A Poxvirus Protein That Binds to and Inactivates IL-18, and Inhibits NK Cell Response

Born, Teresa L.; Morrison, Lynda A.; Esteban, David J.; VandenBos, Tim; Thebeau, Lydia G.; Chen, N; Spriggs, Melanie K.; Sims, John E.; Buller, R. Mark

doi:10.4049/jimmunol.164.6.3246

Cited by 163 publications

(113 citation statements)

References 53 publications

Supporting

Mentioning

109

Contrasting

Order By: Relevance

“…The ectromelia poxvirus p13 protein, which is homologous to IL-18BP, binds human IL-18 and inhibits its activity in vitro. Mice infected with a p13 deletion mutant virus exhibited decreased levels of infectivity (26).…”

Section: Discussionmentioning

confidence: 99%

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

Kim

Azam

Yoon

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Kim

Azam

Yoon

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The IL-18 bp:Fc fusion molecule was generated by joining the entire IL-18 bp cDNA to the CH2 and CH3 domains of human IgG1 in an expression plasmid, as described [41]. In vitro bioassays were used to confirm that recombinant IL-18 bp:Fc blocked the bioactivity of both human and murine IL-18.…”

Section: Il-18bp:fc Construct and Cytokine Measurementsmentioning

confidence: 99%

Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

Nicoletti¹,

Marco²,

Papaccio³

et al. 2003

Eur J Immunol

View full text Add to dashboard Cite

IL-18 is a cytokine structurally and functionally related to IL-1 that, in synergy with IL-12, stimulates the synthesis of IFN-+ from T lymphocytes and natural killer cells. Because IFN-+ plays a key pathogenic role in the development of murine immunoinflammatory diabetes induced by multiple low doses of streptozotocin (STZ) we investigated the effect of negating the actions of endogenous IL-18 in this model by administering recombinant IL-18-binding protein:Fc (IL-18 bp:Fc). C57BL/6 mice were injected once daily with 40 mg/kg STZ for 5 consecutive days, day 0 being the first day of STZ challenge. Relative to control animals treated in parallel with either PBS or human IgG, mice treated from day -3 to day 7 with daily doses of 150 ? g of IL-18 bp:Fc exhibited lower incidence of diabetes and milder insulitis. In contrast, mice that were treated with IL-18 bp:Fc from day 7 to day 14 exhibited clinical and histological signs of STZ-induced diabetes similar to those of control mice treated with IgG. The protective effect of IL-18 bp:Fc was accompanied by modified ex vivo immune responses, in that spleen cells and peritoneal macrophages contained fewer IFN-+ secreting cells and released lower amounts of nitrite (an index of nitric oxide production) and IL-1 g . We conclude that intact IL-18 function is essential for the full diabetogenic effect of low dose STZ in C57BL/6 mice.

show abstract

“…Poxviruses are large DNA viruses that replicate within the cytoplasm and cause large perturbations in many cellular functions, including host protein synthesis. Poxviruses use a wide variety of immune evasion strategies, including interference with cytokines that impact the NK cell response (17,18). The immune response in mice to both the mouse pathogen ectromelia virus (ECTV) and the prototypic poxvirus vaccinia virus (VV) involves NK cells (19)(20)(21)(22).…”

mentioning

confidence: 99%

Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

Williams

Wilson

Davidson

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

Innate immune recognition of virus-infected cells includes NK cell detection of changes to endogenous cell-surface proteins through inhibitory receptors. One such receptor system is the NK cell receptor protein-1B (NKR-P1B) and its ligand C-type lectin-related-b (Clr-b). NKR-P1B and Clr-b are encoded within the NK cell gene complex, a locus that has been linked to strain-dependent differences in susceptibility to infection by poxviruses. In this study, we report the impact of vaccinia virus (VV) and ectromelia virus infection on expression of Clr-b and Clr-b–mediated protection from NK cells. We observed a loss of Clr-b cell-surface protein upon VV and ectromelia virus infection of murine cell lines and bone marrow-derived macrophages. The reduction of Clr-b is more rapid than MHC class I, the prototypic ligand of NK cell inhibitory receptors. Reduction of Clr-b requires active viral infection but not expression of late viral genes, and loss of mRNA appears to lag behind loss of Clr-b surface protein. Clr-b–mediated protection from NK cells is lost following VV infection. Together, these results provide the second example of Clr-b modulation during viral infection and suggest reductions of Clr-b may be involved in sensitizing poxvirus-infected cells to NK cells.

show abstract

A Poxvirus Protein That Binds to and Inactivates IL-18, and Inhibits NK Cell Response

Cited by 163 publications

References 53 publications

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

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

Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

Poxvirus Infection-Associated Downregulation of C-Type Lectin-Related-b Prevents NK Cell Inhibition by NK Receptor Protein-1B

Contact Info

Product

Resources

About