A key role for ATF3 in regulating mast cell survival and mediator release.
Activating transcription factor 3 (ATF3) is a basic leucine zipper transcription factor that plays a regulatory role in inflammation, cell division, and apoptosis. Mast cells (MCs) initiate many inflammatory responses and have a central role in allergy and allergic diseases. We report here that ATF3 has a central role in MC development and function. Bone marrow-derived MC populations from ATF3-deficient mice are unresponsive to interleukin-3 (IL-3)-induced maturation signals, and this correlates with increased apoptosis, diminished activation of the Akt kinase, and decreased phosphorylation of the proapoptotic protein Bad. Furthermore, ATF3-null mice lacked MCs in the peritoneum and dermis, showing that the in vitro results are recapitulated in vivo. ATF3-null MCs also showed functional defects; high-affinity immunoglobulin E receptor-mediated degranulation was significantly inhibited, whereas IL-4 and IL-6 expression was enhanced. This dual role of ATF3 provides insight into the complex interplay between MC development and its subsequent physiologic role.
Gilchrist
Mark
M
Institute for Systems Biology, Seattle, WA 98103, USA.
Henderson
William R
WR
Morotti
Andrew
A
Johnson
Carrie D
CD
Nachman
Alex
A
Schmitz
Frank
F
Smith
Kelly D
KD
Aderem
Alan
A
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D007377:Interleukin-3 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D017455:Receptors, IgE / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C494820:Bad protein, mouse; D018836:Inflammation Mediators; D007377:Interleukin-3; D015850:Interleukin-6; D017455:Receptors, IgE; D051025:bcl-Associated Death Protein; D015847:Interleukin-4