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Activation of Human Neutrophils by Mycobacterium tuberculosis H37Ra Involves Phospholipase Cγ2, Shc Adapter Protein, and p38 Mitogen-Activated Protein Kinase
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk mikrobiologi. Linköpings universitet, Hälsouniversitetet.
2000 (engelsk)Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 164, nr 2, s. 959-965Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Recent studies have shown that human neutrophils play a significant protective role in mycobacteria infection. When encountered with mycobacteria, neutrophils exhibit the typical early bactericidal responses including phagocytosis and generation of reactive oxygen intermediates (ROI), but the underlying mechanisms are largely unknown. The present study shows that stimulation of neutrophils with an attenuated strain of Mycobacterium tuberculosis H37Ra (Mtb) led to a tyrosine kinase-dependent ROI production in these cells. Stimulation with Mtb induces a rapid and transient tyrosine phosphorylation of several proteins, one of which was identified as phospholipase Cγ2 (PLCγ2). Several tyrosine-phosphorylated proteins were associated with the PLCγ2 precipitates from Mtb-stimulated neutrophils, of which pp46 was characterized as the Shc adapter protein. A role for PLCγ2-Shc association in the generation of ROI is supported by the observations that stimulation with Mtb causes the activation of p38 mitogen-activated protein kinase (MAPK), a downstream target of the Shc/Ras signaling cascade, and that the effect of genistein on ROI production coincided with its ability to inhibit both PLCγ2-Shc association and p38 MAPK activation. Moreover, pretreatment of neutrophils with a PLC inhibitor markedly suppresses the Mtb-stimulated ROI production as well as p38 MAPK activation in these cells. Taken together, these results indicate that stimulation of neutrophils with Mtb triggers the tyrosine phosphorylation of PLCγ2 and its association with Shc, and that such association is critical for the Mtb-stimulated ROI production through activating p38 MAPK.

sted, utgiver, år, opplag, sider
2000. Vol. 164, nr 2, s. 959-965
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-49897OAI: oai:DiVA.org:liu-49897DiVA, id: diva2:270793
Tilgjengelig fra: 2009-10-11 Laget: 2009-10-11 Sist oppdatert: 2017-12-12bibliografisk kontrollert
Inngår i avhandling
1. Interaction Between Mycobacterium tuberculosis and Human Neutrophils
Åpne denne publikasjonen i ny fane eller vindu >>Interaction Between Mycobacterium tuberculosis and Human Neutrophils
2001 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is responsible for more deaths each year than any other single pathogen. Mononuclear phagocytes and T cells are crucially involved in the control and local containment of this infection. Less is known about the contribution of neutrophils to control tuberculosis. As one of the most efficient phagocytic cells of the immune system, neutrophils restrict the initial, local replication of numerous pathogens and thereby delay their systemic spread. Neutrophils immigrate quickly to the site of mycobacterial entry and are found in granulomas after infection with M. tuberculosis. The aims of this study were to investigate how neutrophils control M. tuberculosis in the acute phase of mycobacterial infection and the signaling pathways regulating these processes.

When neutrophils are exposed to mycobacteria, they exhibit the typical early bactericidal responses: phagocytosis, generation of reactive oxygen intermediate (ROI), degranulation and the killing of mycobacteria. While production of ROI and M. tuberculosis killing in neutrophils are calcium dependent events, phagocytosis of M. tuberculosis is a calcium-independent process. Measuring intracellular calcium concentration [(Ca+2)]i, revealed that there is no increase in the level of [(Ca+2)]i in single neutrophils upon ingestion of M. tuberculosis. Investigation of the M. tuberculosis-induced phagocytic pathway showed that stimulation of neutrophils by M. tuberculosis triggers tyrosine phosphorylation of PLCγ2 and its association with sch, an adapter protein, and that such association are critical for the M. tuberculosis-stimulated ROI production through activating p38 MAPK. During phagolysosome biogenesis, phagosomes containing M. tuberculosis fused sequentially with secondary granule and late endosomal vacuoles, while delivery of azurophil granule was inhibited. A complex of Rab5a-GTP and syntaxin-4 controlled this fusion process. We suggested that the retention of this complex on the mycobacterial phagosome might allow mycobacteria to avoid the usual physiological destination of phagocytic maturation. Neutrophils infected by M. tuberculosis underwent rapid apoptosis that was mediated by activation of caspase-3 and the expression of Bax and Bcl-x1, two antagonizing members of Bcl-2 family. The level of ROI production controlled this M. tuberculosis induced apoptotic pathway. Apoptotic neutrophils are removed by macrophages, which leads to an augmented mycobactericidal effect in these cells. The results from this work show that neutrophils play an efficient and important role in the early innate immune response against mycobacterial infection, a process that may influence the subsequent specific immune response at the site of infection.

sted, utgiver, år, opplag, sider
Linköping: Linköpings universitet, 2001. s. 71
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 679
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-28623 (URN)13779 (Lokal ID)91-7219-964-4 (ISBN)13779 (Arkivnummer)13779 (OAI)
Disputas
2001-05-31, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (svensk)
Opponent
Tilgjengelig fra: 2009-10-09 Laget: 2009-10-09 Sist oppdatert: 2012-09-07bibliografisk kontrollert

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