Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance

Marriott, Helen M.; Bingle, Colin D.; Read, Robert C.; Braley, Karen; Kroemer, Guido; Hellewell, Paul G.; Craig, Ruth W.; Whyte, Moira K. B.; Dockrell, David H.

doi:10.1172/jci200521766

Cited by 93 publications

(129 citation statements)

References 55 publications

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“…Accordingly, we show here that Mcl-1L accumulates in NSCLC cells following bortezomib treatment, which is consistent with published reports (27,28). Recently, shorter Mcl-1 splice variants (Mcl-1S) have been identified (42,43). These variants retain the PEST and BH3 domains but lack the COOH-terminal domains, generating proapoptotic BH3-only proteins.…”

Section: Discussionsupporting

confidence: 93%

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Luster¹,

Carrell

McCormick³

et al. 2009

Molecular Cancer Therapeutics

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Mapatumumab and lexatumumab are fully human monoclonal antibodies that bind and activate human tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, respectively. These antibodies induce apoptosis in various tumor cell types, although the degree of sensitivity can vary from highly sensitive to completely resistant. Importantly, tumor cells that are partially or completely resistant to mapatumumab or lexatumumab can often be sensitized when treated in combination with chemotherapeutic drugs. In this regard, the proteasome inhibitor bortezomib has recently shown synergistic activity against established lymphoma cell lines and primary lymphomas when combined with mapatumumab and lexatumumab. Here, we report similar findings using a panel of human non-small cell lung cancer (NSCLC) cell lines. Specifically, we show that bortezomib rapidly induces sensitivity to mapatumumab and lexatumumab in NSCLC cell lines that are completely resistant to antibody alone and that bortezomib concentrations as low as 25 nmol/L sensitize NSCLC cells to the antibodies. Furthermore, bortezomib at the tested concentration has minimal effect on its own, indicating the combination generates synergistic cytotoxicity. Combination treatment induces activation of the caspase cascade and the effect of the combination is caspase dependent. Bortezomib treatment increases the intracellular levels of several important apoptosis regulators that may mediate enhanced sensitivity to mapatumumab and lexatumumab. These results suggest future evaluation of mapatumumab or lexatumumab in combination with bortezomib is warranted in NSCLC patients.

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Section: Discussionsupporting

confidence: 93%

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Luster¹,

Carrell

McCormick³

et al. 2009

Molecular Cancer Therapeutics

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“…Bortezomib has been shown to inactivate mcl-1, 27 a bcl-related protein that is thought to be essential to the regulation of monocyte 28 and DC 29 survival. Conversely, there is no evidence that other bclfamily proteins, such as bcl-2, that may play a more important role in lymphocyte survival, are affected by proteasome inhibition.…”

Section: Discussionmentioning

confidence: 99%

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

Arpinati

Chirumbolo

Nicolini

et al. 2008

Bone Marrow Transplant

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“…In murine models of pulmonary infection alveolar macrophages clear bacteria up to a defined threshold without overt features of pneumonia, but when alveolar macrophages fail to control these subclinical infections recruitment of inflammatory cells, predominantly neutrophils, is required to control infection [30,31]. Using defined inocula of S. pneumoniae, depletion of alveolar macrophages with liposomes containing clodronate or mice with genetic modifications that alter intracellular killing of bacteria (as discussed below), we have demonstrated that mice with decreased numbers of alveolar macrophages, or with alveolar macrophages of reduced microbicidal capacity, are more susceptible to development of pneumonia and that the threshold inoculum required to generate pneumonia is reduced significantly [30,[32][33][34]. The capacity of macrophages to clear bacteria is finite, and even in wildtype mice the inoculum can be increased to a 'tippingpoint' beyond which alveolar macrophages no longer control the bacteria in the airway [30,31].…”

Section: Alveolar Macrophages Role In Host Defence Against Pulmonary mentioning

confidence: 99%

Alveolar macrophages in pulmonary host defence – the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing

Aberdein

Cole

Bewley

et al. 2013

Clinical and Experimental Immunology

112

113

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SummaryAlveolar macrophages play an essential role in clearing bacteria from the lower airway, as the resident phagocyte alveolar macrophages must both phagocytose and kill bacteria, and if unable to do this completely must co-ordinate an inflammatory response. The decision to escalate the inflammatory response represents the transition between subclinical infection and the development of pneumonia. Alveolar macrophages are well equipped to phagocytose bacteria and have a large phagolysosomal capacity in which ingested bacteria are killed. The rate-limiting step in control of extracellular bacteria, such as Streptococcus pneumoniae, is the capacity of alveolar macrophages to kill ingested bacteria. Therefore, alveolar macrophages complement canonical microbicidal strategies with an additional level of apoptosis-associated killing to help kill ingested bacteria.

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Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance

Cited by 93 publications

References 55 publications

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

Alveolar macrophages in pulmonary host defence – the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing

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