Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50 % increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA

Numerical and experimental LDL transport through arterial wall

Atherosclerosis develops from oxidized low-density lipoprotein molecules (LDL). When oxidized LDL evolves in plaque formations within an artery wall, a series of reactions occur to repair the damage to the artery wall caused by oxidized LDL. Aim of this study was to compare experimental data of LDL transport through isolated blood vessel with computational results of bounding of oxidized LDL receptor-1 (LOX-1) for endothelial cells with numerical discrete methods such as dissipative particle dynamics (DPD) and lattice Boltzmann (LB) method. Experiments of LDL transport were performed on the isolated rabbit common carotid arteries acquired from fifteen rabbits after 12 weeks of high-fat diet. Oxidative LDL molecule is built and used for docking with LOX-1 receptor. Energies that give the best binding are computed, and the energy with greatest probability of attachment for oxidative LDL molecule and glutamine acid is further used in numerical simulations. Simulations using DPD and LB method use the computed binding energy to calculate the force necessary for binding of LDL molecule to the endothelial blood vessel layer. Experimental results have shown large uptake for shear stress below 1 dyn/cm2. Computational results for both discrete methods DPD and LB have shown good accuracy with experimental data. Calculation of the interactive molecule forces from computational chemistry open a new avenue for multiscale modeling methods, which will give better insight for the understanding and the prediction of LDL transport through the arterial wall for the medical community. © 2013 Springer-Verlag Berlin Heidelberg