Generation of biologically active interleukin-1beta by meprin B.
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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ABSTRACT: Not Available Bibtex entry for this abstract Preferred format for this abstract (see Preferences) Find Similar Abstracts: Use: Authors Title Return: Query Results Return items starting with number Query Form Database: Astronomy Physics arXiv e-printsPLoS ONE 01/2008; 3(5). · 3.53 Impact Factor
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ABSTRACT: Meprin A, comprised of α and β subunits, is a membrane-associated neutral metalloendoprotease that belongs to the astacin family of zinc endopeptidases. It was first discovered as an azocasein and benzoyl-L-tyrosyl-p-aminobenzoic acid hydrolase in the brush-border membranes of proximal tubules and intestines. Meprin isoforms are now found to be widely distributed in various organs (kidney, intestines, leukocytes, skin, bladder, and a variety of cancer cells) and are capable of hydrolyzing and processing a large number of substrates including extracellular matrix proteins, cytokines, adherens junction proteins, hormones, bioactive peptides, and cell surface proteins. The ability of meprin A to cleave various substrates sheds new light on the functional properties of this enzyme including matrix remodeling, inflammation, and cell-cell and cell-matrix processes. Following ischemia-reperfusion (IR)- and cisplatin-induced acute kidney injury (AKI), meprin A is redistributed toward the basolateral plasma membrane and the cleaved form of meprin A is excreted in the urine. These studies suggest that altered localization and shedding of meprin A in places other than the apical membranes may be deleterious in vivo in acute tubular injury. These studies also provide new insight on the importance of a sheddase involved in the release of membrane-associated meprin A under pathological conditions. Meprin A is injurious to the kidney during AKI, as meprin A-knockout mice and meprin inhibition provide protective roles and improve renal function. Meprin A, therefore, plays an important role in AKI and potentially is a unique target for therapeutic intervention during AKI.AJP Renal Physiology 02/2013; · 4.42 Impact Factor
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ABSTRACT: Inflammatory diseases are a significant burden on global healthcare systems, and tackling these diseases is a major focus of modern medicine. Key to many inflammatory diseases is the cytokine, Interleukin-1 (IL-1). Due to its apical role in initiating the inflammatory response, dysregulated IL-1 signalling results in a number of pathologies. Treatment of inflammatory diseases with anti-IL-1 therapies has offered many therapeutic benefits, however current therapies are protein based, with all the accompanying limitations. The non-conventional pathways involved in IL-1 signalling provide a number of potential therapeutic targets for clinical intervention and this has led to the exploitation of a number of model organisms for the study of IL-1 biology. Murine models have long been used to study IL-1 processing and release, but do not allow direct visualisation in vivo. Recently, fish models have emerged as genetically tractable and optically transparent inflammatory disease models. These models have raised questions on the evolutionary origins of the IL-1 family and the conservation in its processing and activation. Here we review the current understanding of IL-1 evolution in fish and discuss the study of IL-1 processing in these models.Developmental and comparative immunology 03/2014; · 3.29 Impact Factor