Meprin A and meprin alpha generate biologically functional IL-1beta from pro-IL-1beta.

Christian Herzog, Randy S Haun, Varsha Kaushal, Philip R Mayeux, Sudhir V Shah, Gur P Kaushal, Christian Herzog, Randy S Haun, Varsha Kaushal, Philip R Mayeux, Sudhir V Shah, Gur P Kaushal

Index: Biochem. Biophys. Res. Commun. 379(4) , 904-8, (2009)

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Abstract

The present study demonstrates that both oligomeric metalloendopeptidase meprin A purified from kidney cortex and recombinant meprin alpha are capable of generating biologically active IL-1beta from its precursor pro-IL-1beta. Amino-acid sequencing analysis reveals that meprin A and meprin alpha cleave pro-IL-1beta at the His(115)-Asp(116) bond, which is one amino acid N-terminal to the caspase-1 cleavage site and five amino acids C-terminal to the meprin beta site. The biological activity of the pro-IL-1beta cleaved product produced by meprin A, determined by proliferative response of helper T-cells, was 3-fold higher to that of the IL-1beta product produced by meprin beta or caspase-1. In a mouse model of sepsis induced by cecal ligation puncture that results in elevated levels of serum IL-1beta, meprin inhibitor actinonin significantly reduces levels of serum IL-1beta. Meprin A and meprin alpha may therefore play a critical role in the production of active IL-1beta during inflammation and tissue injury.