IRF1 Mediates Growth Arrest and the Induction of a Secretory Phenotype in Alveolar Epithelial Cells in Response to Inflammatory Cytokines IFNγ/TNFα

• Published in: International journal of molecular sciences Vol. 25; no. 6; p. 3463
• Main Authors: Recchia Luciani, Giulia, Barilli, Amelia, Visigalli, Rossana, Sala, Roberto, Dall'Asta, Valeria, Rotoli, Bianca Maria
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2024; MDPI
• Subjects: Acute respiratory distress syndrome; Cell cycle; cell cycle arrest; Cell death; Cell growth; COVID-19; Cytokine storm; Edema; Genetic aspects; Growth; IFNγ; Inflammation; IRF1; Lavage; Pathogenesis; SASP; Scientific equipment and supplies industry; Senescence; Severe acute respiratory syndrome coronavirus 2; TNFα; Tumor necrosis factor; United States; United Kingdom; IFNγ; senescence; TNFα; cell cycle arrest; SASP; IRF1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25063463

In COVID-19, cytokine release syndrome can cause severe lung tissue damage leading to acute respiratory distress syndrome (ARDS). Here, we address the effects of IFNγ, TNFα, IL-1β and IL-6 on the growth arrest of alveolar A549 cells, focusing on the role of the IFN regulatory factor 1 (IRF1) transcription factor. The efficacy of JAK1/2 inhibitor baricitinib has also been tested. A549 WT and IRF1 KO cells were exposed to cytokines for up to 72 h. Cell proliferation and death were evaluated with the resazurin assay, analysis of cell cycle and cycle-regulator proteins, LDH release and Annexin-V positivity; the induction of senescence and senescence-associated secretory phenotype (SASP) was evaluated through β-galactosidase staining and the quantitation of secreted inflammatory mediators. While IL-1 and IL-6 proved ineffective, IFNγ plus TNFα caused a proliferative arrest in A549 WT cells with alterations in cell morphology, along with the acquisition of a secretory phenotype. These effects were STAT and IRF1-dependent since they were prevented by baricitinib and much less evident in IRF1 KO than in WT cells. In alveolar cells, STATs/IRF1 axis is required for cytokine-induced proliferative arrest and the induction of a secretory phenotype. Hence, baricitininb is a promising therapeutic strategy for the attenuation of senescence-associated inflammation.