IL-1β enhances cell adhesion to degraded fibronectin.
ABSTRACT IL-1β is a prominent proinflammatory cytokine that mediates degradation of extracellular matrix proteins through increased expression of matrix metalloproteinases, which involves a signaling pathway in adherent cells that is restricted by focal adhesions. Currently, the mechanism by which IL-1β affects cell adhesion to matrix proteins is not defined, and it is not known whether degraded matrix proteins affect IL-1β signaling. We examined adhesion-related IL-1β signaling in fibroblasts attaching to native or MMP3-degraded fibronectin. IL-1β increased cell attachment, resistance to shear force and the numbers of focal adhesions containing activated β(1) integrins. IL-1β-enhanced attachment required FAK, kindlins 1/2, and talin. MMP3-degraded fibronectin-inhibited IL-1β-enhanced cell adhesion and promoted spontaneous ERK activation that was independent of IL-1β treatment. We conclude that IL-1β enhances the adhesion of anchorage-dependent cells to MMP3-degraded fibronectin, which, in turn, is associated with deregulated cellular responses to IL-1β. These data point to a novel role of IL-1β as a proadhesive signaling molecule in inflammation that employs kindlins and talin to regulate adhesion.-Rajshankar, D., Downey, G. P., McCulloch, C. A. IL-1β enhances cell adhesion to degraded fibronectin.
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ABSTRACT: Type 2 diabetes involves defective insulin secretion with islet inflammation governed in part by IL-1beta. Prolonged exposure of islets to high concentrations of IL-1beta (>24 h, 20 ng/ml) impairs beta cell function and survival. Conversely, exposure to lower concentrations of IL-1beta for >24 h improves these same parameters. The impact on insulin secretion of shorter exposure times to IL-1beta and the underlying molecular mechanisms are poorly understood and were the focus of this study. Treatment of rat primary beta cells as well as rat or human whole islets with 0.1 ng/ml IL-1beta for 2 h increased glucose-stimulated (but not basal) insulin secretion whereas 20 ng/ml was without effect. Similar differential effects of IL-1beta depending on concentration were observed after 15 min KCl stimulation but prevented by diazoxide. Studies on sorted rat beta cells indicated that the enhancement of stimulated secretion by 0.1 ng/ml IL-1beta was mediated by the NF-кB pathway and c-Jun/JNK pathway acting in parallel to elicit focal adhesion remodeling and the phosphorylation of paxillin independently of upstream regulation by focal adhesion kinase. Since the beneficial effect of IL-1beta was dependent in part upon transcription, gene expression was analyzed by RNAseq. There were 18 genes regulated uniquely by 0.1 but not 20 ng/ml IL-1beta, which are mostly involved in transcription and apoptosis. These results indicate that 2 h exposure of beta cells to a low but not a high concentration of IL-1beta enhances glucose-stimulated insulin secretion through focal adhesion and actin remodeling as well as modulation of gene expression. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.The Journal of biological chemistry. 01/2015;
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ABSTRACT: Collagen degradation by phagocytosis is essential for physiological collagen turnover and connective tissue homeostasis. The rate limiting step of phagocytosis is the binding of specific adhesion receptors, which include the integrins and discoidin domain receptors (DDR), to fibrillar collagen. While previous data suggest that these two receptors interact, the functional nature of these interactions is not defined. In mouse and human fibroblasts we examined the effects of DDR1 knockdown and over-expression on β1 integrin subunit function. DDR1 expression levels were positively associated with enhanced contraction of floating and attached collagen gels, increased collagen binding and increased collagen remodeling. In DDR1 over-expressing cells compared with control cells, there were increased numbers, area and length of focal adhesions immunostained for talin, paxillin, vinculin and activated β1 integrin. After treatment with the integrin-cleaving protease jararhagin, in comparison to controls, DDR1 over-expressing cells exhibited increased β1 integrin cleavage at the cell membrane, indicating that DDR1 over-expression affected the access and susceptibility of cell-surface β1 integrin to the protease. DDR1 over-expression was associated with increased glycosylation of the β1 integrin subunit, which when blocked by deoxymannojirimycin, reduced collagen binding. Collectively these data indicate that DDR1 regulates β1 integrin interactions with fibrillar collagen, which positively impacts the binding step of collagen phagocytosis and collagen remodeling.Biology open. 11/2013; 2(11):1148-59.
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ABSTRACT: The matrix metalloproteinases (MMPs) encompass a family of zinc-dependent endopeptidases that are secreted into the extracellular environment or remain bound to the cell surface. While MMPs were initially identified based on their ability to degrade collagen and other components of the extracellular matrix, recent studies indicate that their non-degradative functions are physiologically paramount. In particular, MMPs are now known to participate in diverse physiological processes that control key aspects of inflammatory and immune responses and neoplasia, in part by selective triggering of cellular signaling pathways via limited proteolytic processing of extracellular and membrane-associated proteins, including cytokines and cell surface receptors. Herein, we focus on the unique roles of MMP-3 (stromelysin-1) in acute lung injury and repair, pulmonary fibrosis, and lung cancer.Expert Review of Respiratory Medicine 05/2014;