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J Immunol. 1998 Oct 1;161(7):3340-6.

Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing.

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  • 1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.


Biologic activity of IL-1 beta requires processing of the inactive precursor, a function generally ascribed to IL-1 beta-converting enzyme (caspase-1). However, alternative mechanisms of IL-1 beta activation have been postulated in local inflammatory reactions. Expression of IL-1 beta 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-1 beta precursor (pIL-1 beta) into biologically active forms. Detection of both pIL-1 beta processing and biologic IL-1 beta activity demonstrated different processing capacities of the respective MMPs. Conversion of pIL-1 beta 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-1 beta, requiring at least 24 h of coincubation. In contrast, gelatinase B processed pIL-1 beta within minutes, resulting in immunoreactive products as well as biologic activity stable for 72 h. In addition, prolonged incubation of mature IL-1 beta with stromelysin-1, and to a lesser extent also with gelatinases, but not with interstitial collagenase, resulted in the degradation of mature IL-1 beta. None of the MMPs processed the second isoform of IL-1, IL-1 alpha. The present study indicates a biphasic regulation of IL-1 beta activity by MMPs: a caspase-1-independent pathway of IL-1 beta activation and inhibition of IL-1 beta activity by degrading the mature cytokine. The balance of the respective MMPs and pIL-1 beta might regulate the long term appearance of IL-1 beta activity at sites of acute or chronic inflammation.

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