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Title 

Site specific mutations in the mature form of human IL-18 with enhanced biological activity and decreased neutralization by IL-18 binding protein

Authors 

Soo Hyun M KimT AzamDo Young YoonL L ReznikovDanlela NovickMenachem RubinsteinCharles Dinarello

Publisher 

National Academy of Sciences

Issue Date 

2001

Citation 

Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 6, pp. 3304-3309

Keywords 

binding proteininterleukin 18interleukin 18 binding proteinantiinflammatory activitybinding affinitypoint mutationprotein bindingsite directed mutagenesisglycoproteinshumans

Abstract 

IL-18 can be considered a proinflammatory cytokine mediating disease as well as an immunostimulatory cytokine that is important for host defense against infection and cancer. The high-affinity, constitutively expressed, and circulating IL-18 binding protein (IL-18BP), which competes with cell surface receptors for IL-18 and neutralizes IL-18 activity, may act as a natural antiinflammatory as well as immunosuppressive molecule. In the present studies, the IL-18 precursor caspase-1 cleavage site was changed to a factor Xa site, and, after expression in Escherichia coli, mature IL-18 was generated by factor Xa cleavage. Mature IL-18 generated by factor Xa cleavage was fully active. Single point mutations in the mature IL-18 peptide were made, and the biological activities of the wild-type (WT) IL-18 were compared with those of the mutants. Mutants E42A and K89A exhibited 2-fold increased activity compared with WT IL-18. A double mutant, E42A plus K89A, exhibited 4-fold greater activity. Unexpectedly, IL-18BP failed to neutralize the double mutant E42A plus K89A compared with WT IL-18. The K89A mutant was intermediate in being neutralized by IL-18BP, whereas neutralization of the E42A mutant was comparable to that in the WT IL-18. The identification of E42 and K89 in the mature IL-18 peptide is consistent with previous modeling studies of IL-18 binding to IL-18BP and explains the unusually high affinity of IL-18BP for IL-18.

ISSN 

0027-8424

Link 

http://dx.doi.org/10.1073/pnas.051634098

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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