TNF secretion from human mast cells is regulated by mitochondrial dynamics and mitochondrial uncoupling protein 2 (UCP2) (135.11)

Abstract

Abstract Tumor necrosis factor (TNF) is involved in T cell-dependent diseases such as psoriasis, and in T cell activation by mast cells, which can both store and de novo synthesize TNF. Yet, regulation of TNF secretion is unknown hampering our understanding of how mast cells regulate allergic, immune and inflammatory processes. Here we show that stimulated human LAD2 leukemic and umbilical cord-derived cultured mast cell (hCBMCs) by SP or IgE/anti-IgE induces degranulation and prestored TNF release, which is accompanied by mitochondrial fission. Images of Confocal microscopy and electronic transmitted microscopy show fragmented mitochondria and relocation from a perinuclear distribution to the cell surface. Moreover, treatment with a mitochondrial fission blocker inhibits degranulation, indicating the necessarily of mitochondria fission in mast cell secretion. Besides mitochondria morphological changes, SP stimulation of LAD2 and hCBMCs increased expression (8 hr) of the mitochondrial uncoupling protein 2 (UCP2), which regulates production of ROS and intracellular calcium, leading to inhibition of subsequent re-stimulation by SP, when is enough for mast cells to recover. Moreover, UCP2 gene expression was reduced, as compared to control normal skin, in affected psoriatic skin, an inflammatory diseases in which mast cells play important role. These findings indicate that mitochondria play a key regulatory role in mast cell TNF secretion and in psoriasis.