PMID- 26890142
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20181113
IS  - 2041-4889 (Electronic)
VI  - 7
IP  - 2
DP  - 2016 Feb 18
TI  - The anti-apoptotic Bcl-2 family protein A1/Bfl-1 regulates neutrophil survival 
      and homeostasis and is controlled via PI3K and JAK/STAT signaling.
PG  - e2103
LID - 10.1038/cddis.2016.23 [doi]
AB  - Neutrophil granulocytes are innate effector cells of the first line of defense 
      against pyogenic bacteria. Neutrophil lifespan is short, is prolonged by 
      pro-inflammatory stimuli, controls functionality of the cells and can determine 
      tissue damage. Experimental analysis of primary neutrophils is difficult because 
      of their short lifespan and lack of possibilities of genetic manipulation. The 
      Hoxb8 system of neutrophil differentiation from immortalized progenitor cells 
      offers the advantage of unlimited production of neutrophils in vitro as well as 
      easy genetic modification. We here use this system to analyze the role of the 
      poorly characterized anti-apoptotic B-cell lymphoma protein 2 (Bcl-2) family 
      member A1/Bfl-1 (Bcl-2-related protein A1) for survival and homeostasis of 
      neutrophils and of neutrophil progenitors. Low constitutive mRNA and protein 
      expression of A1 was detected, while A1 was transiently upregulated early during 
      differentiation. Pro-inflammatory stimuli caused strong, mainly transcriptional, 
      A1 upregulation, in contrast to posttranscriptional regulation of Mcl-1 (induced 
      myeloid leukemia cell differentiation protein). Inhibitor studies showed that 
      phosphoinositide-3 kinase (PI3K)/Akt and Janus kinase (JAK)/signal transducer and 
      activator of transcription (STAT) is required for A1 expression and survival of 
      progenitors and mature neutrophils. ShRNA-mediated constitutive A1 knockdown (KD) 
      impaired maintenance of progenitors. ShRNA experiments further showed that A1 was 
      required early during neutrophil differentiation as well as in mature neutrophils 
      upon pro-inflammatory stimulation. Our data further indicate differential 
      regulation of the two anti-apoptotic proteins A1 and Mcl-1. Relevant findings 
      were confirmed in primary human neutrophils. Our data indicate that A1, in 
      addition to the well-established Mcl-1, substantially contributes to neutrophil 
      survival and homeostasis. A1 may thus be a promising target for anti-inflammatory 
      therapy.
FAU - Vier, J
AU  - Vier J
AD  - Institute of Medical Microbiology and Hygiene, Department of Medical Microbiology 
      and Hygiene, University Medical Centre Freiburg, Freiburg, Germany.
FAU - Groth, M
AU  - Groth M
AD  - Institute of Medical Microbiology and Hygiene, Department of Medical Microbiology 
      and Hygiene, University Medical Centre Freiburg, Freiburg, Germany.
FAU - Sochalska, M
AU  - Sochalska M
AD  - Division of Developmental Immunology, Biocenter, Medical University Innsbruck, 
      Innsbruck, Austria.
FAU - Kirschnek, S
AU  - Kirschnek S
AD  - Institute of Medical Microbiology and Hygiene, Department of Medical Microbiology 
      and Hygiene, University Medical Centre Freiburg, Freiburg, Germany.
LA  - eng
PT  - Journal Article
DEP - 20160218
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (BCL2-related protein A1)
RN  - 0 (Minor Histocompatibility Antigens)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.2 (Janus Kinases)
SB  - IM
MH  - Animals
MH  - Apoptosis/physiology
MH  - Cell Differentiation/physiology
MH  - Granulocytes/cytology/metabolism
MH  - Homeostasis
MH  - Humans
MH  - Janus Kinases/*metabolism
MH  - Mice
MH  - Minor Histocompatibility Antigens/*metabolism
MH  - Neutrophils/*cytology/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-bcl-2/*metabolism
MH  - Signal Transduction
PMC - PMC5399193
COIS- The authors declare no conflict of interest.
EDAT- 2016/02/20 06:00
MHDA- 2016/12/15 06:00
PMCR- 2016/02/01
CRDT- 2016/02/19 06:00
PHST- 2015/10/23 00:00 [received]
PHST- 2016/01/02 00:00 [revised]
PHST- 2016/01/15 00:00 [accepted]
PHST- 2016/02/19 06:00 [entrez]
PHST- 2016/02/20 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
PHST- 2016/02/01 00:00 [pmc-release]
AID - cddis201623 [pii]
AID - 10.1038/cddis.2016.23 [doi]
PST - epublish
SO  - Cell Death Dis. 2016 Feb 18;7(2):e2103. doi: 10.1038/cddis.2016.23.