4.6 Article

TNFR1 links TNF exocytosis to TNF production in allergen-activated RBL-2H3 cells

Journal

CELLULAR SIGNALLING
Volume 105, Issue -, Pages -

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2023.110607

Keywords

Inflammation; Munc18; Mast cell; Degranulation; Autocrine signaling; Allergy

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The study reveals that maximal production of TNF in antigen-activated RBL-2H3 cells relies on the regulator of exocytic fusion, Munc13-4. It further demonstrates the involvement of various fusion catalysts in TNF production. The findings suggest that soluble TNF and TNFR1 act as autocrine agents and receptors respectively, promoting TNF proliferation during allergic inflammation.
We previously reported that the maximal production of Tumor Necrosis Factor (TNF or TNF alpha) in antigenactivated RBL-2H3 cells (a tumor analog of mucosal mast cells) requires Munc13-4, a regulator of exocytic fusion. In this study, we investigated the involvement of various fusion catalysts in TNF production. We observed a strong correlation between the total TNF level and TNF exocytosis in RBL-2H3 cells. RT-qPCR shows that TNFR1 (TNF receptor 1) is the sole TNFR expressed in these cells, and that its transcription is upregulated upon allergen-mediated activation. Importantly, the addition of soluble TNFR1 inhibits antigen-elicited TNF production in a dosage-dependent fashion. Likewise, TNF production is diminished in the presence of TACE (TNF alpha Converting Enzyme) inhibitor KP-457, which prevents the generation of soluble TNF (sTNF). Together, these findings indicate that sTNF and TNFR1 function as autocrine agent and receptor respectively at the mast cell surface to boost TNF proliferation during allergic inflammation.

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