JAK Signaling Is Critically Important in Cytokine-Induced Viral Susceptibility of Keratinocytes
Abstract
:1. Introduction
2. Results
2.1. Type 2 (IL-4 + IL-13) and Type 3 (IL-22) Cytokines Increase KC Viral Susceptibility
2.2. The Type 1 Cytokine IFNγ Decreases KC Viral Susceptibility
2.3. Neither Cytokine Nor JAKi Exposure Affects KC Viability
2.4. JAK1 Inhibition Reduces Viral Susceptibility of IL-4 + IL-13-Treated KC
2.5. TYK2 Inhibition Reduces Viral Susceptibility of IL-22-Treated KC
2.6. JAK2 Inhibition Reverses IFNγ-Induced Resistance to VV Infection
2.7. A JAK1/JAK2-Selective Inhibitor (Ruxolitinib) Increases Virion Production from IFNγ-Treated KC
2.8. Primary KC Substantiates the Importance of Cytokine Profiles and JAKi in Cutaneous Viral Susceptibility
3. Discussion
4. Materials and Methods
4.1. Cells and Culture Techniques
4.2. Cytokines and JAKi
4.3. Cell Viability Assays
4.4. Viral Plaque Assay
4.5. Viral Titering
4.6. Statistical and Data Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Atopic dermatitis |
HSV-1 | Herpes simplex virus-1 |
JAK | Janus kinase |
JAKi | Janus kinase inhibitor |
KC | Keratinocyte |
MOI | Multiplicity of infection |
PHFK | Primary human foreskin keratinocytes |
STAT | Signal transducer and activator of transcription |
VV | Vaccinia virus |
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Janus Kinase Inhibitor (Shorthand Nomenclature) | For Treatment of: | IC50 (nM) | Cmax | ||||||
---|---|---|---|---|---|---|---|---|---|
JAK1 | JAK2 | JAK3 | TYK2 | REFERENCE | nM | REFERENCE | Human Dose | ||
Pyridone 6 (P6) | Not in clinical development | 15 * | 1 | 5 | 1 | PMID: 11934592 Access Date: 15 July 2021 | N/A | N/A | N/A |
Ruxolitinib (RUX) | Atopic dermatitis #, Myelofibrosis, Polycythemia Vera, Graft-Versus-Host Disease | 3.3 | 2.8 | 428 | 19 | PMID: 20130243 Access Date: 15 July 2021 | 650 | PMID: 35368221 Access Date: 7 December 2022 | 15 mg BID |
Abrocitinib (ABR) | Atopic Dermatitis | 29.2 | 803 | >104 | 1250 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/213871Orig1s000MultidisciplineR.pdf Access Date: 15 July 2021 | 2164 | https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/213871Orig1s000MultidisciplineR.pdf Access Date: 7 December 2022 | 100 mg QD |
Fedratinib (FED) | Myelofibrosis | 105 | 3 | 1002 | 405 | PMID: 18394554 Access Date: 15 July 2021 | 3438 | https://packageinserts.bms.com/pi/pi_inrebic.pdf Access Date: 7 December 2022 | 400 mg QD |
Ritlecitinib (RIT) | Not FDA approved (In multiple clinical trials) | >104 | >104 | 33.1 | >104 | PMID: 27791347 Access Date: 15 July 2021 | N/A | N/A | N/A |
Deucravacitinib (DEU) | Plaque Psoriasis | >104 | >104 | >104 | 0.2 | PMID: 31318208 Access Date: 15 July 2021 | 105 | https://packageinserts.bms.com/pi/pi_sotyktu.pdf Access Date: 7 December 2022 | 6 mg QD |
Effect on Viral Susceptibility | |||||||
Ruxolitinib | Abrocitinib | Fedratinib | Ritlecitinib | Deucravacitinib | |||
Clinical Observations | |||||||
No JAKi | Observed (Significant) | Observed | Not Observed | No Reported Results | Observed | ||
in vitro Observations (Vaccinia Virus) | |||||||
Cytokine | IL-4 + IL-13 | Increase & | Decrease | Decrease | No effect | No effect | No effect |
IL-22 | Increase #,& | No effect | No effect | No effect | No effect | Decrease | |
IL-17A | No effect & | Not Determined | |||||
IFNγ | Decrease #,& | Increase #,& | No effect | Increase #,& | No effect | No effect |
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Arnold, K.A.; Peterson, L.F.; Beck, L.A.; Brewer, M.G. JAK Signaling Is Critically Important in Cytokine-Induced Viral Susceptibility of Keratinocytes. Int. J. Mol. Sci. 2023, 24, 9243. https://doi.org/10.3390/ijms24119243
Arnold KA, Peterson LF, Beck LA, Brewer MG. JAK Signaling Is Critically Important in Cytokine-Induced Viral Susceptibility of Keratinocytes. International Journal of Molecular Sciences. 2023; 24(11):9243. https://doi.org/10.3390/ijms24119243
Chicago/Turabian StyleArnold, Kimberly A., Liam F. Peterson, Lisa A. Beck, and Matthew G. Brewer. 2023. "JAK Signaling Is Critically Important in Cytokine-Induced Viral Susceptibility of Keratinocytes" International Journal of Molecular Sciences 24, no. 11: 9243. https://doi.org/10.3390/ijms24119243