Soluble IFN receptor potentiates in vivo type I IFN signaling and exacerbates TLR4-mediated septic shock

Circulating levels of a soluble type I IFNR are elevated in diseases, such as chronic inflammation, infections, and cancer, but whether it functions as an antagonist, agonist, or transporter is unknown. In this study, we elucidate the in vivo importance of the soluble type I IFNAR, soluble (s)IFNAR2...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2014-05, Vol.192 (9), p.4425-4435
Main Authors: Samarajiwa, Shamith A, Mangan, Niamh E, Hardy, Matthew P, Najdovska, Meri, Dubach, Daphne, Braniff, Susie-Jane, Owczarek, Catherine M, Hertzog, Paul J
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Immunoblotting
Immunophenotyping
Inflammation - immunology
Inflammation - metabolism
Interferon Type I - immunology
Interferon Type I - metabolism
Mice
Mice, Transgenic
Real-Time Polymerase Chain Reaction
Receptor, Interferon alpha-beta - immunology
Receptor, Interferon alpha-beta - metabolism
Shock, Septic - immunology
Shock, Septic - metabolism
Signal Transduction - immunology
Toll-Like Receptor 4 - metabolism
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Summary:Circulating levels of a soluble type I IFNR are elevated in diseases, such as chronic inflammation, infections, and cancer, but whether it functions as an antagonist, agonist, or transporter is unknown. In this study, we elucidate the in vivo importance of the soluble type I IFNAR, soluble (s)IFNAR2a, which is generated by alternative splicing of the Ifnar2 gene. A transgenic mouse model was established to mimic the 10-15-fold elevated expression of sIFNAR2a observed in some human diseases. We generated transgenic mouse lines, designated SolOX, in which the transgene mRNA and protein-expression patterns mirrored the expression patterns of the endogenous gene. SolOX were demonstrated to be more susceptible to LPS-mediated septic shock, a disease model in which type I IFN plays a crucial role. This effect was independent of "classical" proinflammatory cytokines, such as TNF-α and IL-6, whose levels were unchanged. Because the increased levels of sIFNAR2a did not affect the kinetics of the increased interferonemia, this soluble receptor does not potentiate its ligand signaling by improving IFN pharmacokinetics. Mechanistically, increased levels of sIFNAR2a are likely to facilitate IFN signaling, as demonstrated in spleen cells overexpressing sIFNAR2a, which displayed quicker, higher, and more sustained activation of STAT1 and STAT3. Thus, the soluble IFNR is an important agonist of endogenous IFN actions in pathophysiological processes and also is likely to modulate the therapeutic efficacy of clinically administered IFNs.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1302388