Antiviral activities of the soluble extracellular domains of type I interferon receptors

Han, Chunsheng; Chen, Yizhen; Ezashi, Toshihiko; Roberts, R. Michael

doi:10.1073/pnas.111139598

Cited by 29 publications

(16 citation statements)

References 56 publications

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“…Indicated in panels A, F, and G are the relative positions of primers mus15_F and mus16_R along the wild-type (A), conditional KI (F), and ⌬TM (IL7R␣) (47), IL-15 receptor ␣ (IL15R␣) (48), and transforming growth factor ␤ receptor 1 (T␤R-I) (49). Rather than potentiating its cytokine, a splice variant of the interferon ␣ receptor 2 (IFNAR2) can actually substitute for type I IFN in in vitro assays (50).…”

Section: Discussionmentioning

confidence: 99%

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

et al. 2015

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bIL12RB1 is a human gene that is important for resistance to Mycobacterium tuberculosis infection. IL12RB1 is expressed by multiple leukocyte lineages, and encodes a type I transmembrane protein (IL12R␤1) that associates with IL12p40 and promotes the development of host-protective T H 1cells. Recently, we observed that il12rb1-the mouse homolog of IL12RB1-is alternatively spliced by leukocytes to produce a second isoform (IL12R␤1⌬TM) that has biological properties distinct from IL12R␤1. Although the expression of IL12R␤1⌬TM is elicited by M. tuberculosis in vivo, and its overexpression enhances IL12p40 responsiveness in vitro, the contribution of IL12R␤1⌬TM to controlling M. tuberculosis infection has not been tested. Here, we demonstrate that IL12R␤1⌬TM represents a secreted product of il12rb1 that, when absent from mice, compromises their ability to control M. tuberculosis infection in extrapulmonary organs. Furthermore, elevated M. tuberculosis burdens in IL12R␤1⌬TM-deficient animals are associated with decreased lymph node cellularity and a decline in T H 1 development. Collectively, these data support a model wherein IL12R␤1⌬TM is a secreted product of il12rb1 that promotes resistance to M. tuberculosis infection by potentiating T H cells response to IL-12.

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Section: Discussionmentioning

confidence: 99%

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

et al. 2015

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“…The most obvious therapeutic target in SLE is IFN␣, and a humanized monoclonal anti-IFN␣ antibody that neutralizes all IFN␣ subtypes has been developed (109). Soluble IFNAR is another therapeutic option, although such a molecule might also act as a ligand-dependent agonist (110). Furthermore, the NIPCs/PDCs could be directly targeted by human monoclonal antibodies to BDCA-2, because ligation of this molecule turns off the IFN␣ production by NIPCs/PDCs (19,42).…”

Section: Therapeutic Consequencesmentioning

confidence: 99%

The type I interferon system in systemic lupus erythematosus

Rönnblom

Eloranta

Alm

2006

Arthritis & Rheumatism

304

246

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“…Subsequently, mouse Ifnar2 was cloned, and a mechanism of alternative splicing, similar to that in humans, was demonstrated to generate a soluble receptor isoform in the mouse (12). Previous experiments demonstrated that recombinant murine sIFNAR2a and the extracellular domain of tmIFNAR2 can both bind IFN with nanomolar affinity (13,(23)(24)(25)(26)(27). Subsequently, we demonstrated that sIFNAR2a can modulate IFN actions in vitro as either an agonist or an antagonist, analogous to other soluble cytokine receptors (24).…”

mentioning

confidence: 99%

Soluble IFN Receptor Potentiates In Vivo Type I IFN Signaling and Exacerbates TLR4-Mediated Septic Shock

Samarajiwa

Mangan

Hardy

et al. 2014

The Journal of Immunology

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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.

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Antiviral activities of the soluble extracellular domains of type I interferon receptors

Cited by 29 publications

References 56 publications

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

The type I interferon system in systemic lupus erythematosus

Soluble IFN Receptor Potentiates In Vivo Type I IFN Signaling and Exacerbates TLR4-Mediated Septic Shock

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