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Development and Validation of an Ultrasensitive Single Molecule Array Digital Enzyme-linked Immunosorbent Assay for Human Interferon-α
Published on: June 14, 2018
Interferon Receptor Chain Deficiency in Murine Friend Erythroleukemia Cell Clone Resistant to Type I or Type I and II
Zulema Antonia Percario1, Giorgio Mangino2, Arianna Raponi1
1Department of Science, Roma Tre University, 00146 Rome, Italy.
Abstract:
Interferon (IFN)-resistant cell clones 3Cl8 and 3γR8, isolated from wild-type Friend erythroleukemia cells 745A were characterized to identify the resistance defect. The 3Cl8 cell clone is resistant to type I IFNs and sensitive to type II IFN, whereas 3γR8, derived from 3Cl8, is resistant to both type I and II IFNs. Here, we report that no activation of the JAK-STAT pathway is detected after IFN treatment of resistant cells. Interestingly, the absence of major transcripts of the IFNAR2 receptor chain has been observed in type I IFN-resistant cells, and a point mutation relative to the IFNGR2 receptor chain (β chain) has been identified in type II IFN-resistant cells, inducing a frameshift leading to premature termination of translation. In addition, we have identified a new polymorphism of the murine IFNAR1 chain and possibly the presence of a murine IFNAR2b transmembrane, non-transducing chain in 745A cells, similar to that observed in humans and differing from previous reports on other murine systems.
Insights
Friend erythroleukemia cells resistant to interferons (IFNs) were studied. Resistance was linked to defects in IFN receptor signaling pathways, specifically the JAK-STAT pathway, and mutations in IFN receptor chains.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Interferons (IFNs) are crucial cytokines for immune response.
- IFN resistance in cancer cells can impede therapeutic efficacy.
- Understanding IFN resistance mechanisms is vital for developing effective cancer treatments.
Purpose of the Study:
- To characterize IFN-resistant cell clones derived from Friend erythroleukemia cells.
- To identify the molecular defects underlying resistance to type I and type II IFNs.
- To investigate the role of the JAK-STAT pathway and IFN receptor components in IFN resistance.
Main Methods:
- Isolation and characterization of IFN-resistant cell clones (3Cl8 and 3γR8).
- Analysis of JAK-STAT pathway activation following IFN treatment.
- Assessment of IFN receptor gene expression and sequencing to identify mutations.
Main Results:
- IFN-resistant cells showed no JAK-STAT pathway activation upon IFN stimulation.
- Type I IFN resistance in 3Cl8 cells correlated with absent IFNAR2 receptor chain transcripts.
- Type II IFN resistance in 3γR8 cells was associated with an IFNGR2 (beta chain) mutation causing premature translation termination.
- A novel polymorphism in the murine IFNAR1 chain and a potential IFNAR2b chain variant were identified.
Conclusions:
- IFN resistance in these erythroleukemia cells is mediated by defects in IFN receptor signaling.
- Specific mutations in IFN receptor chains (IFNAR2, IFNGR2) are responsible for resistance to different IFN types.
- The findings reveal new insights into IFN receptor biology in murine models, with implications for human systems.
