Abstract

Immune and inflammatory responses are induced through members of the Toll like and IL-1 receptor (TIR) family. Downstream control involves activation of NF-κB, a transcription factor induced by soluble mediators, and by mechanotransduction through flow-mediated shear stress. We have identified an IL-1RI co-receptor, TILRR (Toll-like/IL-1 receptor regulator), which controls IL-1-induced activation of NF-κB and inflammatory genes in a range of cell types, including vascular cells.1 TILRR is required for activation of the Ras GTP-ase, and its expression is controlled by both soluble mediators and events related to cell attachment and cell shape, consistent with a link to structural control and mechanotransduction. Here we study the role of TILRR in inflammatory signalling and gene regulation through flow mediated shear stress, and its control by mechanotransduction. Effects on shear stress-induced NF-κB activity was analysed using a flow system designed for single cell readings and GFP-based methods. The experiments demonstrate that blocking TILRR expression reduces NF-κB activation through flow-mediated shear stress by up to 60%, similar to effects documented for cytokine-regulated responses. Analysis by quantitative Real-Time PCR (qRT-PCR) revealed that both inflammatory and structural genes are regulated by TILRR expression. Continuation of these experiments will use flow-mediated shear stress to determine whether, conversely, activation through mechanotransduction impacts expression of TILRR and related inflammatory and structural regulators.