Abstract
BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. Fibrotic diseases, such as IPF, are characterized by uncontrolled activation of fibroblasts. Since the microenvironment is known to affect cell behavior, activated fibroblasts can in turn activate healthy neighboring cells. Thus, we investigated IPF paracrine signaling in human lung fibroblasts (HLFs) derived from patients with IPF.MethodsPrimary human fibroblast cultures from IPF (IPF-HLF) and control donor (N-HLF) lung tissues were established and their supernatants were collected. These supernatants were then added to N-HLFs for further culture. Protein and RNA were extracted from IPF/ N-HLFs at baseline. Interleukin-6 (IL-6) and TGF-β-related signaling factors (e.g. STAT3, Smad3) were evaluated by western blot and qPCR. IL-6 levels were measured by ELISA. IL-6 signaling was blocked by Tocilizumab (TCZ) (10 ng/ml).ResultsIPF-HLFs were found to significantly overexpress IL-6 receptor (IL-6R), suppressor of cytokine signaling 3 (SOCS3), phospho-STAT3-Y705 and phospho-Smad3 in comparison to N-HLFs (p < 0.05). In addition, they were found to proliferate faster, secrete more IL-6 and express higher levels of the soluble IL-6R. IPF-HLF increased proliferation was inhibited by TCZ. Moreover, IPF-HLF derived supernatants induced both direct and indirect STAT3 activation that resulted in Smad3 phosphorylation and elevated Gremlin levels in N-HLFs. These effects were also successfully blocked by TCZ.ConclusionsIPF-HLF paracrine signaling leads to IL-6R overexpression, which in turn, affects N-HLF survival. The IL-6/STAT3/Smad3 axis facilitates cellular responses that could potentially promote fibrotic disease. This interplay was successfully blocked by TCZ.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease characterized by a progressive decline in lung function
We showed that IPF paracrine signaling significantly alters N-human lung fibroblasts (HLF) phenotype [4]
To the effects of the IPF-HLF-SN, there was an elevated baseline expression of pSTAT3-Y705 and suppressor of cytokine signaling 3 (SOCS3) in these cells (Fig. 2f-h). These findings show that the Signal transducer and activator of transcription (STAT3) pathway is excessively activated in IPFHLFs at baseline
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease characterized by a progressive decline in lung function. Fibrotic diseases, such as IPF, are characterized by uncontrolled activation of fibroblasts. Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease associated with significant morbidity and poor prognosis [1]. Activated fibroblasts were shown to be the key components in the fibrotic process. Their interaction with the microenvironment, Fibrosis, in response to tissue damage or persistent inflammation, is a pathological hallmark of many chronic degenerative diseases [1, 5]. IL-6 was shown to be elevated in lungs of Epstein Shochet et al Respiratory Research (2020) 21:56
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
