Pim-1 kinase is a positive feedback regulator of the senescent lung fibroblast inflammatory secretome
Abstract
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 PIM1, 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 01, 2022
- Source ID
- 10.1152/ajplung.00023.2022
Entities
People
- Aja Aravamudhan
- Ana M. Diaz Espinosa
- Andrew J Haak
- Ashley Y. Gao
- Chase M. Carver
- Colleen M. Bartman
- Fiorenza Gianì
- Giovanni Ligresti
- Marissa J Schafer
- Nunzia Caporarello
- Tho X. Pham
Organizations
- American Lung Association
- Boehringer Ingelheim (United States)
- Boston University
- Mayo Clinic
- National Heart, Lung, and Blood Institute
- Pulmonary Fibrosis Foundation
- United States Department of Defense
- University of Catania