Generation of biologically active interleukin-1beta by meprin B.
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.
Herzog
Christian
C
Department of Pathology, University of Arkansas for Medical Sciences, 4301 West Markham Street #753, Little Rock, AR 72205, USA.
Kaushal
Gur P
GP
Haun
Randy S
RS
D000595:Amino Acid Sequence; D001665:Binding Sites; D015153:Blotting, Western; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005822:Genetic Vectors; D006031:Glycosylation; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D007477:Ions; D007962:Leukocytes / Q000378:metabolism; D013058:Mass Spectrometry; D008666:Metalloendopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D007375:Interleukin-1; D007477:Ions; D011994:Recombinant Proteins; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D008666:Metalloendopeptidases; C095663:meprin B