PMID- 10655506
OWN - NLM
STAT- MEDLINE
DCOM- 20000302
LR  - 20191210
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 3
DP  - 2000 Feb 1
TI  - Structural requirements of six naturally occurring isoforms of the IL-18 binding 
      protein to inhibit IL-18.
PG  - 1190-5
AB  - A novel, constitutively expressed and secreted IL-18 binding protein (IL-18BP)
      neutralizes IL-18 and thereby suppresses the production of IFN-gamma, resulting
      in reduced T-helper type 1 immune responses. In the present study, four human and
      two mouse isoforms, resulting from mRNA splicing and found in various cDNA
      libraries, were expressed, purified, and assessed for binding and neutralization 
      of IL-18 biological activities. Human IL-18BP isoform a (IL-18BPa) exhibited the 
      greatest affinity for IL-18 with a rapid on-rate, a slow off-rate, and a
      dissociation constant (K(d)) of 399 pM. IL-18BPc shares the Ig domain of IL-18BPa
      except for the 29 C-terminal amino acids; the K(d) of IL-18BPc is 10-fold less
      (2.94 nM). Nevertheless, IL-18BPa and IL-18BPc neutralize IL-18 >95% at a molar
      excess of two. IL-18BPb and IL-18BPd isoforms lack a complete Ig domain and lack 
      the ability to bind or neutralize IL-18. Murine IL-18BPc and IL-18BPd isoforms,
      possessing the identical Ig domain, also neutralize >95% murine IL-18 at a molar 
      excess of two. However, murine IL-18BPd, which shares a common C-terminal motif
      with human IL-18BPa, also neutralizes human IL-18. Molecular modeling identified 
      a large mixed electrostatic and hydrophobic binding site in the Ig domain of
      IL-18BP, which could account for its high affinity binding to the ligand. It is
      likely that preferential secretion of functional and nonfunctional isoforms of
      IL-18BP affect the immune response.
FAU - Kim, S H
AU  - Kim SH
AD  - University of Colorado Health Sciences Center, Denver, CO 80262, USA.
FAU - Eisenstein, M
AU  - Eisenstein M
FAU - Reznikov, L
AU  - Reznikov L
FAU - Fantuzzi, G
AU  - Fantuzzi G
FAU - Novick, D
AU  - Novick D
FAU - Rubinstein, M
AU  - Rubinstein M
FAU - Dinarello, C A
AU  - Dinarello CA
LA  - eng
SI  - GENBANK/AF215907
GR  - P30 CA046934/CA/NCI NIH HHS/United States
GR  - A-15614/PHS HHS/United States
GR  - AI-2532359/AI/NIAID NIH HHS/United States
GR  - CA 46934/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Interleukin-18)
RN  - 0 (Protein Isoforms)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (interleukin-18 binding protein)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - COS Cells
MH  - Cell Line
MH  - Chlorocebus aethiops
MH  - Glycoproteins/*chemistry/pharmacology
MH  - Humans
MH  - Immune Tolerance
MH  - Intercellular Signaling Peptides and Proteins
MH  - Interleukin-18/*antagonists & inhibitors/metabolism
MH  - Mice
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein Isoforms/*chemistry/pharmacology
MH  - Recombinant Fusion Proteins/chemistry/metabolism
MH  - Sequence Alignment
MH  - Species Specificity
MH  - Structure-Activity Relationship
PMC - PMC15564
EDAT- 2000/02/03 09:00
MHDA- 2000/03/04 09:00
CRDT- 2000/02/03 09:00
PHST- 2000/02/03 09:00 [pubmed]
PHST- 2000/03/04 09:00 [medline]
PHST- 2000/02/03 09:00 [entrez]
AID - 10.1073/pnas.97.3.1190 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1190-5. doi: 10.1073/pnas.97.3.1190.