Alveolar macrophage-derived progranulin mediated pro-inflammatory Il-6 expression via regulating Creb1 in silicosis model.

Int Immunopharmacol

Department of Environment and Occupational Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Department of Occupational Disease, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China; Research Center For Prevention and Therapy of Occupational Disease, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China; Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address:

Published: June 2022

Progranulin (PGRN) is a secreted factor involved in inflammatory diseases. However, the function of PGRN in silica-induced lung inflammation has not been elucidated. In this study, we demonstrated that PGRN in serum and lung tissues was markedly increased in silicosis mouse model. And immunohistochemistry results showed that PGRN was mainly expressed in alveolar macrophages, which was further confirmed in silica-treated alvelar macrophages cell line (MH-S) in vitro. PGRN promoted pro-inflammatory cytokines transcription such as interleukin (Il)-6, tumor necrosis factor-α (Tnf-α) and Il-1β in MH-S cells, and the increasing of Il-6 was most obvious. Knockdown of PGRN blocked the silica-induced elevation of intracellular Il-6 in MH-S cells. Furthermore, we also found that PGRN could increase the phosphorylation of Cyclic AMP-responsive element-binding protein 1 (Creb1), a transcriptional regulator of Il-6. Inhibition of p-Creb1 by the phosphorylation inhibitor of Creb1 (666-15) decreased PGRN-induced intracellular Il-6 production in MH-S cells. In conclusion, PGRN was highly increased in silicosis mouse model and upregulated inflammatory cytokines expression. These findings suggested that PGRN might be a key mediator in silica-induced inflammation and provided a new clue for the diagnosis and drug therapy of silicosis.

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http://dx.doi.org/10.1016/j.intimp.2022.108705DOI Listing

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