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.
"Meprin A and filamin C were also elevated in patients with incomplete presentations of KD, suggesting that these markers may be used to improve the diagnosis of incomplete presentations of KD. Similarly, meprin A is a protease that regulates a variety of inflammatory cytokines, including biologically active IL-1b, a key pro-inflammatory cytokine (Herzog et al, 2005), polymorphisms of which have been associated with resistance to treatment of KD (Weng et al, 2010). Thus, meprin A may contribute to the initiation, propagation or compensatory "
[Show abstract][Hide abstract] ABSTRACT: Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Absence of definitive diagnostic markers limits the accuracy of clinical evaluations of suspected KD with significant increases in morbidity. In turn, incomplete understanding of its molecular pathogenesis hinders the identification of rational targets needed to improve therapy. We used high-accuracy mass spectrometry proteomics to analyse over 2000 unique proteins in clinical urine specimens of patients with KD. We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A. Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients. Meprin A and filamin C exhibited superior diagnostic performance as compared to currently used markers of disease in a blinded case-control study of 107 patients with suspected KD, with receiver operating characteristic areas under the curve of 0.98 (95% confidence intervals [CI] of 0.97-1 and 0.95-1, respectively). Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD. In all, urine proteome profiles revealed novel candidate molecular markers of KD, including filamin C and meprin A that exhibit excellent diagnostic performance. These disease markers may improve the diagnostic accuracy of clinical evaluations of children with suspected KD, lead to the identification of novel therapeutic targets, and allow the development of a biological classification of Kawasaki disease.
EMBO Molecular Medicine 02/2013; 5(2). DOI:10.1002/emmm.201201494 · 8.67 Impact Factor
"Meprin α is secreted into the intestinal lumen or it is retained at the brush border membrane in association with transmembrane meprin β . A variety of substrates that include extracellular matrix proteins, growth factors, and cytokines , , , , ,  are cleaved by meprins whose biological function however is still poorly understood. The location and the proteolytic activity of meprins are evidence of functions at the interface of the host and the luminal environment. "
[Show abstract][Hide abstract] ABSTRACT: Ileal lesions in Crohn's disease (CD) patients are colonized by pathogenic adherent-invasive Escherichia coli (AIEC) able to adhere to and invade intestinal epithelial cells (IEC), and to survive within macrophages. The interaction of AIEC with IEC depends on bacterial factors mainly type 1 pili, flagella, and outer membrane proteins. In humans, proteases can act as host defence mechanisms to counteract bacterial colonization. The protease meprin, composed of multimeric complexes of the two subunits alpha and beta, is abundantly expressed in IECs. Decreased levels of this protease correlate with the severity of the inflammation in patients with inflammatory bowel disease. The aim of the present study was to analyze the ability of meprin to modulate the interaction of AIEC with IECs. In patients with ileal CD we observed decreased levels of meprins, in particular that of meprin β. Dose-dependent inhibition of the abilities of AIEC strain LF82 to adhere to and invade intestinal epithelial T84 cells was observed when bacteria were pre-treated with both exogenous meprin α and meprin β. Dose-dependent proteolytic degradation of type 1 pili was observed in the presence of active meprins, but not with heat-inactivated meprins, and pretreatment of AIEC bacteria with meprins impaired their ability to bind mannosylated host receptors and led to decreased secretion of the pro-inflammatory cytokine IL-8 by infected T84 cells. Thus, decreased levels of protective meprins as observed in CD patients may contribute to increased AIEC colonization.
PLoS ONE 06/2011; 6(6):e21199. DOI:10.1371/journal.pone.0021199 · 3.23 Impact Factor
"Outside the intestine, there is selective activation of meprin α by plasmin , and of meprin β by tissue kallikrein-related peptidase 4 (KLK4) , respectively. Upon secretion into the extracellular matrix (ECM), meprins are able to cleave a number of ECM proteins like laminin, fibronectin, collagen IV and nidogen, peptide hormones like bradykinin , , as well as cytokines and growth factors like TGF-α, interleukin-1β and interleukin-18 , , , . "
[Show abstract][Hide abstract] ABSTRACT: Meprin metalloproteases are thought to be involved in basic physiological functions such as cell proliferation and tissue differentiation. However, the specific functions of these enzymes are still ambiguous, although a variety of growth factors and structural proteins have been identified as meprin substrates. The discovery of meprins alpha(1), alpha(2) and beta in teleost fish provided the basis for uncovering their physiological functions by gene silencing in vivo.
A Morpholino knockdown in zebrafish embryos targeting meprin alpha(1) and beta mRNA caused defects in general tissue differentiation. But meprin alpha(2) morphants were affected more specifically and showed severe failures in the formation of the vascular system provoking the hypothesis of a pro-angiogenic effect. The blood circulation was largely diminished resulting in erythrocyte accumulation. These phenotypes mimic a previously described VEGF-A morphant, revealing a possible role of meprin alpha in VEGF-A activation. Indeed, human recombinant meprin alpha processed the vascular endothelial growth factor-A (VEGF-A) specifically, revealing the same cleavage products detectable for VEGF from zebrafish whole lysate.
Our results demonstrate that meprin metalloproteases are important for cell differentiation and proliferation already during embryogenesis, predominantly by the activation of growth factors. Thus, we conclude that meprins play a significant role in VEGF-A processing, subsequently regulating angiogenesis. Therefore, meprin alpha might be a new therapeutic target in cardiovascular diseases or in tumor growth inhibition.
PLoS ONE 01/2010; 5(1):e8835. DOI:10.1371/journal.pone.0008835 · 3.23 Impact Factor
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