A Critical Role for IFN-β Signaling for IFN-κ Induction in Keratinocytes.

Autor:	Xu B; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Musai J; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Tan YS; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Hile GA; Department of Dermatology, University of Michigan, Ann Arbor, Michigan., Swindell WR; University of Texas Southwestern Medical Center, Department of Internal Medicine, Dallas, Texas, 75390-9175., Klein B; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor., Qin JT; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA., Sarkar MK; Department of Dermatology, University of Michigan, Ann Arbor, Michigan., Gudjonsson JE; Department of Dermatology, University of Michigan, Ann Arbor, Michigan., Kahlenberg JM; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor.
Jazyk:	angličtina
Zdroj:	Frontiers in lupus [Front Lupus] 2024; Vol. 2. Date of Electronic Publication: 2024 Mar 19.
DOI:	10.3389/flupu.2024.1359714
Abstrakt:	Background/purpose: Cutaneous lupus erythematosus (CLE) affects up to 70% of patients with systemic lupus erythematosus (SLE), and type I interferons (IFNs) are important promoters of SLE and CLE. Our previous work identified IFN-kappa (IFN-κ), a keratinocyte-produced type I IFN, as upregulated in non-lesional and lesional lupus skin and as a critical regulator for enhanced UVB-mediated cell death in SLE keratinocytes. Importantly, the molecular mechanisms governing regulation of IFN-κ expression have been relatively unexplored. Thus, this study sought to identify critical regulators of IFN-κ and identified a novel role for IFN-beta (IFN-β). Methods: Human N/TERT keratinocytes were treated with the RNA mimic poly (I:C) or 50 mJ/cm 2 ultraviolet B (UVB), followed by mRNA expression quantification by RT-qPCR in the presence or absence neutralizing antibody to the type I IFN receptor (IFNAR). IFNB and STAT1 knockout (KO) keratinocytes were generated using CRISPR/Cas9. Results: Time courses of poly(I:C) and UVB treatment revealed a differential expression of IFNB , which was upregulated between 3-6 hours and IFNK , which was upregulated 24 hours after stimulation. Intriguingly, only IFNK expression was substantially abrogated by neutralizing antibodies to IFNAR, suggesting that IFNK upregulation required type I IFN signaling for induction. Indeed, deletion of IFNB abrogated IFNK expression . Further exploration confirmed a role for type I IFN-triggered STAT1 activation. Conclusion: Collectively, our work describes a novel mechanistic paradigm in keratinocytes in which initial IFN-κ induction in response to poly(I:C) and UVB is IFNβ1-dependent, thus describing IFNK as both an IFN gene and an interferon-stimulated gene. Competing Interests: JMK has received grant support from Q32 Bio, Celgene/Bristol-Myers Squibb, Ventus Therapeutics, Rome Therapeutics, and Janssen. JMK has served on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, EMD serrano, Exo Therapeutics, Gilead, GlaxoSmithKline, Aurinia Pharmaceuticals, Rome Therapeutics, and Ventus Therapeutics. JEG has received support from Eli Lilly, Janssen, BMS, Sanofi, Prometheus, Almirall, Kyowa-Kirin, Novartis, AnaptysBio, Boehringer Ingelheim, Regeneron, Abbvie, and Galderma. All other authors have nothing to disclose.
Databáze:	MEDLINE
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