Researchers have identified a new role for Pim-1 kinase as a driver of inflammatory cytokine production in senescent idiopathic pulmonary fibrosis (IPF) fibroblasts.

The study, published in Lung Cellular and Molecular Physiology, found that phosphorylation of p65/ReIA by Pim-1 enhances interleukin (IL)-6 production, thereby amplifying Pim-1 expression, which results in a positive feedback loop and drives premature cell senescence in vitro.

“IPF patient-derived fibroblasts exhibits a senescence-associated secretory phenotype (SASP), producing heightened inflammatory cytokines including IL-6, IL-1β and MCP-1 (CCL2), which contribute to fibrosis progression,” the authors wrote. “In this study, we aimed to assess the role of Pim-1 kinase in modulating NF-κB activity and downstream SASP presentation in IPF patient-derived lung fibroblasts.”


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The research team obtained, isolated, and cultured non-IPF and patient-derived IPF fibroblasts for their experiments. They used western blotting to assess the role of Pim-1 kinase in lung fibroblast NF-κB by which they observed the phosphorylation of p65/ReIA, subsequent IL-6 production, and further expression of Pim-1. This effect was dramatically reduced by Pim-1 knockdown.

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The expression of Pim-1 and phosphorylation of p65/ReIA were higher in fibroblasts from IPF patients compared with non-IPF control fibroblasts. Further patient-derived IPF cell treatment to inhibit Pim-1 resulted in the inhibition of multiple genes that encode inflammatory cytokines, suggesting that Pim-1 is an important regulator of inflammation in IPF.

In previous studies, inhibition of Pim-1 has been shown to reduce pulmonary fibrosis in a mouse model of IPF. The authors note that their new findings further suggest that Pim-1 kinase plays a critical role in regulating the inflammatory secretome in IPF lung fibroblasts and that Pim-1 kinase inhibition is a potential therapeutic target in this disease.

Reference

Gao, A, Espinosa A, Gianí F, et al. Pim-1 kinase is a positive feedback regulator of the senescent lung fibroblast inflammatory secretome. Lung Cell Mol Phys. Published online October 12, 2022. doi:10.1152/ajplung.00023.2022