Meprin A and B metalloproteinases both hydrolyze interleukin‐6

Meprin A and B metalloproteinases both hydrolyze interleukin‐6 Meprins have been implicated in the pathogenesis of several diseases such as Inflammatory Bowel Disease (IBD) and Acute Renal Failure (ARF). Previous work with meprin knock‐out (KO) mice in experimental models for IBD and ARF showed that meprin KO mice have altered cytokine profiles in these models. Interleukin‐6 (IL‐6) was one of the cytokines significantly increased in meprin α and α/β knock‐out mice with IBD, and decreased in meprin β mice with ARF. The purpose of this study was to determine if there was any difference of IL‐6 processing by meprin A and B isoforms. Cleavage of recombinant human IL‐6 by meprins was monitored by densitometry on SDS‐PAGE. Kinetic values were determined by non‐regression analysis. Our results show that IL‐6 is a substrate for both homomeric meprin A and B isoforms and that both isoforms generate identical, stable IL‐6 products. Meprin A and B had similar Michaelis constants (K m ) for IL‐6, 8 and 14 μM respectively, indicating that meprins have higher affinities towards IL‐6 than most known meprin substrates. The specificity constants (k cat /K m ) were 1 × 10 6 and 4 × 10 6 (M −1 sec −1 ) for meprin A and B, respectively. Mass spectrometry analysis of meprin A and B processed IL‐6 show these products lack five residues from the C‐terminus; this result predicts a decrease in bioactivity. The data support our contention that meprins modulate the immune response by decreasing cytokine biological activity. Supported by NIH DK 19691 and PA Tobacco Settlement Funds.