title: Thalidomide modulates Mycobacterium leprae-induced NF-κB pathway and lower cytokine response.
abstract: It is widely accepted that tumor necrosis factor alpha (TNF-α) plays a critical role in the development of tissue and nerve damage in leprosy and during the reactional episodes of acute inflammation. Thalidomide (N-α-phthalimidoglutarimide), a drug used to treat leprosy reaction, modulates immune response, inhibits inflammation and NF-κB activity. Here we investigated whether thalidomide inhibits NF-κB activation induced by Mycobacterium leprae, p38 and ERK1/2 MAPK activation. EMSA and supershift assays were performed to investigate NF-κB 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-κB 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-κB complexes composed mainly of p65/p50 and p50/p50 dimers was observed. Induction of NF-κB activation and DNA binding activity was inhibited by thalidomide. The drug also reduced M. leprae-induced TNF-α 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-κB activation and to control the inflammatory manifestations due to enhanced TNF-α response as observed in leprosy and in leprosy reactions.
authors.affiliation: Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Av. Brasil 4365, Manguinhos, Rio de Janeiro, RJ, Brazil.
authors.forename: Maristela de Oliveira
authors.initials: Mde O
authors.lastname: Hernandez
authors.forename: Tatiana de Oliveira
authors.initials: Tde O
authors.lastname: Fulco
authors.forename: Roberta Olmo
authors.initials: RO
authors.lastname: Pinheiro
authors.forename: Renata de Meirelles Santos
authors.initials: Rde M
authors.lastname: Pereira
authors.forename: Paulo
authors.initials: P
authors.lastname: Redner
authors.forename: Euzenir Nunes
authors.initials: EN
authors.lastname: Sarno
authors.forename: Ulisses Gazos
authors.initials: UG
authors.lastname: Lopes
authors.forename: Elizabeth Pereira
authors.initials: EP
authors.lastname: Sampaio
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007917:Leprostatic Agents / Q000494:pharmacology*; D007918:Leprosy / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009166:Mycobacterium leprae / Q000187:drug effects* / Q000472:pathogenicity*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013792:Thalidomide / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D007917:Leprostatic Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D004247:DNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases