Mast cell derived mediators

Michael Gurish, PhD, Mariana C Castells, MD, PhD |

Mast cells release various mediators upon activation. These mediators can be divided into three overlapping categories: preformed mediators, newly-synthesized lipid mediators, and cytokines and chemokines. This topic will review mast cell mediators. The information in this topic pertains to human mast cells whenever possible, and notation is made when data are derived purely from murine studies. The development, physiologic roles, surface receptors, and signal transduction of mast cells are reviewed separately. (See “Mast cells: Development, identification, and physiologic roles” and “Mast cells: Surface receptors and signal transduction”)

Performed Mediators
Mast cell secretory granules contain preformed mediators that are rapidly (within seconds to minutes) released into the extracellular environment upon cell stimulation. These mediators include histamine, neutral proteases, proteoglycans, and some cytokines, such as TNF-alpha (TNF-α). They are responsible for many of the acute signs and symptoms of mast cell mediated allergic reactions, including edema, bronchoconstriction, and increased vascular permeability. Specific pharmacotherapy to inhibit and/or antagonize mast cell mediators is reviewed elsewhere. (See “Treatment and prognosis of systemic mastocytosis”, section on ‘Pharmacotherapy for all subtypes’.)

Histamine — Histamine is produced predominantly by mast cells, but also is elaborated by basophils, neutrophils [1], and platelets. It is stored in both scroll-like and lattice secretory granules of the human mast cell [2]. Human cutaneous mast cells are estimated to contain 1.9 micrograms of histamine per 10(6) cells [3]. Secretory granule exocytosis and release of histamine occurs rapidly after either immunologic or nonimmunologic stimuli [4]. The effects of histamine are mediated through H1, H2, H3, and H4 receptors located on target cells:

  • H1-mediated actions include increased venular permeability, bronchial and intestinal smooth muscle contraction, increased nasal mucus production, widened pulse pressure, increased heart rate and cardiac output, flushing, and T cell neutrophil and eosinophil chemotaxis [5,6]. In mice, lack of H1 receptors leads to reduced lung inflammation as a consequence of the decreased T cell influx [6].
  • The effects mediated through the H2 receptor include increased venular permeability, increased gastric acid secretion, and airway mucus production, but inhibition of neutrophil and eosinophil influx [7,8].
  • An H3 receptor has been located in the brain, but its precise role is uncharacterized [9].
  • An H4 receptor has been identified and cloned in both mice and humans [10,11]. This receptor modulates Th2 responses, and H4 deficient mice have decreased lung inflammation with less infiltration of eosinophils and lymphocytes [12]. Acting through the H4 receptor, histamine can act as a chemoattractant for mouse bone marrow-derived mast cells and modulate calcium influx [13]. In humans, the actions of histamine at the H4 receptor provide a potent chemotactic pathway for human eosinophils [14].

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