The Role of TGFβ and Other Cytokines in Regulating Mast Cell Functions in Allergic Inflammation

Abstract

Mast cells (MC) are a key effector cell in multiple types of immune responses, including atopic conditions. Allergic diseases have been steadily rising across the globe, creating a growing public health problem. IgE-mediated activation of MCs leads to the release of potent mediators that can have dire clinical consequences. Current therapeutic options to inhibit MC activation and degranulation are limited; thus, a better understanding of the mechanisms that regulate MC effector functions in allergic inflammation are necessary in order to develop effective treatment options with minimal side effects. Several cytokines have been identified that play multifaceted roles in regulating MC activation, including TGFβ, IL-10, and IL-33, and others that appear to serve primarily anti-inflammatory functions, including IL-35 and IL-37. Here, we review the literature examining cytokines that regulate MC-mediated allergic immune responses.

Keywords: TGFβ; allergy; cytokines; inflammation; mast cells.

Figure 1

Currently Known Roles of Mast Cell (MC) Derived TGFβ. MC produce TGFβ upon IgE and antigen crosslinking. MC derived TGFβ has been shown to promote Treg function, which may be beneficial in controlling autoimmune and allergic inflammation. More detrimentally, it may also promote fibrosis, such as in the liver. Exosomes originating from MCs have been shown to carry active TGFβ that is able to induce Smad signaling in mesenchymal stem cells, suggesting MC derived TGFβ may have systemic effects.

Figure 2

Currently Known Mechanisms of Cytokine-Mediated Regulation of MC Effector Functions. FcεRI signaling is initiated when IgE and specific antigen bind to its extracellular domain, recruiting Src family kinases Hck, Lyn, and Fyn leading to downstream activation of Syk, Lat, p38, Erk, and Jnk which leads to transcription factor activation and translocation into the nucleus to induce gene expression. Concurrently, Erk activation leads to the release of lipid mediators, and calcium influx downstream of Lat activation leads to degranulation. TGFβ signaling has been shown to suppress IgE mediated signaling most likely through Stat5 inhibition through an unknown mechanism. Acute IL-33 exposure enhances IgE mediated degranulation and cytokine production through an unclear signaling mechanism, most likely synergistically. Chronic IL-33 exposure inhibits IgE induced degranulation most likely by inhibition of PLCγ and calcium influx which is necessary for degranulation. IL-35 is thought to inhibit mast cell effector functions by suppressing p38, Erk and Jnk activation. IL-37 suppresses cytokine production by an unknown mechanism, which may involve signaling through its receptor and/or intracellular mechanisms.