TGF-β1 Induces Mucosal Mast Cell Genes and is Negatively Regulated by the IL-3/ERK1/2 Axis.

Abstract

Mast cells develop from the myeloid lineage and are released from the bone marrow as immature cells, which then differentiate at the destination tissue based on cues from the local environment. In the liver, mast cells are recruited in diseased states to fibrogenic surroundings rich in TGF-β1. The aim of this study was to investigate TGF-β1 signaling in primary and permanent mast cells to identify common and unique mechanisms. The TGF-β receptor repertoire is similar among mast cells, with high expression of type I and type II receptors and very low expression of type III receptors (Betaglycan and Endoglin). Downstream, TGF-β1 activates the SMAD2/3 signaling axis and also SMAD1/5 with target genes Smad6 and Id1 in a transient manner. Initially, TGF-β1 upregulates the transcription of mucosal mast cell effectors Mcpt1 and Mcpt2 in all analyzed mast cells. This upregulation is reduced in the presence of IL-3, which promotes proliferation. Inhibition of ERK1/2 activation reduces proliferation and mitigates the negative effect of IL-3 on Mcpt1 mRNA and protein expression in the immortalized mast cell line PMC-306 but not in bone marrow-derived mast cells. Therefore, extracellular signal-regulated kinases ERK1/2 are identified as a mutual switch between IL-3-driven proliferation and TGF-β1-promoted mucosal mast cell differentiation in PMC-306. In conclusion, TGF-β1 promotes a mucosal gene signature and inhibits proliferation in mast cells, with these effects being counter-regulated by IL-3/ERK1/2.