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IL‐6 is a Newly‐Discovered Substrate for Meprin Metalloproteinases
Author(s) -
Keiffer Timothy Robert,
Bond Judith
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.683.5
Subject(s) - proteases , matrix metalloproteinase , inflammation , pathogenesis , cytokine , chemistry , metalloproteinase , microbiology and biotechnology , biology , immunology , enzyme , biochemistry
Meprins are unique metalloproteinases that are highly expressed in intestinal, kidney, and skin epithelial cells, and also in certain leukocytes (eg., monocytes and natural killer cells). Meprins are secreted and membrane‐bound proteases comprised of alpha and/or beta subunits. These proteases have been implicated in the pathogenesis of several inflammatory diseases such as: Inflammatory Bowel Disease (IBD), Urinary Tract Infections (UTI), Acute Renal Failure (ARF), and cancer. Previous work has demonstrated, using experimental mouse models, that meprin knock‐out mice have altered cytokine profiles compared to their wild‐type counterparts in the IBD, UTI, and ARF models. IL‐6 was one of the cytokines significantly increased in meprin alpha and alpha/beta knock‐out mice with IBD, leading us to hypothesize that IL‐6 is a meprin substrate and that meprin plays a role in modulating inflammation by inactivating IL‐6. So far, we have determined through SDS‐PAGE gel‐shift analysis that meprins do cleave IL‐6, which is the first direct in vitro evidence that IL‐6 is a meprin substrate. Additionally, the homomeric meprin A isoform fragmented IL‐6 differently than the homomeric meprin B isoforms. Subsequent studies are being done to measure the affinity of IL‐6 as a meprin substrate and determine whether meprin‐generated IL‐6 products are bioactive. (Supported by NIH DK 19691).