Two functionally distinct isoforms of TL1A (TNFSF15) generated by differential ectodomain shedding

Area of Science:

• Endocrinology
• Cell Biology
• Molecular Biology

Background:

• Tumor necrosis factor-like cytokine 1A (TL1A) is implicated in T-cell activation through an extracellular fragment.
• Previous studies noted TL1A fragments induced endothelial cell growth arrest and apoptosis, but mechanisms were unclear.

Purpose of the Study:

• To investigate the role of full-length TL1A and its fragments in endothelial cell senescence.
• To identify novel TL1A fragments involved in endothelial cell regulation.

Main Methods:

• Quantification of TL1A gene product in human umbilical vein endothelial cells (HUVECs) and circulating endothelial progenitor cells (CEPs).
• Analysis of TL1A expression in senescent vs. non-senescent cells.
• TL1A knockdown and overexpression studies.
• Identification and functional characterization of novel TL1A extracellular fragments.

Main Results:

• Full-length TL1A is the predominant form in HUVECs and CEPs.
• TL1A expression increases in senescent CEPs; TL1A knockdown partially reverses senescence.
• TL1A overexpression induces premature senescence in HUVECs and CEPs.
• A novel TL1A fragment, TL1A(V84-L251), induces growth arrest and apoptosis in HUVECs.

Conclusions:

• TL1A plays a significant role in regulating endothelial cell senescence.
• Differential ectodomain shedding produces novel TL1A fragments with potent effects on endothelial cells.
• TL1A and its fragments are potential targets for managing vascular-related pathologies.