PLCE1 alleviates lipopolysaccharide-induced acute lung injury by inhibiting PKC and NF-κB signaling pathways

Main Article Content

Xianpeng Qiu
Jijun Chen
Jinsong Li
Linyan Pan

Keywords

acute lung injury, phospholipase C epsilon-1, LPS, PKC, NF-κB

Abstract

Background: Acute lung injury (ALI) is a clinical syndrome characterized by hyperosmotic pulmonary edema and increased alveolar fluid. Phospholipase C epsilon-1 (PLCE1), identified as a member of phospholipase family, and the relationship between PLCE1 and lung injury is not clear.


Objective: To assess the possible role of Phospholipase C Epsilon 1 (PLCE1) in Acute lung injury (ALI) progression and related mechanisms.


Materials and methods: The effects of LPS and PLCE1 on cell viability and apoptosis were examined by MTT and flow cytometry. Also, the level of PLCE1 was controlled by transfection of its plasmid and shRNA. The inflammatory response in response to PLCE1 overexpression or ablation was analyzed by quantitative PCR and ELISA assay. And the involvement of PKC and NF-κB signal pathway were detected by Immunoblot.


Results: In this study, we developed a LPS-induced ALI cell model. We found PLCE1 was upregulated in LPS-induced pneumonia cells and affected cell viability. Also, knockdown of PLCE1 reduced LPS-induced apoptosis of pneumonia cells. In addition, depletion of PLCE1 suppressed LPS-induced secretion of proinflammatory cytokines in pneumonia cells. Mechanically, we found depletion of PLCE1 inhibited PKC and NF-κB signal pathway, and therefore alleviated LPS-induced ALI.


Conclusion: We therefore thought PLCE1 could serve as a promising drug for ALI.

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References

1. Yang J, Do-Umehara HC, Zhang Q, Wang H, Hou C, Dong H, et al. miR-221-5p-mediated downregulation of JNK2 aggravates acute lung injury. Front Immunol. 2021;12:700933. 10.3389/fimmu.2021.700933

2. Nelin LD, Jin Y, Chen B, Liu Y, Rogers LK, Reese J. Cyclooxygenase-2 deficiency attenuates lipopolysaccharide-induced inflammation, apoptosis and acute lung injury in adult mice. Am J Physiol Regul Integr Comp Physiol. 2022, Feb 1;322(2):R126-35. 10.1152/ajpregu.00140.2021

3. Martin AK. Predicting the price of the pump: Examining the incidence and predictive factors of acute kidney injury following off-pump lung transplantation. J Cardiothorac Vasc Anesth. 2022;36(1):100–2. 10.1053/j.jvca.2021.10.031

4. Jin X, Gao X, Lan M, Li CN, Sun JM, Zhang H. Study the mechanism of peimisine derivatives on NF-kappa-B inflammation pathway in mice with acute lung injury induced by lipopolysaccharide. Chem Biol Drug Design. 2021, Dec 28. Online ahead of print. 10.1111/cbdd.14013

5. Li Y, Luan C. PLCE1 promotes the invasion and migration of esophageal cancer cells by up-regulating the PKCalpha/NF-kappaB pathway. Yonsei Med J. 2018;59(10):1159–65. 10.3349/ymj.2018.59.10.1159

6. Chen Y, Wang D, Peng H, Chen X, Han X, Yu J, et al. Epigenetically upregulated oncoprotein PLCE1 drives esophageal carcinoma angiogenesis and proliferation via activating the PI-PLCepsilon-NF-kappaB signaling pathway and VEGF-C/Bcl-2 expression. Mol Cancer. 2019;18(1):1. 10.1186/s12943-018-0930-x

7. Bye H, Prescott NJ, Lewis CM, Matejcic M, Moodley L, Robertson B, et al. Distinct genetic association at the PLCE1 locus with oesophageal squamous cell carcinoma in the South African population. Carcinogenesis. 2012;33(11):2155–61. 10.1093/carcin/bgs262

8. Sharma KL, Umar M, Pandey M, Misra S, Kumar A, Kumar V, et al. Association of potentially functional genetic variants of PLCE1 with gallbladder cancer susceptibility in north Indian population. J Gastrointest Cancer. 2013;44(4):436–43. 10.1007/s12029-013-9537-z

9. Wang Q, Chen P, Chen D, Liu F, Pan W. Association between phospholipase C epsilon gene (PLCE1) polymorphism and colorectal cancer risk in a Chinese population. J Int Med Res. 2014;42(2):270–81. 10.1177/0300060513492484 10.1177/0300060514559792

10. Umar M, Upadhyay R, Kumar S, Ghoshal UC, Mittal B. Role of novel and GWAS originated PLCE1 genetic variants in susceptibility and prognosis of esophageal cancer patients in northern Indian population. Tumour Biol. 2014;35(11):11667–76. 10.1007/s13277-014-2458-z

11. Herrlich A. Interorgan crosstalk mechanisms in disease: The case of acute kidney injury-induced remote lung injury. FEBS Lett. 2021. Online ahead of print. doi: 10.1002/1873-3468.14262

12. Chen W, Chen H, Yang ZT, Mao EQ, Chen Y, Chen EZ. Free fatty acids-induced neutrophil extracellular traps lead to dendritic cells activation and T cell differentiation in acute lung injury. Aging. 2021;13(24):26148–60. 10.18632/aging.203802

13. Song J, Chen D, Pan Y, Shi X, Liu Q, Lu X, et al. Discovery of a novel MyD88 inhibitor M20 and its protection against sepsis-mediated acute lung injury. Front Pharmacol. 2021;12:775117. 10.3389/fphar.2021.775117

14. Sun H, Wu X, Wu F, Li Y, Yu Z, Chen X, et al. Associations of genetic variants in the PSCA, MUC1 and PLCE1 genes with stomach cancer susceptibility in a Chinese population. PloS One. 2015;10(2):e0117576. 10.1371/journal.pone.0117576

15. Malik MA, Srivastava P, Zargar SA, Mittal B. Phospholipase C epsilon 1 (PLCE1) haplotypes are associated with increased risk of gastric cancer in Kashmir valley. Saudi J Gastroenterol. 2014;20(6):371–7. 10.4103/1319-3767.145330

16. Li Y, An J, Huang S, Liao H, Weng Y, Cai S, et al. PLCE1 suppresses p53 expression in esophageal cancer cells. Cancer Investig. 2014;32(6):236–40. 10.3109/07357907.2014.905588

17. Qu Y, Zhang S, Cui L, Wang K, Song C, Wang P, et al. Two novel polymorphisms in PLCE1 are associated with the susceptibility to esophageal squamous cell carcinoma in Chinese population. Dis Esophagus. 2017;30(1):1–7. 10.1111/dote.12463

18. Shekarriz R, Faghani S, Tafazoli A, Hashemi-Soteh MB. The correlation between phospholipase C epsilon (PLCE1) gene polymorphisms and risk of gastric adenocarcinoma in Iranian population. Int J Hematol Oncol Stem Cell Res. 2019;13(3): 108–15. 10.18502/ijhoscr.v13i3.1268

19. Li W, Li Y, Chu Y, Wu W, Yu Q, Zhu X, et al. PLCE1 promotes myocardial ischemia-reperfusion injury in H/R H9c2 cells and I/R rats by promoting inflammation. Biosci Rep. 2019;39(7):BSR20181613. 10.1042/BSR20181613

20. Hu X, Jia J, Yang Z, Chen S, Xue J, Duan S, et al. PLCE1 polymorphisms are associated with gastric cancer risk: The changes in protein spatial structure may play a potential role. Front Genet. 2021;12:714915. 10.3389/fgene.2021.714915