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: Innate immune responses have the ability to both combat infectious microbes and drive pathological inflammation. Inflammasome complexes are a central component of these processes through their regulation of interleukin 1β (IL-1β), IL-18 and pyroptosis. Inflammasomes recognize microbial products or endogenous molecules released from damaged or dying cells both through direct binding of ligands and indirect mechanisms. The potential of the IL-1 family of cytokines to cause tissue damage and chronic inflammation emphasizes the importance of regulating inflammasomes. Many regulatory mechanisms have been identified that act as checkpoints for attenuating inflammasome signaling at multiple steps. Here we discuss the various regulatory mechanisms that have evolved to keep inflammasome signaling in check to maintain immunological balance.Nature Immunology 01/2012; 13(4):333-2. · 26.20 Impact Factor
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ABSTRACT: An expanding spectrum of acute and chronic non-infectious inflammatory diseases is uniquely responsive to IL-1β neutralization. IL-1β-mediated diseases are often called "auto-inflammatory" and the dominant finding is the release of the active form of IL-1β driven by endogenous molecules acting on the monocyte/macrophage. IL-1β activity is tightly controlled and requires the conversion of the primary transcript, the inactive IL-1β precursor, to the active cytokine by limited proteolysis. Limited proteolysis can take place extracellularly by serine proteases, released in particular by infiltrating neutrophils or intracellularly by the cysteine protease caspase-1. Therefore, blocking IL-1β resolves inflammation regardless of how the cytokine is released from the cell or how the precursor is cleaved. Endogenous stimulants such as oxidized fatty acids and lipoproteins, high glucose concentrations, uric acid crystals, activated complement, contents of necrotic cells, and cytokines, particularly IL-1 itself, induce the synthesis of the inactive IL-1β precursor, which awaits processing to the active form. Although bursts of IL-1β precipitate acute attacks of systemic or local inflammation, IL-1β also contributes to several chronic diseases. For example, ischemic injury, such as myocardial infarction or stroke, causes acute and extensive damage, and slowly progressive inflammatory processes take place in atherosclerosis, type 2 diabetes, osteoarthritis and smoldering myeloma. Evidence for the involvement of IL-1β and the clinical results of reducing IL-1β activity in this broad spectrum of inflammatory diseases are the focus of this review.European Journal of Immunology 05/2011; 41(5):1203-17. · 4.97 Impact Factor
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ABSTRACT: We have generated a monoclonal antibody (mAb), 9EG7, against mouse endothelial cells that blocks adhesion of lymphocytes to endothelial cells. Sequencing of four tryptic peptides of the purified antigen revealed its identity with the integrin chain beta 1. The only beta 1 integrin that is known to mediate cell-cell adhesion is alpha 4 beta 1 (VLA-4). This is not the integrin that is functionally defined by the mAb 9EG7 on endothelial cells. First, alpha 4 is not present on the analyzed endothelial cells. Second, mAb 9EG7 does not block the cell-adhesion function of alpha 4 beta 1 on the nonactivated mouse lymphoma L1-2. Thus, the mAb 9EG7 can functionally distinguish between different beta 1 integrins and defines a beta 1 integrin other than alpha 4 beta 1 as a newly discovered cell-cell adhesion molecule. This integrin is most likely alpha 6 beta 1, since an antibody against the alpha 6 chain blocks lymphocyte adhesion to the same degree as the mAb 9EG7, the effect of both antibodies is not additive, and the alpha 6 chain is coprecipitated with beta 1 in 9EG7 immunoprecipitations. Surprisingly, activation of alpha 4 beta 1 on L1-2 cells with phorbol ester or Mn2+ allows blocking of alpha 4 beta 1-mediated adhesion of L1-2 cells to endothelial cells with mAb 9EG7. Furthermore, only the activated alpha 4 beta 1 heterodimer, but not the unactivated complex, is detectable with 9EG7 in immunoprecipitations and by flow cytometry. Thus, mAb 9EG7 defines an epitope on integrin chain beta 1, which is accessible on the alpha 4 beta 1 heterodimer only after activation of this integrin.Proceedings of the National Academy of Sciences 11/1993; 90(19):9051-5. · 9.74 Impact Factor