N-acetyl Cysteine Mediates Protection from 2-hydroxyethyl Methacrylate Induced Apoptosis Via Nuclear Factor Kappa B-dependent and Independent Pathways: Potential Involvement of JNK

Overview

Journal Toxicol Sci

Publisher Oxford University Press

Specialty Toxicology

Date 2009 Jan 30

PMID 19176594

Citations 7

Authors

Avina Paranjpe

Nicholas A Cacalano

Wyatt R Hume

Anahid Jewett

Affiliations

Soon will be listed here.

Abstract

The mechanisms by which resin based materials induce adverse effects in patients have not been completely elucidated. Here we show that 2-hydroxyethyl methacrylate (HEMA) induces apoptotic cell death in oral keratinocytes. Functional loss and cell death induced by HEMA was significantly inhibited in the presence of N-acetyl cysteine (NAC) treatment. NAC also prevented HEMA mediated decrease in vascular endothelial growth factor secretion. The protective effect of NAC was partly related to its ability to induce NF-kappaB in the cells, since HEMA mediated inhibition of nuclear NF-kappaB expression and function was significantly blocked in the presence of NAC treatment. Moreover, blocking of nuclear translocation of NF-kappaB in oral keratinocytes sensitized these cells to HEMA mediated apoptosis. In addition, since NAC was capable of rescuing close to 50% of NF-kappaB knockdown cells from HEMA mediated cell death, there is, therefore, an NF-kappaB independent pathway of protection from HEMA mediated cell death by NAC. NAC mediated prevention of HEMA induced cell death in NF-kappaB knockdown cells was correlated with a decreased induction of c-Jun N-terminal kinase (JNK) activity since NAC inhibited HEMA mediated increase in JNK levels. Furthermore, the addition of a pharmacologic JNK inhibitor to HEMA treated cells prevented cell death and restored NF-kappaB knockdown cell function significantly. Therefore, NAC protects oral keratinocytes from the toxic effects of HEMA through NF-kappaB dependent and independent pathways. Moreover, our data suggest the potential involvement of JNK pathway in NAC mediated protection.

Citing Articles

Biological aspects of modern dental composites.

Samuelsen J, Dahl J Biomater Investig Dent. 2023; 10(1):2223223.

PMID: 37347059 PMC: 10281392. DOI: 10.1080/26415275.2023.2223223.

Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials.

Horowitz R, Freeman P Med Hypotheses. 2020; 143:109851.

PMID: 32534175 PMC: 7242962. DOI: 10.1016/j.mehy.2020.109851.

Probiotic-Treated Super-Charged NK Cells Efficiently Clear Poorly Differentiated Pancreatic Tumors in Hu-BLT Mice.

Kaur K, Kozlowska A, Topchyan P, Ko M, Ohanian N, Chiang J Cancers (Basel). 2019; 12(1).

PMID: 31878338 PMC: 7017229. DOI: 10.3390/cancers12010063.

The influences of N-acetyl cysteine (NAC) on the cytotoxicity and mechanical properties of Poly-methylmethacrylate (PMMA)-based dental resin.

Jiao Y, Ma S, Li J, Shan L, Yang Y, Li M PeerJ. 2015; 3:e868.

PMID: 25922788 PMC: 4411485. DOI: 10.7717/peerj.868.

NF-kB mediated down-regulation of collagen synthesis upon HEMA (2-hydroxyethyl methacrylate) treatment of primary human gingival fibroblast/Streptococcus mutans co-cultured cells.

Grande R, Pacella S, Di Giulio M, Rapino M, Di Valerio V, Cellini L Clin Oral Investig. 2014; 19(4):841-9.

PMID: 25200938 PMC: 4429030. DOI: 10.1007/s00784-014-1304-4.

References

Kanerva L, Pelttari M, Jolanki R, Alanko K, Estlander T, Suhonen R . Occupational contact urticaria from diglycidyl ether of bisphenol A epoxy resin. Allergy. 2002; 57(12):1205-7. DOI: 10.1034/j.1398-9995.2002.13118.x. View

Baeuerle P, Henkel T . Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994; 12:141-79. DOI: 10.1146/annurev.iy.12.040194.001041. View

Cacalano N, Le D, Paranjpe A, Wang M, Fernandez A, Evazyan T . Regulation of IGFBP6 gene and protein is mediated by the inverse expression and function of c-jun N-terminal kinase (JNK) and NFkappaB in a model of oral tumor cells. Apoptosis. 2008; 13(12):1439-49. DOI: 10.1007/s10495-008-0270-1. View

Hibi M, Lin A, Smeal T, Minden A, Karin M . Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 1993; 7(11):2135-48. DOI: 10.1101/gad.7.11.2135. View

Spagnuolo G, Mauro C, Leonardi A, Santillo M, Paterno R, Schweikl H . NF-kappaB protection against apoptosis induced by HEMA. J Dent Res. 2004; 83(11):837-42. DOI: 10.1177/154405910408301103. View

Paranjpe A, Sung E, Cacalano N, Hume W, Jewett A . N-acetyl cysteine protects pulp cells from resin toxins in vivo. J Dent Res. 2008; 87(6):537-41. DOI: 10.1177/154405910808700603. View

Xia Z, Dickens M, Raingeaud J, Davis R, Greenberg M . Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995; 270(5240):1326-31. DOI: 10.1126/science.270.5240.1326. View

Hamid A, Okamoto A, Iwaku M, Hume W . Component release from light-activated glass ionomer and compomer cements. J Oral Rehabil. 1998; 25(2):94-9. DOI: 10.1046/j.1365-2842.1998.00247.x. View

Chang H, Guo M, Kasten F, Chang M, Huang G, Wang Y . Stimulation of glutathione depletion, ROS production and cell cycle arrest of dental pulp cells and gingival epithelial cells by HEMA. Biomaterials. 2004; 26(7):745-53. DOI: 10.1016/j.biomaterials.2004.03.021. View

10.

Chen Y, Wang X, Templeton D, Davis R, Tan T . The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem. 1996; 271(50):31929-36. DOI: 10.1074/jbc.271.50.31929. View

11.

Kyriakis J, Avruch J . Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem. 1996; 271(40):24313-6. DOI: 10.1074/jbc.271.40.24313. View

12.

Spagnuolo G, DAnto V, Cosentino C, Schmalz G, Schweikl H, Rengo S . Effect of N-acetyl-L-cysteine on ROS production and cell death caused by HEMA in human primary gingival fibroblasts. Biomaterials. 2005; 27(9):1803-9. DOI: 10.1016/j.biomaterials.2005.10.022. View

13.

Parasassi T, Brunelli R, Bracci-Laudiero L, Greco G, Gustafsson A, Krasnowska E . Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms. Cell Death Differ. 2005; 12(10):1285-96. DOI: 10.1038/sj.cdd.4401663. View

14.

Gustafsson A, Kupershmidt I, Edlundh-Rose E, Greco G, Serafino A, Krasnowska E . Global gene expression analysis in time series following N-acetyl L-cysteine induced epithelial differentiation of human normal and cancer cells in vitro. BMC Cancer. 2005; 5:75. PMC: 1182358. DOI: 10.1186/1471-2407-5-75. View

15.

Murley J, Kataoka Y, Hallahan D, Roberts J, Grdina D . Activation of NFkappaB and MnSOD gene expression by free radical scavengers in human microvascular endothelial cells. Free Radic Biol Med. 2001; 30(12):1426-39. DOI: 10.1016/s0891-5849(01)00554-8. View

16.

Beg A, Baltimore D . An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996; 274(5288):782-4. DOI: 10.1126/science.274.5288.782. View

17.

Eliyahu D, Raz A, Gruss P, Givol D, Oren M . Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature. 1984; 312(5995):646-9. DOI: 10.1038/312646a0. View

18.

Tang F, Tang G, Xiang J, Dai Q, Rosner M, Lin A . The absence of NF-kappaB-mediated inhibition of c-Jun N-terminal kinase activation contributes to tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol. 2002; 22(24):8571-9. PMC: 139858. DOI: 10.1128/MCB.22.24.8571-8579.2002. View

19.

Lane D . Cell immortalization and transformation by the p53 gene. Nature. 1984; 312(5995):596-7. DOI: 10.1038/312596a0. View

20.

Jewett A, Wang M, Teruel A, Poupak Z, Bostanian Z, Park N . Cytokine dependent inverse regulation of CD54 (ICAM1) and major histocompatibility complex class I antigens by nuclear factor kappaB in HEp2 tumor cell line: effect on the function of natural killer cells. Hum Immunol. 2003; 64(5):505-20. DOI: 10.1016/s0198-8859(03)00039-9. View