Prointerleukin-18 is activated by meprin beta in vitro and in vivo in intestinal inflammation.
Interleukin-18 (IL-18), a pro-inflammatory cytokine, is a key factor in inflammatory bowel disease (IBD). Caspase-1 activates this cytokine, but other proteases are likely involved in maturation. Because meprin metalloproteinases have been implicated in IBD, the interaction of these proteases with proIL-18 was studied. The results demonstrate that the meprin beta subunit of meprins A and B cleaves proIL-18 into a smaller 17-kDa product. The cleavage is at the Asn51-Asp52 bond, a site C-terminal to caspase-1 cleavage. The cleavage occurred in vitro with a Km of 1.3 microm and in Madin-Darby canine kidney cells transfected with meprin beta when proIL-18 was added to the culture medium. The product of meprin B cleavage of proIL-18 activated NF-kappaB in EL-4 cells, indicating that it was biologically active. To determine the physiological significance of the interactions of meprins with proIL-18, an experimental model of IBD was produced by administering dextran sulfate sodium (DSS) to wild-type and meprin beta knock-out (betaKO) mice, and the serum levels of active IL-18 were determined. DSS-treated meprin betaKO mice had lower levels of the active cytokine in the serum compared with wild-type mice. Furthermore, in meprin alphaKO mice, which express meprin beta but not alpha, active IL-18 was elevated in the serum of DSS-treated mice compared with wild-type mice, indicating that the meprin isoforms have opposing effects on the IL-18 levels in vivo. This study identifies proIL-18 as a biologically important substrate for meprin beta and implicates meprins in the modulation of inflammation.
Banerjee
Sanjita
S
Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Bond
Judith S
JS
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism*; D016264:Dextran Sulfate / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D020382:Interleukin-18 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D020382:Interleukin-18; D007527:Isoenzymes; D011498:Protein Precursors; D016264:Dextran Sulfate; D008666:Metalloendopeptidases; C095663:meprin B
Science. 1997 Jan 10;275(5297):206-9
8999548
J Immunol. 2004 Apr 1;172(7):4510-9
15034068
Gut. 2002 Jun;50(6):812-20
12010883
FEBS J. 2008 Sep;275(18):4490-509
18671728
J Biol Chem. 2001 Apr 20;276(16):13248-55
11278902
J Biol Chem. 2004 Aug 13;279(33):34856-64
15187079
Arthritis Res Ther. 2003;5(2):94-103
12718749
Biol Chem. 2002 Jul-Aug;383(7-8):1175-83
12437103
J Clin Immunol. 1999 Jan;19(1):1-11
10080100
Cytokine. 2005 Sep 7;31(5):394-403
16095909
Eur J Immunol. 2004 Sep;34(9):2347-55
15307167
Leukemia. 2000 Sep;14(9):1695-703
10995018
Biochem Biophys Res Commun. 1998 Mar 6;244(1):183-6
9514903
J Biol Chem. 2003 Jan 24;278(4):2522-32
12399461
J Immunol. 1999 Jul 1;163(1):143-7
10384110
FEBS Lett. 2005 Jun 13;579(15):3317-22
15943977
Biochemistry. 2002 Jul 30;41(30):9462-9
12135369
Eur J Biochem. 1999 Jan;259(1-2):496-504
9914532
World J Gastroenterol. 2005 Jan 28;11(4):605-8
15641156
J Biol Chem. 1994 May 27;269(21):15388-93
8195177
J Biol Chem. 1994 Aug 19;269(33):20952-7
8063713
J Biol Chem. 2005 Apr 8;280(14):13895-901
15695509
FEBS Lett. 1993 Dec 13;335(3):367-75
8262185
Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9745-50
15192144
Arch Biochem Biophys. 1996 Jul 1;331(1):87-94
8660687
Biochem J. 2004 Mar 1;378(Pt 2):383-9
14594449
J Invest Dermatol. 2007 May;127(5):1115-25
17195012
J Biol Chem. 2001 Jul 13;276(28):26237-42
11283002
Nat Rev Immunol. 2004 Aug;4(8):617-29
15286728
Protein Sci. 1995 Jul;4(7):1247-61
7670368
J Biol Chem. 2001 Feb 9;276(6):3820-6
11056157
J Biol Chem. 2003 Oct 24;278(43):42545-50
12888571
J Immunol. 2001 Dec 1;167(11):6568-75
11714826
Gastroenterology. 2001 Oct;121(4):875-88
11606501