Surface Toll-Like Receptor 3 Expression in Metastatic Intestinal Epithelial Cells induces Inflammatory Cytokine Production and Promotes Invasiveness [Signal Transduction]

Toll-like receptors (TLR)s are innate immune receptors for sensing microbial molecules and damage-associated molecular patterns released from host cells. Double-stranded RNA and the synthetic analog polyinosinic:polycytidylic acid (Poly(I:C)) bind and activate TLR3. This stimulation leads to recruitment of the adaptor molecule TRIF and activation of the transcription factors nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3), classically inducing IFNβ production. Here, we report that unlike non-metastatic intestinal epithelial cells (IECs), metastatic IECs express TLR3, and that TLR3 promotes invasiveness of these cells. In response to Poly(I:C) addition, the metastatic IECs also induced the chemokine CXCL10 in a TLR3-, TRIF- and IRF3- dependent manner, but failed to produce IFNβ. This was in contrast to healthy and non-metastatic IECs, which did not respond to Poly(I:C) stimulation. Endolysosomal acidification and the endosomal transporter protein UNC93B1 was required for the Poly(I:C)- induced CXCL10 production. However, TLR3- induced CXCL10 was triggered by immobilized Poly(I:C), was only modestly affected by inhibition of endocytosis, and could be blocked with an anti-TLR3 antibody, indicating that TLR3 still can signal from the cell surface of these cells. Furthermore, plasma membrane fractions from metastatic IECs contained both full-length and cleaved TLR3, demonstrating surface expression of both forms of TLR3. Our results imply that metastatic IECs express surface TLR3, allowing it to sense extracellular stimuli, which trigger chemokine responses, and promote invasiveness in these cells. We conclude that altered TLR3 expression and localization may have implications for cancer progression.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vvRXze
via IFTTT