Soluble IFN receptor potentiates in vivo type I IFN signaling and exacerbates TLR4-mediated septic shock
| Autor: | Paul J. Hertzog, Daphne Dubach, Niamh E. Mangan, Matthew Hardy, Shamith A. Samarajiwa, Susie-Jane Braniff, Catherine M Owczarek, Meri Najdovska |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Genetically modified mouse
Agonist medicine.drug_class Transgene Immunology Immunoblotting Enzyme-Linked Immunosorbent Assay Mice Transgenic Receptor Interferon alpha-beta Real-Time Polymerase Chain Reaction Proinflammatory cytokine Immunophenotyping Mice medicine Immunology and Allergy Animals STAT1 Receptor Inflammation biology Flow Cytometry Shock Septic Toll-Like Receptor 4 Disease Models Animal Interferon Type I biology.protein TLR4 Cancer research Signal transduction Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 192(9) |
| ISSN: | 1550-6606 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|