PMID- 18786924
OWN - NLM
STAT- MEDLINE
DCOM- 20090107
LR  - 20211020
IS  - 0021-9258 (Print)
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
VI  - 283
IP  - 46
DP  - 2008 Nov 14
TI  - Prointerleukin-18 is activated by meprin beta in vitro and in vivo in intestinal 
      inflammation.
PG  - 31371-7
LID - 10.1074/jbc.M802814200 [doi]
AB  - 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.
FAU - Banerjee, Sanjita
AU  - Banerjee S
AD  - Department of Biochemistry and Molecular Biology, Pennsylvania State University 
      College of Medicine, Hershey, Pennsylvania 17033, USA.
FAU - Bond, Judith S
AU  - Bond JS
LA  - eng
GR  - DK19691/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080911
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Interleukin-18)
RN  - 0 (Isoenzymes)
RN  - 0 (Protein Precursors)
RN  - 9042-14-2 (Dextran Sulfate)
RN  - EC 3.4.24.- (Metalloendopeptidases)
RN  - EC 3.4.24.63 (meprin B)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Line
MH  - Colitis/chemically induced/*metabolism
MH  - Dextran Sulfate/pharmacology
MH  - Dogs
MH  - Humans
MH  - Interleukin-18/chemistry/genetics/*metabolism
MH  - Isoenzymes/metabolism
MH  - Kinetics
MH  - Male
MH  - Metalloendopeptidases/deficiency/genetics/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Molecular Sequence Data
MH  - Protein Binding
MH  - Protein Precursors/genetics/*metabolism
MH  - Rats
PMC - PMC2581578
EDAT- 2008/09/13 09:00
MHDA- 2009/01/08 09:00
PMCR- 2009/11/14
CRDT- 2008/09/13 09:00
PHST- 2008/09/13 09:00 [pubmed]
PHST- 2009/01/08 09:00 [medline]
PHST- 2008/09/13 09:00 [entrez]
PHST- 2009/11/14 00:00 [pmc-release]
AID - S0021-9258(20)56877-4 [pii]
AID - 31371 [pii]
AID - 10.1074/jbc.M802814200 [doi]
PST - ppublish
SO  - J Biol Chem. 2008 Nov 14;283(46):31371-7. doi: 10.1074/jbc.M802814200. Epub 2008 
      Sep 11.