IL-3-mediated TNF production is necessary for mast cell development.
Mouse mast cell development and survival are largely controlled by the cytokines IL-3 and stem cell factor (SCF). We have found that IL-3 stimulation of bone marrow cells induces the production of TNF via a PI3K- and MAPK kinase/ERK-dependent pathway. Specifically, Mac-1-positive cells were responsible for TNF production, which peaked on days 7-10 of culture and decreased rapidly thereafter. The importance of IL-3-induced TNF secretion was demonstrated by the failure of TNF-deficient bone marrow cells to survive for >3 wk when cultured in IL-3 and SCF, a defect that was reversed by the addition of soluble TNF. The development of human mast cells from bone marrow progenitors was similarly hampered by the addition of TNF-blocking Abs. Cell death was due to apoptosis, which occurred with changes in mitochondrial membrane potential and caspase activation. Apoptosis appeared to be due to loss of IL-3 signaling, because TNF-deficient cells were less responsive than their wild-type counterparts to IL-3-mediated survival. In vitro cultured mast cells from TNF-deficient mice also demonstrated reduced expression of the high affinity IgE receptor, which was restored to normal levels by the addition of soluble TNF. Finally, TNF-deficient mice demonstrated a 50% reduction in peritoneal mast cell numbers, indicating that TNF is an important mast cell survival factor both in vitro and in vivo.
Wright
Harry V
HV
Department of Biology, Virginia Commonwealth University, Richmond, 23284, USA.
Bailey
Daniel
D
Kashyap
Mohit
M
Kepley
Christopher L
CL
Drutskaya
Marina S
MS
Nedospasov
Sergei A
SA
Ryan
John J
JJ
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007377:Interleukin-3 / Q000276:immunology / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
D007377:Interleukin-3; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha