Syndecans are cell surface proteoglycans that bind and modulate various proinflammatory mediators and can be proteolytically shed from the cell surface. Within the lung, syndecan-1 and -4 are expressed as transmembrane proteins on epithelial cells and released in the bronchoalveolar fluid during inflammation. We here characterize the mechanism leading to the generation of soluble syndecan-1 and -4 in cultured epithelial cells and murine lung tissue. We show that the bladder carcinoma epithelial cell line ECV304, the lung epithelial cell line A459 and primary alveolar epithelial cells express and constitutively release syndecan-1 and -4. This release involves the activity of the disintegrin-like metalloproteinase ADAM17 as demonstrated by use of specific inhibitors and lentivirally transduced shRNA. Stimulation of epithelial cells with PMA, thrombin, or proinflammatory cytokines (TNF␣/IFN␥) led to the down-regulation of surface-expressed syndecan-1 and -4, which was associated with a significant increase of soluble syndecans and cell-associated cleavage fragments. The enhanced syndecan release was not related to gene induction of syndecans or ADAM17, but rather due to increased ADAM17 activity. Soluble syndecan-1 and -4 were also released into the bronchoalveolar fluid of mice. Treatment with TNF␣/IFN␥ increased ADAM17 activity and syndecan release in murine lungs. Both constitutive and induced syndecan shedding was prevented by the ADAM17 inhibitor. ADAM17 may therefore be an important regulator of syndecan functions on inflamed lung epithelium.Syndecans are a family of cell surface proteoglycans that play regulatory roles in wound healing, inflammation, angiogenesis, and neuronal patterning. There are four members of the syndecan family (syndecan-1, -2, -3, and -4) each consisting of an ectodomain carrying heparan sulfate-or chondroitin sulfaterich glucosaminoglycan chains, a transmembrane domain, and a short cytoplasmic tail (1). Syndecan-1 is predominantly found on endothelial and epithelial cells whereas syndecan-4 is ubiquitously expressed (2). Syndecans are also released as soluble variants that have been found in various body fluids including serum of cancer patients, wound fluid, or bronchoalveolar fluid of inflamed lungs (3-7).Recent research with syndecan-1 Ϫ/Ϫ and syndecan-4mice has demonstrated that syndecans play an important role in the regulation of inflammation and wound healing (1). Syndecans act as coreceptors modulating binding and signaling of cytokines, chemokines, and adhesion molecules. Syndecan-1 deficiency results in increased acute lung inflammation. Syndecan-1 cleavage by matrix metalloproteinase 7 (MMP7) 2 helps to establish a gradient for the chemokine KC guiding transepithelial migration of neutrophils into the airway (8). These activities can be partially reversed by soluble syndecans competing with transmembrane syndecans for their extracellular ligands (9). Soluble syndecans are generated by proteolytic shedding at the cell surface (4, 10, 11). A basal shedding activity results i...

Background: The metalloproteinases ADAM10 and ADAM17 are involved in various diseases: neurodegeneration, cancer and inflammation. Objective: The inhibition of these proteases is a promising target in the treatment of inflammation and cancer. Methods and Results: In this study, we present an improved synthesis of the ADAM10 reference inhibitor GI254023X with a higher overall yield, enhanced detection ability and increased acid stability, providing easier handling. Conclusion: This upscaled synthesis, free of diastereomeric intermediates, ensures single-batch identity, thus warranting its reproducibility in further biological investigations.

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Fused phenylcycloalkyl derivatives Q 1040 Synthesis of Bicyclic Salicylates by [3 + 3] Cyclization of 1,3-Bis(silyl enol ethers) with Cyclic 3-(Silyloxy)alk-2-en-1-ones. -(HOETTECKE, N.; REINKE, H.; FISCHER, C.; LANGER*, P.; Z. Naturforsch., B: Chem. Sci. 64 (2009) 6, 699-706; Inst. Chem., Univ. Rostock, D-18059 Rostock, Germany; Eng.) -R. Staver 44-103