Pim-1 kinase is a positive feedback regulator of the senescent lung fibroblast inflammatory secretome

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 323; no. 6; pp. L685 - L697
• Main Authors: Gao, Ashley Y, Diaz Espinosa, Ana M, Gianì, Fiorenza, Pham, Tho X, Carver, Chase M, Aravamudhan, Aja, Bartman, Colleen M, Ligresti, Giovanni, Caporarello, Nunzia, Schafer, Marissa J, Haak, Andrew J
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2022
• Series: Senescence in the Lung
• Subjects: Cellular Senescence; Cytokines - metabolism; Fibroblasts - metabolism; Humans; Idiopathic Pulmonary Fibrosis - metabolism; Lung - metabolism; NF-kappa B - metabolism; Pneumonia - metabolism; Proto-Oncogene Proteins c-pim-1 - metabolism; Proto-Oncogene Proteins c-pim-1 - pharmacology; senescence; Pim kinase; idiopathic pulmonary fibrosis; secretome; lung fibrosis
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00023.2022

Cellular senescence is emerging as a driver of idiopathic pulmonary fibrosis (IPF), a progressive and fatal disease with limited effective therapies. The senescence-associated secretory phenotype (SASP), involving the release of inflammatory cytokines and profibrotic growth factors by senescent cells, is thought to be a product of multiple cell types in IPF, including lung fibroblasts. NF-κB is a master regulator of the SASP, and its activity depends on the phosphorylation of p65/RelA. The purpose of this study was to assess the role of Pim-1 kinase as a driver of NF-κB-induced production of inflammatory cytokines from low-passage IPF fibroblast cultures displaying markers of senescence. Our results demonstrate that Pim-1 kinase phosphorylates p65/RelA, activating NF-κB activity and enhancing IL-6 production, which in turn amplifies the expression of , generating a positive feedback loop. In addition, targeting Pim-1 kinase with a small molecule inhibitor dramatically inhibited the expression of a broad array of cytokines and chemokines in IPF-derived fibroblasts. Furthermore, we provide evidence that Pim-1 overexpression in low-passage human lung fibroblasts is sufficient to drive premature senescence, in vitro. These findings highlight the therapeutic potential of targeting Pim-1 kinase to reprogram the secretome of senescent fibroblasts and halt IPF progression.