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B and TNF-
: A Positive Autocrine Loop in Human Lung Mast Cells?
Division of Infection, Inflammation and Repair, School of Medicine, Southampton General Hospital, Southampton, United Kingdom
The generation of cytokines, particularly TNF-
, by mast cells is
crucial for the initiation of the allergic response. A key
transcription factor involved in the synthesis of TNF- is NF-
B.
Using a mAb specific for the activated form of NF-B,
immunocytochemistry, confocal microscopy, and gel shift assays have
been used in conjunction to localize this transcription factor to human
lung mast cells and to study its activation. Activation of mast cells
with stem cell factor (10 ng/ml) and anti-IgE (1 µg/ml)
induced maximal activation of NF-B at 4 and 2 h, respectively.
In contrast, with TNF- (5 ng/ml) maximal activation occurred within
15 min. Parallel falls in IB were demonstrated. Confocal microscopy
demonstrated the localization of the activated form of NF-B to the
nuclei of activated mast cells. NF-B activation was verified using a
gel shift assay. A supershift assay showed mast cell NF-B to be
composed primarily of p50 with smaller amounts of p65. No interaction
with Abs for Rel-A, c-Rel, Rel-B, and p52 was seen. Immunocytochemistry
and ELISAs showed TNF- to be stored within mast cells and released
into the extracellular environment following activation. The possible
participation of TNF- generated by mast cells in NF-B activation
by anti-IgE was investigated using a blocking Ab for TNF-. The
blocking Ab reduced NF-B activation by anti-IgE by >50%,
suggesting that the release of preformed mast cell-associated TNF-
acts as a positive autocrine feedback signal to augment NF-B
activation and production of further cytokine, including GM-CSF and
IL-8.
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