TILRR, a novel IL-1RI co-receptor, potentiates MyD88 recruitment to control Ras-dependent amplification of NF-kappaB.

Host defense against infection is induced by Toll-like and interleukin (IL)-1 receptors, and controlled by the transcription factor NF-kappaB. Our earlier studies have shown that IL-1 activation impacts cytoskeletal structure and that IL-1 receptor (IL-1RI) function is substrate-dependent. Here we identify a novel regulatory component, TILRR, which amplifies activation of IL-1RI and coordinates IL-1-induced control with mechanotransduction. We show that TILRR is a highly conserved and widely expressed enhancer of IL-1-regulated inflammatory responses and, further, that it is a membrane-bound glycosylated protein with sequence homology to members of the FRAS-1 family. We demonstrate that TILRR is recruited to the IL-1 receptor complex and magnifies signal amplification by increasing receptor expression and ligand binding. In addition, we show that the consequent potentiation of NF-kappaB is controlled through IL-1RI-associated signaling components in coordination with activation of the Ras GTPase. Using mutagenesis, we demonstrate that TILRR function is dependent on association with its signaling partner and, further, that formation of the TILRR-containing IL-1RI complex imparts enhanced association of the MyD88 adapter during ligand-induced activation of NF-kappaB. We conclude that TILRR is an IL-1RI co-receptor, which associates with the signaling receptor complex to enhance recruitment of MyD88 and control Ras-dependent amplification of NF-kappaB and inflammatory responses.

Distinct NF-kappaB regulation by shear stress through Ras-dependent IkappaBalpha oscillations: real-time analysis of flow-mediated activation in live cells.

NF-kappaB, a transcription factor central to inflammatory regulation during development of atherosclerosis, is activated by soluble mediators and through biomechanical inputs such as flow-mediated shear- stress. To investigate the molecular mechanisms underlying shear stress mediated signal transduction in vascular cells we have developed a system that applies flow-mediated shear stress in a controlled manner, while inserted in a confocal microscope. In combination with GFP-based methods, this allows continuous monitoring of flow induced signal transduction in live cells and in real time. Flow-mediated shear stress, induced using the system, caused a successive increase in NF-kappaB-regulated gene activation. Experiments assessing the mechanisms underlying the NF-kappaB induced activity showed time and flow rate dependent effects on the inhibitor, IkappaBalpha, involving nuclear translocation characterized by a biphasic or cyclic pattern. The effect was observed in both endothelial- and smooth muscle cells, demonstrated to impact noncomplexed IkappaBalpha, and to involve mechanisms distinct from those mediating cytokine signals. In contrast, effects on the NF-kappaB subunit relA were similar to those observed during cytokine stimulation. Further experiments showed the flow induced inter-compartmental transport of IkappaBalpha to be regulated through the Ras GTP-ase, demonstrating a pronounced reduction in the effects following blocking of Ras activity. These studies show that flow-mediated shear stress, regulated by the Ras GTP-ase, uses distinct mechanisms of NF-kappaB control at the molecular level. The oscillatory pattern, reflecting inter-compartmental translocation of IkappaBetaalpha, is likely to have fundamental impact on pathway regulation and on development of shear stress-induced distinct vascular cell phenotypes.

An ultrastructural study of chronic chromate hand dermatitis.

Occupational chromate dermatitis is one of the most common occupational diseases, predominantly causing hand eruptions. The ultrastructural manifestations of this condition have not been previously described. In this study, 7 cases of chronic occupational chromate hand dermatitis were investigated. Biopsies were taken from palmar skin and examined using light and electron microscopy. The ultrastructural features of chronic chromate dermatitis are similar to those of acute inflammatory dermatoses, even in the absence of clinical or histological features of an acute inflammatory process. Most changes are probably mechanical in nature and are a result of increasing intercellular oedema. Several features of chronic chromate dermatitis are common to other inflammatory dermatoses, including the presence of marked intercellular oedema of the lower epidermal keratinocytes, the formation of intracellular vacuoles in cells of the lower epidermis and the presence of milder ultrastructural changes in the midepidermis. The study has documented the presence of dendritic, spindle-shaped granular cells in the upper dermis, which have not previously been described in chromate dermatitis. The epidermis in chromate dermatitis appears to have fewer desmosomes when compared with other forms of dermatitis.