Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: A general mechanism to accumulate effector cells in inflammation

Dibbert, Birgit; Weber, Martina; Nikolaizik, Wilfried H.; Vogt, Peter R.; Schöni, Martin H.; Blaser, Kurt; Simon, Hans‐Uwe

doi:10.1073/pnas.96.23.13330

Cited by 262 publications

(288 citation statements)

References 38 publications

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“…under inflammatory conditions is associated with a reduced Bax expression. 45 Under steady state conditions the activity of Bax is antagonized by anti-apoptotic Bcl-2 proteins such as BCL-xL. 20 In this study, we clearly show that endogenous IFN-b drives the expression of Bax and BCL-xL in tumor infiltrating neutrophils towards a proapoptotic ratio, thus resulting in a shorter life span of such cells.…”

Section: Discussionmentioning

confidence: 61%

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Andzinski

Lienenklaus

et al. 2014

Intl Journal of Cancer

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The importance of neutrophils in tumor immune surveillance, invasive growth and angiogenesis becomes increasingly clear. Many of neutrophil activities are controlled by endogenous IFN-b. Here, we provide evidence that endogenous IFN-b is regulating the apoptosis of pro-angiogenic tumor infiltrating neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Accordingly, the life span of tumor associated neutrophils (TANs) is remarkably prolonged in tumor bearing Ifnb1 2/2 mice compared to wild type controls. Lower expression of Fas, reactive oxygen species, active Caspase 3 and 9, as well as a change in expression pattern of proapoptotic and antiapoptotic members of the Bcl-2 family and the major apoptosome constituent Apaf-1 is observed under such conditions. In line with inhibition of apoptosis and the prolonged neutrophil survival, in the absence of endogenous IFN-b, a strong enhancement of G-CSF expression and PI3 Kinase phosphorylation is detected. These data explain the increased longevity of tumor infiltrating neutrophils and the accumulation of such cells in tumors. Taken together, our findings add to the important role of Type I IFN in immune surveillance against cancer.Neutrophilic granulocytes are the most abundant white blood cells in circulation, that are released from the bone marrow as terminally differentiated, nondividing cells. 1 Besides their role in immunity, neutrophils strongly influence growth, metastasis, 2 angiogenesis 3,4 and immune surveillance 5 of tumors. In contrast to cells of the adaptive immune system, neutrophils need no activation to acquire an effector phenotype. In accordance with their pleiotropic function, neutrophils are equipped with a large array of effector molecules like proteolytic enzymes, antimicrobial proteins/peptides and are able to produce reactive oxygen species. 6 Due to their potential toxicity against host tissue, the life span of such cells is strictly regulated. 7 In the absence of noxious or inflammatory stimuli, neutrophils are removed from circulation by apoptosis shortly after their emigration from the bone marrow. However, several proinflammatory cytokines have been shown to influence the longevity of neutrophils. 8 Type I interferons (IFNs) were first identified as factors responsible for the phenomenon of viral interference. In the meantime, they are recognized to influence a broad variety of biological processes, such as maintenance of cellular homeostasis, 9 hematopoiesis, 10 lymphocyte development 11 and apoptosis of dendritic 12 or CD4 1 T cells 13 besides their role in infections. In addition, Type I IFNs display strong antitumor effects by exhibiting direct antiproliferative and proapoptotic effects on tumor cells 14 as well as supporting systemic immunity against tumor targets by up-regulation of MHC class I expression, enhancement of cytotoxic T cell responses and activation of natural killer cells and macrophages. 15 Nevertheless, the mechanism of how Type I IFNs contribute to immune surveillance against tumo...

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Section: Discussionmentioning

confidence: 61%

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Andzinski

Lienenklaus

et al. 2014

Intl Journal of Cancer

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“…Both Il-5 and GM-CSF have been detected in bronchoalveolar lavage (BAL) fluids from allergic individuals [29], and in vitro-culture of eosinophils in the presence of these cytokines up-regulated of the anti-apopoptotic family member Bcl-xL, thus contributing to the delayed apoptosis [30]. On the other hand, a GM-CSF-induced delay of neutrophil apoptosis was associated with reduced levels of Bax, a pro-apoptotic member of the Bcl-2 family [31].…”

Section: Discussionmentioning

confidence: 99%

Caspase activation in the absence of mitochondrial changes in granulocyte apoptosis

Nopp¹,

Lundahl²,

Stridh

2002

Clinical and Experimental Immunology

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SUMMARY Eosinophils and neutrophils are two different types of granulocytes evolved from a common haematopoetic precursor in the bone marrow. Eosinophils are mainly involved in parasitic infection and allergic inflammation while neutrophils mainly participate in the defence against bacterial infections. Prolongation of granulocyte life span by inhibition of apoptosis may lead to tissue load of cells, and this has been detected in different inflammatory reactions. The molecular mechanisms and the potential role of the mitochondria in granulocyte apoptosis are poorly understood. In the present study we have characterized further the role of the mitochondria in granulocyte-apoptosis by studying the sequence of mitochondrial permeability transition (MPT) induction, loss of mitochondrial membrane potential (Δψm) and release of cytochrome c. This was made possible by applying tributyltin (TBT), a well-characterized apoptotic stimulus and MPT-inducer. We also studied potential differences in apoptosis-susceptibility between eosinophils and neutrophils. Ten minutes of TBT-exposure resulted in a substantial caspase-3 activity in both eosinophils and neutrophils, followed by phosphatidylserine (PS)-exposure after 30–120 min. Interestingly, caspase-3 activity was not preceded by MPT-induction, loss of Δψm or by cytochrome c-release in either eosinophils or neutrophils. In conclusion, we have demonstrated an extremely rapid induction of caspase-3 activity and apoptosis in human blood granulocytes without prior mitochondrial changes, including loss of mitochondrial membrane potential and release of cytochrome c. Our results open the possibility for a mitochondrial-independent activation of caspase 3 and subsequent apoptosis in granulocytes.

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“…The 3 0 -oligonucleotides were biotinylated to facilitate the monitoring of intracellular uptake. The sequences employed were as follows: AS 1: 5 0 -TGCTC-CCGGACCCGTCCAT-3 0 (Gillardon et al, 1996); scrambled 1: 5 0 -TCATCGCTGGTAGAACACCT-3 0 ; AS 2: 5 0 -TCGATCCTGGAT-GAAACCCT-3 0 (Dibbert et al, 1999); scrambled 2: 5 0 -TGGTCCC-GCTCCCGCCACAT-3 0 .…”

Section: Cell Transfection and Bax Antisense (As) Treatmentmentioning

confidence: 99%

“…Two Bax AS oligonucleotide sequences, previously reported to suppress Bax expression (Gillardon et al, 1996;Dibbert et al, 1999), were used. Since no significant difference was found between the two sequences with regard to the suppression of either Bax protein level or apoptosis, the results were pooled, and in later experiments only AS 1 was used.…”

Section: Suppression Of Bax Expression With Bax As Oligonucleotides Smentioning

confidence: 99%

Bax is essential for mitochondrion-mediated apoptosis but not for cell death caused by photodynamic therapy

et al. 2003

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The role of Bax in the release of cytochrome c from mitochondria and the induction of apoptosis has been demonstrated in many systems. Using immunocytochemical staining, we observed that photodynamic therapy (PDT) with the photosensitiser Pc 4 induced Bax translocation from the cytosol to mitochondria, and the release of cytochrome c from mitochondria as early signalling for the intrinsic pathway of apoptosis in human breast cancer MCF-7c3 cells. To test the role of Bax in apoptosis, MCF-7c3 cells were treated with Bax antisense oligonucleotides, which resulted in as much as a 50% inhibition of PDT-induced apoptosis. In the second approach, Bax-negative human prostate cancer DU-145 cells were studied. Following PDT, the hallmarks of apoptosis, including the release of cytochrome c from mitochondria, loss of mitochondrial membrane potential, caspase activation, and chromatin condensation and fragmentation, were completely blocked in these cells. Restoration of Bax expression in DU-145 cells restored apoptosis, indicating that the resistance of DU-145 cells to PDT-induced apoptosis is due to the lack of Bax rather than to another defect in the apoptotic machinery. However, despite the inhibition of apoptosis, the Bax-negative DU-145 cells were as photosensitive as Bax-replete MCF7c3 cells, as determined by clonogenic assay. Thus, for Pc 4-PDT, the commitment to cell death occurs prior to Bax activation.

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Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: A general mechanism to accumulate effector cells in inflammation

Cited by 262 publications

References 38 publications

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Caspase activation in the absence of mitochondrial changes in granulocyte apoptosis

Bax is essential for mitochondrion-mediated apoptosis but not for cell death caused by photodynamic therapy

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