PTPRO activates TLR4/NF-κB signaling to intensify lipopolysaccharide-induced pneumonia cell injury

Main Article Content

Yao Chen
Buming Sun


PTPRO, apoptosis, inflammation, lipopolysaccharide, HFL1, TLR4/NF-κB, pneumonia


Background: Protein tyrosine phosphatase receptor type O (PTPRO) belongs to the PTP (protein tyrosine phosphatase) family and is widely expressed in parenchymal cells, such as breast and lung epithelial cells. PTPRO has been shown to enhance inflammatory responses and has been implicated in the pathogenesis of inflammation-associated diseases. The role of PTPRO in pneumonia was investigated.

Methods: Human embryonic lung fibroblasts (HFL1) were treated with increasing concentrations of lipopolysaccharide at 5, 10, or 20 μg/mL to induce inflammatory and apoptotic injuries. Expression of PTPRO was detected by western blot. Inflammation and apoptosis were assessed by ELISA and flow cytometry assays, respectively.

Results: Lipopolysaccharide induced decreased cell viability, and increased inflammation and apoptosis in HFL1. PTPRO was upregulated in HFL1 post lipopolysaccharide treatment, and silencing of PTPRO enhanced lipopolysaccharide-induced cell viability of HFL1, and suppressed the inflammation and apoptosis. However, overexpression of PTPRO aggravated lipopolysaccharide-induced cytotoxicity in HFL1. Overexpression of PTPRO upregulated protein expression of TLR4 and p-p65 in lipopolysaccharide-induced HFL1, while knockdown of PTPRO reduced the level of p-IκBα to downregulate levels of TLR4 and p-p65.

Conclusion: PTPRO contributed to pro-inflammatory and pro-apoptotic effects on lipopolysaccharide-induced HFL1 through activation of TLR4/NF-κB signaling.

Abstract 63 | PDF Downloads 50 HTML Downloads 51 XML Downloads 1


1. Yang X, Yang Y, Wu Y, Fu M. METTL3 promotes inflammation and cell apoptosis in a pediatric pneumonia model by regulating EZH2. Allergol Immunopathol. 2021;49(5):49–56. 10.15586/aei.v49i5.445

2. Eslamy HK, Newman B. Pneumonia in normal and immunocompromised children: an overview and update. Radiol Clin North Am. 2011;49(5):895–920. 10.1016/j.rcl.2011.06.007

3. Hooven TA, Polin RA. Pneumonia. Semin Fetal Neonatal Med. 2017;22(4):206–213. 10.1016/j.siny.2017.03.002

4. Esposito S, Cohen R, Domingo JD, Pecurariu OF, Greenberg D, Heininger U, et al. Do we know when, what and for how long to treat?: Antibiotic therapy for pediatric community-acquired pneumonia. Pediatr Infect Dis J. 2012;31(6):e78–e85. 10.1097/INF.0b013e318255dc5b

5. Hou J, Xu J, Jiang R, Wang Y, Chen C, Deng L, et al. Estrogen-sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3. Hepatology. 2012;57(2):678–688. 10.1002/hep.25980

6. Ren W, Yi H, Bao Y, Liu Y, Gao X. Oestrogen inhibits PTPRO to prevent the apoptosis of renal podocytes. Exp Ther Med. 2019;17(3):2373–2380. 10.3892/etm.2019.7167

7. Gan J, Zhang H. PTPRO predicts patient prognosis and correlates with immune infiltrates in human clear cell renal cell carcinoma. Transl Cancer Res. 2020;9(8):4800–4810. 10.21037/tcr-19-2808

8. Hou X, Du J, Fang H. PTPRO is a therapeutic target and correlated with immune infiltrates in pancreatic cancer. J Cancer. 2021;12(24):7445–7453. 10.7150/jca.64661

9. Motiwala T, Kutay H, Ghoshal K, Bai S, Seimiya H, Tsuruo T, et al. Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc Natl Acad Sci U S A. 2004;101(38):13844. 10.1073/pnas.0405451101

10. Dong H, Xie C, Jiang Y, Li K, Lin Y, Pang X, et al. Tumor-derived exosomal protein tyrosine phosphatase receptor type O polarizes macrophage to suppress breast tumor cell invasion and migration. Front Cell Dev Biol. 2021;9:703537. 10.3389/fcell.2021.703537

11. Zhang X, Tan Z, Wang Y, Tang J, Jiang R, Hou J, et al. PTPRO-associated hepatic stellate cell activation plays a critical role in liver fibrosis. Cell Physiol Biochem. 2015;35(3):885–898. 10.1159/000369746

12. Jiang R, Chen D, Hou J, Tan Z, Wang Y, Huang X, et al. Survival and inflammation promotion effect of PTPRO in fulminant hepatitis is associated with NF-B activation. J Immunol. 2014;193:5161–5170. 10.4049/jimmunol.1303354

13. Cen X, Liu S, Cheng K. The role of toll-like receptor in inflammation and tumor immunity. Front Pharmacol. 2018;9:878.

14. Nong W. Long non-coding RNA NEAT1/miR-193a-3p regulates LPS-induced apoptosis and inflammatory injury in WI-38 cells through TLR4/NF-κB signaling. Am J Transl Res. 2019;11(9):5944–5955. 10.3389/fphar.2018.00878

15. Fan Y, Wang J, Feng Z, Cao K, Xu H, Liu J. Pinitol attenuates LPS-induced pneumonia in experimental animals: possible role via inhibition of the TLR-4 and NF-κB/IκBα signaling cascade pathway. J Biochem Mol Toxicol. 2020;35:e22622. 10.1002/jbt.22622

16. Hendriks WJAJ, Elson A, Harroch S, Pulido R, Stoker A, den Hertog J. Protein tyrosine phosphatases in health and disease. FEBS J. 2013;280(2):708–730. 10.1111/febs.12000

17. Zaman Z, Khan S, Nouroz F, Farooq U, Urooj A. Targeting protein tyrosine phosphatase to unravel possible inhibitors for Streptococcus pneumoniae using molecular docking, molecular dynamics simulations coupled with free energy calculations. Life Sci. 2021;264:118621. 10.1016/j.lfs.2020.118621

18. Lee C-H, Chen J-C, Hsiang C-Y, Wu S-L, Wu H-C, Ho T-Y. Berberine suppresses inflammatory agents-induced interleukin-1β and tumor necrosis factor-α productions via the inhibition of IκB degradation in human lung cells. Pharmacol Res. 2007;56(3):193–201. 10.1016/j.phrs.2007.06.003

19. Cui J, Wang J, Lv Y, Xu D. LncRNA NEAT1 regulates infantile pneumonia by sponging miR-146b. Mol Biotechnol. 2021;63(8):694–701. 10.1007/s12033-021-00331-w

20. Kazzaz J, Horowitz S, Xu J, Khullar P, Niederman M, Fein AM, et al. Differential patterns of apoptosis in resolving and nonresolving bacterial pneumonia. Am J Respir Crit Care Med. 2000;161:2043–2050. 10.1164/ajrccm.161.6.9806158

21. Liang C, Wang X, Hu J, Lian X, Zhu T, Zhang H, et al. PTPRO promotes oxidized low-density lipoprotein induced oxidative stress and cell apoptosis through toll-like receptor 4/nuclear factor κB pathway. Cell Physiol Biochem. 2017;42:495–505. 10.1159/000477596

22. Chou C-W, Lin F-C, Tsai H-C, Chang S-C. The importance of pro-inflammatory and anti-inflammatory cytokines in Pneumocystis jirovecii pneumonia. Med Mycol. 2013;51(7):704–712. 10.3109/13693786.2013.772689

23. Mizgerd JP. Inflammation and pneumonia: why are some more susceptible than others? Clin Chest Med. 2018;39(4):669–676. 10.1016/j.ccm.2018.07.002

24. Meijvis SCA, van de Garde EMW, Rijkers GT, Bos WJW. Treatment with anti-inflammatory drugs in community-acquired pneumonia. J Intern Med. 2012;272(1):25–35. 10.1111/j.1365-2796.2012.02554.x

25. Zhao J, Yan S, Zhu X, Bai W, Li J, Liang C. PTPRO exaggerates inflammation in ulcerative colitis through TLR4/NF-κB pathway. J Cell Biochem. 2020;121(2):1061–1071. 10.1002/jcb.29343

26. Pincemail J, Cavalier E, Charlier C, Cheramy-Bien J-P, Brevers E, Courtois A, et al. Oxidative stress status in COVID-19 patients hospitalized in intensive care unit for severe pneumonia. A pilot study. Antioxidants (Basel). 2021;10(2):257. 10.3390/antiox10020257

27. Chen Y, Luo G, Yuan J, Wang Y, Yang X, Wang X, et al. Vitamin C mitigates oxidative stress and tumor necrosis factor-alpha in severe community-acquired pneumonia and LPS-induced macrophages. Mediat Inflam. 2014;2014:426740. 10.1155/2014/426740

28. Zhang H, Lang W, Wang S, Li B, Li G, Shi Q. Echinacea polysaccharide alleviates LPS-induced lung injury via inhibiting inflammation, apoptosis and activation of the TLR4/NF-κB signal pathway. Int Immunopharmacol. 2020;88:106974. 10.1016/j.intimp.2020.106974

29. Pan W, Xu X, Wang Y, Song X. Interleukin-35 reduces inflammation in acute lung injury through inhibiting TLR4/NF-κB signaling pathways. Exp Ther Med. 2020;19(3):1695–700. 10.3892/etm.2020.8407

30. Xu D, Wang X, Yan S, Yin Y, Hou J, Wang X, et al. Interaction of PTPRO and TLR4 signaling in hepatocellular carcinoma. Tumor Biol. 2014;35(10):10267–10273. 10.1007/s13277-014-2302-5