PMID- 11698289
OWN - NLM
STAT- MEDLINE
DCOM- 20011221
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 98
IP  - 10
DP  - 2001 Nov 15
TI  - Receptor engagement by viral interleukin-6 encoded by Kaposi sarcoma-associated 
      herpesvirus.
PG  - 3042-9
AB  - Receptor usage by viral interleukin-6 (vIL-6), a virokine encoded by Kaposi 
      sarcoma- associated herpesvirus, is an issue of controversy. Recently, the 
      crystal structure of vIL-6 identified vIL-6 sites II and III as directly binding 
      to glycoprotein (gp)130, the common signal transducer for the IL-6 family of 
      cytokines. Site I of vIL-6, however, comprising the outward helical face of 
      vIL-6, where human IL-6 (hIL-6) would interact with the specific alpha-chain IL-6 
      receptor (IL-6R), is accessible and not occupied by gp130. This study examined 
      whether this unused vIL-6 surface is available for IL-6R binding. By 
      enzyme-linked immunosorbent assay, vIL-6 bound to soluble gp130 (sgp130) but not 
      to soluble IL-6R (sIL-6R). Using plasmon surface resonance, vIL-6 bound to sgp130 
      with a dissociation constant of 2.5 microM, corresponding to 1000-fold lower 
      affinity than that of hIL-6/sIL-6R complex for gp130. sIL-6R neither bound to 
      vIL-6 nor affected vIL-6 binding to gp130. In bioassays, vIL-6 activity was 
      neutralized by 4 monoclonal antibodies (mAbs) recognizing a domain within vIL-6 
      site I, mapped to the C-terminal part of the AB-loop and the beginning of helix 
      B. The homologous region in hIL-6 participates in site I binding to IL-6R. In 
      addition, binding of vIL-6 to sgp130 was interfered with specifically by the 4 
      neutralizing anti-vIL-6 mAbs. Based on the vIL-6 crystal structure, the vIL-6 
      neutralizing mAbs map outside the binding interface to gp130, suggesting that 
      they either produce allosteric changes or block necessary conformational changes 
      in vIL-6 preceding its binding to gp130. These results document that vIL-6 does 
      not bind IL-6R and suggest that conformational change may be critical to vIL-6 
      function.
FAU - Aoki, Y
AU  - Aoki Y
AD  - Medicine Branch, National Cancer Institute, National Institutes of Health, 
      Bethesda, MD 20892, USA. aokiy@mail.nih.gov
FAU - Narazaki, M
AU  - Narazaki M
FAU - Kishimoto, T
AU  - Kishimoto T
FAU - Tosato, G
AU  - Tosato G
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antigens, CD)
RN  - 0 (Epitopes)
RN  - 0 (IL6ST protein, human)
RN  - 0 (Il6st protein, mouse)
RN  - 0 (Interleukin-6)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, Interleukin-6)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Viral Proteins)
RN  - 133483-10-0 (Cytokine Receptor gp130)
SB  - IM
MH  - Allosteric Regulation
MH  - Animals
MH  - Antibodies, Monoclonal/biosynthesis/immunology
MH  - Antigens, CD/chemistry/metabolism
MH  - Blotting, Western
MH  - Crystallography, X-Ray
MH  - Cytokine Receptor gp130
MH  - Epitopes/immunology
MH  - Herpesvirus 8, Human/*genetics
MH  - Humans
MH  - Interleukin-6/chemistry/genetics/immunology/*metabolism
MH  - Macromolecular Substances
MH  - Membrane Glycoproteins/chemistry/metabolism
MH  - Mice
MH  - Models, Molecular
MH  - Neutralization Tests
MH  - Protein Binding
MH  - Protein Conformation
MH  - Receptors, Interleukin-6/chemistry/*metabolism
MH  - Recombinant Fusion Proteins/chemistry
MH  - Solubility
MH  - Structure-Activity Relationship
MH  - Surface Plasmon Resonance
MH  - Viral Proteins/chemistry/genetics/immunology/*metabolism
EDAT- 2001/11/08 10:00
MHDA- 2002/01/05 10:01
CRDT- 2001/11/08 10:00
PHST- 2001/11/08 10:00 [pubmed]
PHST- 2002/01/05 10:01 [medline]
PHST- 2001/11/08 10:00 [entrez]
AID - S0006-4971(20)56839-0 [pii]
AID - 10.1182/blood.v98.10.3042 [doi]
PST - ppublish
SO  - Blood. 2001 Nov 15;98(10):3042-9. doi: 10.1182/blood.v98.10.3042.