Interleukin-4 elicits apoptosis of developing mast cells via a Stat6-dependent mitochondrial pathway.
OBJECTIVE
The aim of this study was to assess the effects of interleukin-4 and signal transducer and activator of transcription (Stat)-6 on IL-3+SCF-induced mast cell development.


METHODS
Unseparated mouse bone marrow cells were cultured in IL-3+SCF, giving rise to mast cells and monocytes/macrophages. The addition of IL-4, the use of Stat6-deficient bone marrow cells, and expression of a constitutively active Stat6 mutant were employed to assess the effects of IL-4 and Stat6 on cell viability, proliferation, and differentiation. Bax-deficient and bcl-2 transgenic bone marrow cells were used to assess the importance of the mitochondria in IL-4-mediated effects.


RESULTS
IL-4 elicited apoptosis and limited the cell cycle progression of developing bone marrow cells, without affecting cell differentiation. Apoptosis required that IL-4 be present during the first 8 days of the 21-day culture period. Cell death correlated with loss of mitochondrial membrane potential. Accordingly, IL-4-mediated apoptosis was inhibited by Bax deletion or bcl-2 overexpression. Lastly, Stat6 activation was both necessary and sufficient to inhibit cell survival.


CONCLUSIONS
IL-4 exerts potent apoptotic effects on developing mast cells and monocyte/macrophages through mitochondrial damage and Stat6 activation.
Bailey
Daniel P
DP
Department of Biology, Virginia Commonwealth University, Richmond, Va. 23284-2012, USA.
Kashyap
Mohit
M
Mirmonsef
Paria
P
Bouton
L Andrew
LA
Domen
Jos
J
Zhu
Jingfang
J
Dessypris
Emmanuel N
EN
Ryan
John J
JJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D007377:Interleukin-3 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D050800:STAT6 Transcription Factor; D019089:Stem Cell Factor / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology*
D007377:Interleukin-3; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D019089:Stem Cell Factor; D015534:Trans-Activators; D015847:Interleukin-4