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Generation of biologically active interleukin-1beta by meprin B.

Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street #753, Little Rock, AR 72205, USA.
Cytokine (Impact Factor: 2.87). 10/2005; 31(5):394-403. DOI: 10.1016/j.cyto.2005.06.012
Source: PubMed

ABSTRACT Interleukin-1beta (IL-1beta) is a proinflammatory cytokine that is synthesized as an inactive precursor molecule that must be proteolytically processed to generate the biologically active form. Maturation of the precursor is primarily performed by caspase-1, an intracellular cysteine protease; however, processing by other proteases has been described. Meprins are cell surface and secreted metalloproteases expressed by renal and intestinal brush-border membranes, leukocytes, and cancer cells. In this study we show that purified recombinant meprin B can process the interleukin-1beta precursor to a biologically active form. Amino-terminal sequencing and mass spectrometry analysis of the product of digestion by activated meprin B determined that proteolytic cleavage resulted in an additional six amino acids relative to the site utilized by caspase-1. The biological activity of the meprin B-cleaved cytokine was confirmed by measuring the proliferative response of helper T-cells. These results suggest that meprin may play an important role in activation of this proinflammatory cytokine in various pathophysiological conditions.

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    • "The substrates analyzed are those listed in the paper by (Bertenshaw, Turk et al. 2001). Listed below are substrates and inhibitors of meprin subunits (Bertenshaw, Turk et al. 2001; Kruse, Becker et al. 2004; Herzog, Kaushal et al. 2005; Hirano, Ma et al. 2005). "
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    • "However, this does not apply to promeprin b, whose activation site appears to be inaccessible for peptidases larger than trypsin (Becker et al., 2003). There are various in vitro observations of a cleavage of basement membrane proteins (e.g., collagen IV, nidogen-1, and fibronectin), protein kinases, growth factors, cytokines (interleukin-1b), and other bioactive peptides by meprin, but both subunits exhibit markedly different cleavage specificities (Choudry and Kenny, 1991; Kaushal et al., 1994; Chestukhin et al., 1997; Kö hler et al., 2000; Bertenshaw et al., 2001; Kruse et al., 2004; Herzog et al., 2005). Meanwhile, a broader range of sites of meprin expression other than kidney and intestine has been discovered, which varies between species and between developmental stages within a species. "
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