Chapter 10 - FcɛRI-mediated Induction of TNF-α Gene Expression in Mast Cell Lines

Abstract

This chapter summarizes the FcɛRI-mediated induction of tumor necrosis factor-⍺ (TNF-⍺) gene expression in mast cell lines. Strong tissue-dependent regulatory mechanisms have been shown to be operative in TNF-⍺ gene expression. Induction of TNF-⍺ gene expression is initiated by a number of stimuli, including various cytokines, bacterial products, immunological stimuli as well as some non-specific activators. Mast cells are critical effectors of IgE-dependent immune responses mediated through their high-affinity IgE receptor (FcɛRI). In these cells aggregation of receptor-bound IgE provides a potent stimulus for TNF-⍺ production first recognized in the RBL-2H3 and PT18 mast cell lines. The Fc∼RI-stimulated TNF-⍺ gene expression in mast cells is tightly regulated and follows the roles of an immediate early gene with a rapid induction independent of protein synthesis. The low levels of mRNA detected in non-stimulated cells do not lead to a significant release of protein in short-term cultures. Upon stimulation through FcɛRI, TNF-⍺ mRNA steady-state levels rapidly increase with the maxima being achieved at around 1 h and then the decline starts. This is followed by the secretion of newly synthesized protein starting between 30 and 60 minutes after addition of stimulus, whereas secretion of pre-formed TNF-⍺ is complete within 10 minutes. Signaling pathways and mechanisms involved in FcɛRI-induced TNF-⍺ production are also discussed here. Much work has yet to be accomplished to fully elucidate the different mechanisms that control TNF-⍺ gene expression in mast cells.