflammatory manifestations due to enhanced TNF-alpha response as observed in leprosy and in leprosy reactions. (C) 2011 Elsevier B.V. All rights reserved.
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