Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival.
Human neutrophils possess a very short half-life because they constitutively undergo apoptosis. Cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and other agents can rescue neutrophils from apoptosis but the molecular mechanisms involved in this rescue are undefined. Here, we show by Western blotting that human neutrophils do not express Bcl-2 or Bcl-X but constitutively express Bax. However, cellular levels of these proteins are unaffected by agents which either accelerate or delay neutrophil apoptosis. In contrast, neutrophils express the antiapoptotic protein Mcl-1 and levels of this protein correlate with neutrophil survival. Thus, cellular levels of Mcl-1 decline as neutrophils undergo apoptosis and are enhanced by agents (eg, GM-CSF, interleukin-1beta, sodium butyrate, and lipopolysaccharide) that promote neutrophil survival. Neutrophils only possess few, small mitochondria, and much of the Mcl-1 protein seems to be located in nuclear fractions. These observations provide the first evidence implicating a Bcl-2 family member in the regulation of neutrophil survival. Moreover, this work also provides a potential mechanism whereby cytokine-regulated gene expression regulates the functional lifespan of neutrophils and hence their ability to function for extended time periods during acute inflammation.
Moulding
D A
DA
School of Biological Sciences, Life Sciences Building; and the Department of Medical Microbiology, University of Liverpool, Liverpool, UK.
Quayle
J A
JA
Hart
C A
CA
Edwards
S W
SW
D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D016207:Cytokines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D002087:Butyrates; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020148:Butyric Acid; D016178:Granulocyte-Macrophage Colony-Stimulating Factor