PDE4B Modulates Phosphorylation of P65 (Ser468) Via CAMP/PKA in Acute Lung Injury

Overview

Journal Lung

Specialty Pulmonary Medicine

Date 2025 Feb 16

PMID 39956855

Authors

Rana Dhar

YaJun Li

Zhengqiang Hu

Shunde Song

Zhewen Zhang

Jie Ji

Xuefeng Wang

Xuyang Zheng

Zigang Li

Chunguang Yan

Huifang Tang

Affiliations

Soon will be listed here.

Abstract

Aim: The important role of phosphodiesterase 4B (PDE4B) inhibition on lipopolysaccharide (LPS)-induced ALI has been reported. However, the corresponding mechanisms remain unclear. In the present study, the relationship between PDE4B and phosphorylation of p65 (Ser468) in LPS-induced injury by in vivo and in vitro models was investigated.

Methods And Results: pde4b mice, inflammation was significantly up-regulated after LPS stimulation, including the highest number of immune cells, especially neutrophils, and the level of pro-inflammatory cytokines measured by ELISA, while all those were blunted in pde4b mice. Moreover, pde4b mice improved the expression of PKA in lung tissues and down-regulated the IKKα/β-NF-κB p65 signaling determined by western blotting. In vitro experiments in MH-S cells revealed that siRNA-mediated specific silence of PDE4B expression resulted in a decrease of inflammatory markers and phosphorylation of p65 at Ser468 after LPS treatment, but overexpressing PDE4B increased the inflammation and phosphorylation of p65 at Ser468. In MH-S cells, luciferase analysis indicated that PDE4B acts as a positive regulator of p65 in inflammation. PKA inhibitor (H-89) increased pP65 and PDE4B expression, while PKA activator (6-BZ-cAMP) showed the opposite effect in macrophages. More importantly, the proteasome-mediated degradation of cAMP effector was negatively correlated with the phosphorylation of p65 (Ser468) and PDE4B expression in MH-S cells.

Conclusions: PDE4B plays a critical role in orchestrating LPS-induced acute lung inflammation by cAMP/PKA axis-mediated phosphorylation of p65.

References

Fanelli V, Ranieri V . Mechanisms and clinical consequences of acute lung injury. Ann Am Thorac Soc. 2015; 12 Suppl 1:S3-8. DOI: 10.1513/AnnalsATS.201407-340MG. View

Butt Y, Kurdowska A, Allen T . Acute Lung Injury: A Clinical and Molecular Review. Arch Pathol Lab Med. 2016; 140(4):345-50. DOI: 10.5858/arpa.2015-0519-RA. View

Oliveira E, Parikh A, Lopez-Ruiz A, Carrilo M, Goldberg J, Cearras M . ICU outcomes and survival in patients with severe COVID-19 in the largest health care system in central Florida. PLoS One. 2021; 16(3):e0249038. PMC: 7993561. DOI: 10.1371/journal.pone.0249038. View

Chen H, Bai C, Wang X . The value of the lipopolysaccharide-induced acute lung injury model in respiratory medicine. Expert Rev Respir Med. 2010; 4(6):773-83. DOI: 10.1586/ers.10.71. View

Shirey K, Blanco J, Vogel S . Targeting TLR4 Signaling to Blunt Viral-Mediated Acute Lung Injury. Front Immunol. 2021; 12:705080. PMC: 8285366. DOI: 10.3389/fimmu.2021.705080. View

Alharbi K, Fuloria N, Fuloria S, Rahman S, Al-Malki W, Shaikh M . Nuclear factor-kappa B and its role in inflammatory lung disease. Chem Biol Interact. 2021; 345:109568. DOI: 10.1016/j.cbi.2021.109568. View

Barnabei L, Laplantine E, Mbongo W, Rieux-Laucat F, Weil R . NF-κB: At the Borders of Autoimmunity and Inflammation. Front Immunol. 2021; 12:716469. PMC: 8381650. DOI: 10.3389/fimmu.2021.716469. View

Ahmad F, Murata T, Shimizu K, Degerman E, Maurice D, Manganiello V . Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets. Oral Dis. 2014; 21(1):e25-50. PMC: 4275405. DOI: 10.1111/odi.12275. View

Song S, Tang H . [Progress in PDE4 targeted therapy for inflammatory diseases]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2014; 43(3):353-8. DOI: 10.3785/j.issn.1008-9292.2014.05.015. View

10.

Oldenburger A, Roscioni S, Jansen E, Menzen M, Halayko A, Timens W . Anti-inflammatory role of the cAMP effectors Epac and PKA: implications in chronic obstructive pulmonary disease. PLoS One. 2012; 7(2):e31574. PMC: 3283666. DOI: 10.1371/journal.pone.0031574. View

11.

Wen R, Feng W, Liang J, Zhang H . Role of phosphodiesterase 4-mediated cyclic AMP signaling in pharmacotherapy for substance dependence. Curr Pharm Des. 2014; 21(3):355-64. DOI: 10.2174/1381612820666140826114412. View

12.

Al-Sajee D, Yin X, Gauvreau G . An evaluation of roflumilast and PDE4 inhibitors with a focus on the treatment of asthma. Expert Opin Pharmacother. 2019; 20(5):609-620. DOI: 10.1080/14656566.2019.1570132. View

13.

Phillips J . Inhaled Phosphodiesterase 4 (PDE4) Inhibitors for Inflammatory Respiratory Diseases. Front Pharmacol. 2020; 11:259. PMC: 7080983. DOI: 10.3389/fphar.2020.00259. View

14.

Parikh N, Chakraborti A . Phosphodiesterase 4 (PDE4) Inhibitors in the Treatment of COPD: Promising Drug Candidates and Future Directions. Curr Med Chem. 2015; 23(2):129-41. DOI: 10.2174/0929867323666151117121334. View

15.

Abdulrahim H, Thistleton S, Adebajo A, Shaw T, Edwards C, Wells A . Apremilast: a PDE4 inhibitor for the treatment of psoriatic arthritis. Expert Opin Pharmacother. 2015; 16(7):1099-108. DOI: 10.1517/14656566.2015.1034107. View

16.

Spadaccini M, DAlessio S, Peyrin-Biroulet L, Danese S . PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue. Int J Mol Sci. 2017; 18(6). PMC: 5486098. DOI: 10.3390/ijms18061276. View

17.

Brandon N . Uncovering the function of Disrupted in Schizophrenia 1 through interactions with the cAMP phosphodiesterase PDE4: Contributions of the Houslay lab to molecular psychiatry. Cell Signal. 2015; 28(7):749-52. DOI: 10.1016/j.cellsig.2015.09.019. View

18.

Link A, Selejan S, Maack C, Lenz M, Bohm M . Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shock. Crit Care. 2008; 12(6):R159. PMC: 2646324. DOI: 10.1186/cc7158. View

19.

Miotla J, Teixeira M, Hellewell P . Suppression of acute lung injury in mice by an inhibitor of phosphodiesterase type 4. Am J Respir Cell Mol Biol. 1998; 18(3):411-20. DOI: 10.1165/ajrcmb.18.3.2913. View

20.

Kubo S, Kobayashi M, Iwata M, Takahashi K, Miyata K, Shimizu Y . Disease-modifying effect of ASP3258, a novel phosphodiesterase type 4 inhibitor, on subchronic cigarette smoke exposure-induced lung injury in guinea pigs. Eur J Pharmacol. 2011; 659(1):79-84. DOI: 10.1016/j.ejphar.2011.02.042. View