Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing.
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.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Schönbeck
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Mach
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Libby
D000818:Animals; D020170:Caspase 1; D002460:Cell Line; D017364:Collagenases / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D005110:Extracellular Space / Q000201:enzymology; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9; D008666:Metalloendopeptidases / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008970:Molecular Weight; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes; D013997:Time Factors
D007375:Interleukin-1; D011498:Protein Precursors; D011994:Recombinant Proteins; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9