Growth, phenotype, and function of human intestinal mast cells are tightly regulated by transforming growth factor  1

Abstract

Background and aims: Transforming growth factor b1 (TGF-b1) is expressed in the healthy human intestine and controls mucosal immune responses and inflammation by regulating the function of lymphocytes, macrophages, dendritic cells, and eosinophils. Here, we asked whether human intestinal mast cells (MC) might also be subject to immunoregulation by TGF-b1. Methods: MC were isolated from the intestinal mucosa, purified, and cultured in vitro in the presence of stem cell factor (SCF) with or without TGF-b1. Growth characteristics, phenotype, and immunological mediator release of MC were analysed by reverse transcription-polymerase chain reaction, flow cytometry, immunocytochemistry, western blot, and different immunoassays, respectively. Results: TGF-b1 dose dependently (ED50 < 0.1 ng/ml) inhibited SCF dependent growth of human intestinal MC by both enhancing apoptosis and decreasing proliferation. In parallel, TGF-b1 increased the percentage of connective tissue-type MC expressing tryptase and chymase while downregulating expression of the receptors for IgE and SCF. Furthermore, TGF-b1 dramatically changed the profile of mediators released by MC following IgE receptor crosslinking. Release of histamine, cysteinyl-leukotrienes, and tumour necrosis factor a was strongly reduced whereas prostaglandin D2 generation and cyclooxygenase 1 and 2 expression were upregulated by TGF-b1. Conclusions: Our data indicate that TGF-b1 acts as a novel potent inhibitor and modulator of human intestinal MC effector functions. The change in MC mediator release profile and protease expression induced by TGF-b1 might be of relevance for the control of MC associated disorders of the intestine such as allergic reactions, Crohn's disease, irritable bowel syndrome, and parasitic infection.

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…As part of its negative regulatory functions, TGF-b inhibits the expression of the high-affinity IgE receptor Fc1RI, a mechanism that activates mast cells (Gomez et al 2005). TGF-b was also reported to inhibit mast cell proliferation, degranulation, and production of several effector molecules (Broide et al 1989;Bissonnette et al 1997;Gebhardt et al 2005;Gomez et al 2005). However, in mast cells, TGF-b can also promote expression of inflammatory mediators, such as IL-6 and lymphotactin (Rumsaeng et al 1997;Miller et al 1999;Ganeshan and Bryce 2012).…”

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

“…For example, IL-4 enhances FceRI-mediated reactions from human mast cells [13]. In addition to enhancing activation of mast cells, several modulatory cytokines produced by regulatory T cells such as IL-10 and TGF-b can decrease FceRI-mediated reactions [14,15].…”

Perinatal Immune Activation and Risk of Autism

“…CSF and microglia of ASD patients had high levels of macrophage chemoattractant protein-1 (MCP-1) (Vargas et al, 2005), which is also a potent chemoattractant for mast cells (Conti et al, 1997). In contrast, ASD plasma levels of transforming growth factorbeta1 (TGF-β1) were low , which is important in view of the fact that TGF-β1 inhibits mast cell function (Gebhardt et al, 2005). Many children with ASD also report gastrointestinal symptoms (Buie et al, 2010).…”