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Increased levels of IL-6 are documented in asthma, but its contribution to the pathology is unknown. Asthma is characterized by airway wall thickening due to increased extracellular matrix deposition, inflammation, angiogenesis, and airway smooth muscle (ASM) mass. IL-6 binds to a specific membrane-bound receptor, IL-6 receptor-α (mIL-6Rα, and subsequently to the signaling protein gp130. Alternatively, IL-6 can bind to soluble IL-6 recpetor-s (sIL-6Rα) to stimulate membrane receptor-deficient cells, a process called trans-signaling. We discovered that primary human ASM cells do not express mIL-6Rα and, therefore, investigated the effect of IL-6 trans-signaling on the pro-remodeling phenotype of ASM. ASM required sIL-6Rα to activate signal transducer and activator 3, with no differences observed between cells from asthmatic subjects compared with controls. Further analysis revealed that IL-6 alone or with sIL-6Rα did not induce release of matrix-stimulating factors (including connective tissue growth factor, fibronectin, or integrins) and had no effect on mast cell adhesion to ASM or ASM proliferation. However, in the presence of sIL-6Rα, IL-6 increased eotaxin and VEGF release and may thereby contribute to local inflammation and vessel expansion in airway walls of asthmatic subjects. As levels of sIL-6Rα are increased in asthma, this demonstration of IL-6 trans-signaling in ASM has relevance to the development of airway remodeling. [ABSTRACT FROM AUTHOR]

Airway remodeling describes the structural changes that occur in the asthmatic airway that include airway smooth muscle hyperplasia, increases in vascularity due to angiogenesis, and thickening of the basement membrane. Our aim in this study was to examine the effect of transforming growth factor-β on the release of connective tissue growth factor and vascular endothelial growth factor from human airway smooth muscle cells derived from asthmatic and nonasthmatic patients. In addition we studied the immunohistochemical localization of these cytokines in the extracellular matrix after stimulating bronchial rings with transforming growth factor-β. Connective tissue growth factor and vascular endothelial growth factor were released from both cell types and colocalized in the surrounding extracellular matrix. Prostaglandin E2 inhibited the increase in connective tissue growth factor mRNA but augmented the release of vascular endothelial growth factor. Matrix metalloproteinase-2 decreased the amount of connective tissue growth factor and vascular endothelial growth factor, but not fibronectin deposited in the extracellular matrix. This report provides the first evidence that connective tissue growth factor may anchor vascular endothelial growth factor to the extracellular matrix and that this deposition is decreased by matrix metalloproteinase-2 and prostaglandin E2. This relationship has the potential to contribute to the changes that constitute airway remodeling, therefore providing a novel focus for therapeutic intervention in asthma. [ABSTRACT FROM AUTHOR]