Regulation of TLR4 expression is a tale about tail.

Toll-like receptor (TLR) 4 is the first identified mamalian homolog of the Drosophila Toll protein.1 TLR4 recognizes bacterial lipopolysaccharide (LPS), and also senses endogenous ligands including hyaluronic acid, oxidized low-density lipoprotein, and heat-shock proteins. Engagement of TLR4 with its ligand triggers a cascade of cellular signals through the intracellular signal transduction domain, known as Toll/interleukin (IL)-1 receptor (TIR), leading to the activation of nuclear factorB (NFB) and mitogen-activated protein kinase (MAPK) signal transduction pathways, consequently inducing expression of inflammatory genes.2 Although the TLR family of molecules normally contributes to host defense, excess TLR signaling has been implicated in many inflammatory diseases. That TLR4 is implicated in cardiovascular diseases was first suggested by observations of increased expression of TLR4 in failing hearts3 and in atherosclerotic lesions.4,5 The functional importance of TLR4 has subsequently been demonstrated by the attenuated vascular inflammation and reduced lesion size in TLR4-deficient atherosclerosis prone mice,6 and by the association of hyporesponsive TLR4 variants with disease development.7,8 Furthermore, excessive activation of TLR4 by LPS induces endotoxin shock, a serious systemic disorder with a high mortality rate. Therefore TLR signaling must be tightly controlled to avoid improper activation or suppression. Yet regulation of TLR4 expression in cardiovascular disease remains elusive. In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, two sister papers by Feng-Yen Lin and colleagues9,10 lend new mechanistic insights that oxidative stress induces posttranscriptional stabilization of TLR4 mRNA in vascular cells.