Cooperative Regulation of the Mucosal Mast Cell–Specific Protease Genes Mcpt1 and Mcpt2 by GATA and Smad Transcription Factors

Abstract

Mouse mast cell proteases (mMCP)-1 and -2 are specifically expressed in mucosal mast cells (MCs). However, the transcriptional regulation mechanism of the Mcpt1 and Mcpt2 genes induced in mucosal MCs is largely unknown. In the current study, we found that TGF-b stimulation drastically induced upregulation of Mcpt1 and Mcpt2 mRNA in mouse bone marrow-derived MCs (BMMCs). TGF-b-induced expression of Mcpt1 and Mcpt2 was markedly suppressed by transfection with small interfering RNA targeting Smad2 or Smad4 and moderately reduced by Smad3 small interfering RNA. We next examined the roles of the hematopoietic cell-specific transcription factors GATA1 and GATA2 in the expression of Mcpt1 and Mcpt2 and demonstrated that knockdown of GATA1 and GATA2 reduced the mRNA levels of Mcpt1 and Mcpt2 in BMMCs. The recruitment of GATA2 and acetylation of histone H4 of the highly conserved GATA-Smad motifs, which were localized in the distal regions of the Mcpt1 and Mcpt2 genes, were markedly increased by TGF-b stimulation, whereas the level of GATA2 binding to the proximal GATA motif was not affected by TGF-b. A reporter assay showed that TGF-b stimulation upregulated GATA2-mediated transactivation activity in a GATA-Smad motif-dependent manner. We also observed that GATA2 and Smad4 interacted in TGF-b-stimulated BMMCs via immunoprecipitation and Western blotting analysis. Taken together, these results demonstrate that TGF-b induced mMCP-1 and -2 expression by accelerating the recruitment of GATA2 to the proximal regions of the Mcpt1 and Mcpt2 genes in mucosal MCs.

Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

“…The stimulatory response displayed by MCs in these circumstances could be the result of an evolutionary advantage to resist immunosuppression by parasites/worms; MCs may also activate to some degree in the context of wound repair. TGF-β1 stimulation of murine bone marrow-derived MCs is also sufficient in inducing mMCP-1 and mMCP-2 expression facilitated through GATA2 and Smad (2,4, potentially 3) signaling [82]. This response may prime MCs as localized protective effector cells during wound repair or during the resolution of an immune response in tissues.…”

Altered gene expression signatures by calcitonin gene‐related peptide promoted mast cell activity in the colon of stress‐induced visceral hyperalgesia mice

“…Accumulating evidence showed that transcription factors can play a critical role in proliferation, differentiation, and activation of MCs. 32,33 Some transcription factors such as Crem, fosB, and Nr4a3 are known to be involved in FcεR-mediated immune responses of MCs. 34,35 Therefore, association with MC activation and Nr4a3 is implicated in various physiological and pathophysiological processes including, immune and inflammatory responses, apoptosis, and cell cycle control.…”

“…Among identified candidate genes, transcription factor genes showed the greatest upregulation (e.g., Scrt1, 15.94 fold; Nr4a3, 8.44 fold). Accumulating evidence showed that transcription factors can play a critical role in proliferation, differentiation, and activation of MCs 32,33 . Some transcription factors such as Crem, fosB, and Nr4a3 are known to be involved in FcεR‐mediated immune responses of MCs 34,35 .…”

Anaphylaxis: Focus on Transcription Factor Activity

“…These results are similarly found in GATA2 deleted-DNA domain in mice BMMCs [ 51 ]. GATA2 also affects Mcpt1 and Mcpt2 gene expression, which are specific proteases in mucosal mouse mast cells [ 54 ].…”

“…GATA1 and GATA2 regulate tryptases (including mTMT, mMCP6, and mMCP7). Furthermore, GATA2 regulates histamine and proteases (Cpa3, Mcpt4, Mcpt8, Cma1) synthesis [ 27 , 54 ]. GATA3 defines a Tfh13 population involved in anaphylactic IgE production [ 59 ].…”