Differential release of mast cell mediators and the pathogenesis of inflammation

Abstract

Mast cells are well known for their involvement in allergic and anaphylactic reactions, during which immunoglobulin E (IgE) receptor (Fc epsilon RI) aggregation leads to exocytosis of the content of secretory granules (1000 nm), commonly known as degranulation, and secretion of multiple mediators. Recent findings implicate mast cells also in inflammatory diseases, such as multiple sclerosis, where mast cells appear to be intact by light microscopy. Mast cells can be activated by bacterial or viral antigens, cytokines, growth factors, and hormones, leading to differential release of distinct mediators without degranulation. This process appears to involve de novo synthesis of mediators, such as interleukin-6 and vascular endothelial growth factor, with release through secretory vesicles (50 nm), similar to those in synaptic transmission. Moreover, the signal transduction steps necessary for this process appear to be largely distinct from those known in Fc epsilon RI-dependent degranulation. How these differential mast cell responses are controlled is still unresolved. No clinically available pharmacological agents can inhibit either degranulation or mast cell mediator release. Understanding this process could help develop mast cell inhibitors of selective mediator release with novel therapeutic applications.

Editorial: Irritable Bowel Syndrome and the Elusive Mast Cells

“…Mast cell activation may be discernible only by the ultrastructural appearance termed as " intragranular activation " , as reported in the gastrointestinal tract and in the bladder of interstitial cystitis / bladder pain syndrome patients ( 13 ). Th is process involves selective release of mediators, as shown for serotonin, eicosanoids, interleukin-6, or vascular endothelial growth factor ( 13 ). It is of particular signifi cance that CRH secreted in the gut under stress induces mast cell release of vascular endothelial growth factor ( 14 ), which is also vasodilatory and pro-infl ammatory.…”

“…Th is does not need to involve degranulation. Mast cell activation may be discernible only by the ultrastructural appearance termed as " intragranular activation " , as reported in the gastrointestinal tract and in the bladder of interstitial cystitis / bladder pain syndrome patients ( 13 ). Th is process involves selective release of mediators, as shown for serotonin, eicosanoids, interleukin-6, or vascular endothelial growth factor ( 13 ).…”

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Furthermore, mast cells can participate in multiple cycles of activation for mediator release and can be differentially activated to release distinct patterns of mediators or cytokines, depending on the type and strength of the activating stimuli 1,6,13,18,20,21 . The strength and nature of the responsiveness of mast cells to various activating stimuli may be influenced by genetic or microenvironmental factors that affect the expression pattern or functional properties of the surface receptors or signalling molecules that contribute to such responses 1,4,20 .…”

Mast Cells in Irritable Bowel Syndrome and Ulcerative Colitis: Function Not Numbers Is What Makes All the Difference

“…One way to identify degranulated MC is to stain for c-kit (CD117), the surface MC receptor for stem cell factor. Nevertheless, since mediator secretion can also occur without degranulation [5], MC activation can best be identified either by ultrastructural appearance or by qPCR measurement of histidine decarboxylase or tryptase gene expression.…”