VGLL3 activates inflammatory responses by inducing interleukin-1α secretion

Vestigial-like family member 3 (VGLL3), a member of the vestigial-like family, is a cofactor of the TEA-domain-containing transcription factor (TEAD). Although elevation in VGLL3 expression is associated with inflammatory diseases, such as inflammatory sarcomas and autoimmune diseases, the molecular mechanisms underlying VGLL3-mediated inflammation remain largely unknown. In this study, we analyzed the relationship between elevated VGLL3 expression and the levels of NF-kappa B, a transcription factor that plays a pivotal role in inflammation. NF-kappa B was found to be activated in a cell line stably expressing VGLL3. Mechanistically, VGLL3 was shown to promote the expression and secretion of the potent NF-kappa B-activating cytokine interleukin (IL)-1 alpha, probably through its association with TEADs. As VGLL3 is a target of transforming growth factor beta (TGF-beta) signaling, we analyzed IL-1 alpha induction upon TGF-beta stimulation. TGF-beta stimulation was observed to induce IL-1 alpha secretion and NF-kappa B activation, and VGLL3 was associated with this phenomenon. The TGF-beta transcription factors Smad3 and Smad4 were shown to be necessary for inducing VGLL3 and IL-1 alpha expression. Lastly, we found that VGLL3-dependent IL-1 alpha secretion is involved in constitutive NF-kappa B activation in highly malignant breast cancer cells. Collectively, the findings suggested that VGLL3 expression and TGF-beta stimulation activate the inflammatory response by inducing IL-1 alpha secretion.

Automated summary

Elevated VGLL3 expression is associated with NF-kappa B activation and IL-1 alpha secretion, potentially leading to an inflammatory response. TGF-beta signaling induces VGLL3 expression, which in turn promotes IL-1 alpha secretion and NF-kappa B activation, contributing to inflammation in diseases like highly malignant breast cancer.