IL-3-Mediated TNF Production Is Necessary for Mast Cell Development

Abstract

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.

Prostagladin D 2 is a mast cell-derived antiangiogenic factor in lung carcinoma

“…S3 B and C). As previously described (14), gene deficiency of TNF-α reduced the proliferation and c-kit high FcεRI high population of bone marrow cells (TNF-α −/− and H-PGDS −/− TNF-α −/− ), that were rescued by a supplement with 1 ng/mL TNF-α. Thus, PGD 2 does not influence IL-3-mediated mast cell growth and differentiation in vitro, but TNF-α is required for it to occur.…”

“…In response to LLC growth, H-PGDS-deficient mast cells produce TNF-α excessively. This response is suppressed by the administration of a synthetic PGD 2 receptor agonist or a degradation product of PGD 2 , 15-deoxy-Δ 12,14 -PGJ 2 . Additional TNF-α deficiency partially counteracts the tumorigenic properties seen in H-PGDS-deficient mast cells.…”

A key role for ATF3 in regulating mast cell survival and mediator release

“…Mac1 ϩ macrophages may be acting as feeder cells during the early time points of MC culture. 14 We attempted mixing experiments to determine whether the growth defect was intrinsic to the MCs or other cells types present early in culture. MC cultures did not develop when ATF3-null MCs were plated onto adherent WT feeder cells.…”

Mast cells are an essential hematopoietic component for polyp development

“…9). It has been suggested that TNF␣ supports MC differentiation (21). To test this, we performed MCp assays with MNCs derived from the diseased intestines of APC ⌬468 mice, in the presence or absence of exogenous TNF␣.…”