Meprin A and meprin alpha generate biologically functional IL-1beta from pro-IL-1beta.
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.
Herzog
Christian
C
Central Arkansas Veterans Healthcare System, 4300 W. 7th Street, 111D, Little Rock, AR 72205, USA.
Haun
Randy S
RS
Kaushal
Varsha
V
Mayeux
Philip R
PR
Shah
Sudhir V
SV
Kaushal
Gur P
GP
D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D006877:Hydroxamic Acids / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D007672:Kidney Cortex / Q000201:enzymology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018805:Sepsis / Q000201:enzymology* / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology
D006877:Hydroxamic Acids; D007375:Interleukin-1; D053583:Interleukin-1beta; D011498:Protein Precursors; D011994:Recombinant Proteins; C043830:interleukin 1 precursor; D008666:Metalloendopeptidases; C053833:meprin A; C010531:actinonin