Transglutaminase II/MicroRNA-218/-181a Loop Regulates Positive Feedback Relationship between Allergic Inflammation and Tumor Metastasis

Young Myeong Kim,Youngmi Kim,Sangkyung Eom,Misun Kim,Deokbum Park,Hansoo Lee,Yun Sil Lee,Jongseon Choe,Dooil Jeoung

doi:10.1074/jbc.m114.603480

Young Myeong Kim, Youngmi Kim + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m114.603480

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Abstract

The molecular mechanism of transglutaminase II (TGaseII)-mediated allergic inflammation remains largely unknown. TGaseII, induced by antigen stimulation, showed an interaction and co-localization with FcϵRI. TGaseII was necessary for in vivo allergic inflammation, such as triphasic cutaneous reaction, passive cutaneous anaphylaxis, and passive systemic anaphylaxis. TGaseII was necessary for the enhanced metastatic potential of B16F1 melanoma cells by passive systemic anaphylaxis. TGaseII was shown to be a secreted protein. Recombinant TGaseII protein increased the histamine release and β-hexosaminidase activity, and enhanced the metastatic potential of B16F1 mouse melanoma cells. Recombinant TGaseII protein induced the activation of EGF receptor and an interaction between EGF receptor and FcϵRI. Recombinant TGaseII protein displayed angiogenic potential accompanied by allergic inflammation. R2 peptide, an inhibitor of TGaseII, exerted negative effects on in vitro and in vivo allergic inflammation by regulating the expression of TGaseII and FcϵRI signaling. MicroRNA (miR)-218 and miR-181a, decreased during allergic inflammation, were predicted as negative regulators of TGaseII by microRNA array and TargetScan analysis. miR-218 and miR-181a formed a negative feedback loop with TGaseII and regulated the in vitro and in vivo allergic inflammation. TGaseII was necessary for the interaction between mast cells and macrophages during allergic inflammation. Mast cells and macrophages, activated during allergic inflammation, were responsible for the enhanced metastatic potential of tumor cells that are accompanied by allergic inflammation. In conclusion, the TGaseII/miR-218/-181a feedback loop can be employed for the development of anti-allergy therapeutics.

Highlights

The mechanism of transglutaminase II-mediated allergic inflammation-promoted tumor metastasis remains unknown at the molecular level
Antigen stimulation induced the expression of transglutaminase II (TGaseII) and an interaction between TGaseII and Fc⑀RI␤ in bone marrow-derived mouse mast cells (BMMCs) (Fig. 1E)
The down-regulation of TGaseII prevented antigen from increasing the secretion of histamine and prevents antigen from increasing ␤-hexosaminidase activity (Fig. 1G). These results suggest that TGaseII mediates allergic inflammation through interaction with Fc⑀RI␤

Summary

Background

The mechanism of transglutaminase II-mediated allergic inflammation-promoted tumor metastasis remains unknown at the molecular level. Results: The transglutaminase II/miR-218/-181a loop regulates allergic inflammation-promoted tumor metastasis. R2 peptide, an inhibitor of TGaseII, exerted negative effects on in vitro and in vivo allergic inflammation by regulating the expression of TGaseII and Fc⑀RI signaling. Mast cells and macrophages, activated during allergic inflammation, were responsible for the enhanced metastatic potential of tumor cells that are accompanied by allergic inflammation. Tissue transglutaminase mediates airway inflammation of toluene diisocyanate-induced occupational asthma by regulating the production of reactive oxygen species [12]. TGaseII/miR-218/-181a Loop in Allergic Inflammation allergic responses by regulating NF-␬B/TGaseII activity in a mouse model of allergic asthma [15]. We present evidence that in vivo allergic inflammation promotes the metastatic potential of mouse melanoma cells and involves the interaction between tumor cells and stromal cells, such as mast cells and macrophages. The TGaseII/miR-218/-181a feedback loop would be a valuable target for the development of antiallergic drugs

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DISCUSSION