03000nas a2200445   4500000000100000008004100001260001300042653001000055653000900065653001400074653002000088653001100108653003100119653001100150653002100161653001200182653000900194653002200203653001600225653001400241653002500255653001900280653001700299653002800316653003600344653003200380653004700412653003100459100001800490700001200508700001400520700001700534700001400551700001600565245012400581300001100705490000800716520181600724022001402540       2003                            d  c2003 May10aAdult10aAged10aApoptosis10aCells, Cultured10aFemale10aGene Expression Regulation10aHumans10aInterferon-gamma10aleprosy10aMale10aMembrane Proteins10aMiddle Aged10aMonocytes10aMycobacterium leprae10aPentoxifylline10aPhagocytosis10aProto-Oncogene Proteins10aProto-Oncogene Proteins c-bcl-210aTumor Necrosis Factor-alpha10aBcl-2 Homologous Antagonist-Killer Protein10aBcl-2-Associated X Protein1 aHernandez M O1 aNeves I1 aSales J S1 aCarvalho D S1 aSarno E N1 aSampaio E P00aInduction of apoptosis in monocytes by Mycobacterium leprae in vitro: a possible role for tumour necrosis factor-alpha.  a156-640 v1093 a<p>A diverse range of infectious organisms, including mycobacteria, have been reported to induce cell death in vivo and in vitro. Although morphological features of apoptosis have been identified in leprosy lesions, it has not yet been determined whether Mycobacterium leprae modulates programmed cell death. For that purpose, peripheral blood mononuclear cells obtained from leprosy patients were stimulated with different concentrations of this pathogen. Following analysis by flow cytometry on 7AAD/CD14+ cells, it was observed that M. leprae induced apoptosis of monocyte-derived macrophages in a dose-dependent manner in both leprosy patients and healthy individuals, but still with lower efficiency as compared to M. tuberculosis. Expression of tumour necrosis factor-alpha (TNF-alpha), Bax-alpha, Bak mRNA and TNF-alpha protein was also detected in these cultures; in addition, an enhancement in the rate of apoptotic cells (and of TNF-alpha release) was noted when interferon-gamma was added to the wells. On the other hand, incubation of the cells with pentoxifylline impaired mycobacterium-induced cell death, the secretion of TNF-alpha, and gene expression in vitro. In addition, diminished bacterial entry decreased both TNF-alpha levels and the death of CD14+ cells, albeit to a different extent. When investigating leprosy reactions, an enhanced rate of spontaneous apoptosis was detected as compared to the unreactive lepromatous patients. The results demonstrated that M. leprae can lead to apoptosis of macrophages through a mechanism that could be at least partially related to the expression of pro-apoptotic members of the Bcl-2 protein family and of TNF-alpha. Moreover, while phagocytosis may be necessary, it seems not to be crucial to the induction of cell death by the mycobacteria.</p>  a0019-2805