Generation of Biologically Active IL-1β by Matrix Metalloproteinases: A Novel Caspase-1-Independent Pathway of IL-1β Processing

作者：Uwe Schönbeck, François Mach, Peter Libby · 发表于：The Journal of Immunology · 年份：1998 · DOI：10.4049/jimmunol.161.7.3340 · 被引用次数：603 · 研究领域：Protease and Inhibitor Mechanisms、Streptococcal Infections and Treatments、Blood Coagulation and Thrombosis Mechanisms

Abstract Biologic activity of IL-1β requires processing of the inactive precursor, a function generally ascribed to IL-1β-converting enzyme (caspase-1). However, alternative mechanisms of IL-1β activation have been postulated in local inflammatory reactions. Expression of IL-1β and matrix metalloproteinases (MMPs) frequently occurs simultaneously at sites of inflammation. We describe here that stromelysin-1 (MMP-3), as well as the gelatinases A (MMP-2) and B (MMP-9), processes recombinant human IL-1β precursor (pIL-1β) into biologically active forms. Detection of both pIL-1β processing and biologic IL-1β activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1β by stromelysin-1 required coincubation for at least 1 h, and biologic activity faded after 8 h to 24 h. Gelatinase A was less effective in processing pIL-1β, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1β within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1β with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1β. None of the MMPs processed the second isoform of IL-1, IL-1α. The present study indicates a biphasic regulation of IL-1β activity by MMPs: a caspase-1-independent pathway of IL-1β activation and inhibition of IL-1β activity by degrading the mature ...