BH3 mimetics efficiently induce apoptosis in mouse basophils and mast cells.

Reinhart, Ramona; Rohner, Lionel; Wicki, Simone; Fux, Michaela; Kaufmann, Thomas (2018). BH3 mimetics efficiently induce apoptosis in mouse basophils and mast cells. Cell death and differentiation, 25(1), pp. 204-216. Nature Publishing Group 10.1038/cdd.2017.154

[img]
Preview
Text
Kaufmann_BH3 mimetics efficiently.pdf - Published Version
Available under License Creative Commons: Attribution-Noncommercial-Share Alike (CC-BY-NC-SA).

Download (2MB) | Preview

Basophil granulocytes and mast cells are recognized for their roles in immunity and are central effectors of diverse immunological disorders. Despite their similarities, there is emerging evidence for non-redundant roles of the circulating yet scarce basophils and tissue-resident mast cells, respectively. Because of their importance in allergic pathogenesis, specific induction of apoptosis in basophils and mast cells may represent an interesting novel treatment strategy. The pro-inflammatory cytokine interleukin-3 serves as a key factor for basophil and mouse mast cell survival. Interleukin-3 increases the expression of anti-apoptotic BCL-2 family members, such as BCL-2, BCL-XL or MCL-1; however, little is known how strongly these individual proteins contribute to basophil survival. Here, we were applying small molecule inhibitors called BH3 mimetics, some of which show remarkable success in cancer treatments, to neutralize the function of anti-apoptotic BCL-2 family members. We observed that expression levels of anti-apoptotic BCL-2 proteins do not necessarily correlate with their respective importance for basophil survival. Whereas naive in vitro-differentiated mouse basophils efficiently died upon BCL-2 or BCL-XL inhibition, interleukin-3 priming rendered the cells highly resistant toward apoptosis, and this could only be overcome upon combined targeting of BCL-2 and BCL-XL. Of note, human basophils differed from mouse basophils as they depended on BCL-2 and MCL-1, but not on BCL-XL, for their survival at steady state. On the other hand, and in contrast to mouse basophils, MCL-1 proved critical in mediating survival of interleukin-3 stimulated mouse mast cells, whereas BCL-XL seemed dispensable. Taken together, our results indicate that by choosing the right combination of BH3 mimetic compounds, basophils and mast cells can be efficiently killed, even after stimulation with potent pro-survival cytokines such as interleukin-3. Because of the tolerable side effects of BH3 mimetics, targeting basophils or mast cells for apoptosis opens interesting possibilities for novel treatment approaches.Cell Death and Differentiation advance online publication, 29 September 2017; doi:10.1038/cdd.2017.154.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Institute of Diagnostic, Interventional and Paediatric Radiology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Reinhart, Ramona; Rohner, Lionel; Wicki, Simone; Fux, Michaela and Kaufmann, Thomas

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1350-9047

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Jana Berger

Date Deposited:

19 Oct 2017 15:59

Last Modified:

09 Feb 2018 13:45

Publisher DOI:

10.1038/cdd.2017.154

PubMed ID:

28960207

BORIS DOI:

10.7892/boris.106229

URI:

https://boris.unibe.ch/id/eprint/106229

Actions (login required)

Edit item Edit item
Provide Feedback