Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Glutamine Inhibits TNF-α-induced Cytosolic Phospholipase A2 Activation via Upregulation of MAPK Phosphatase-1

  • Yoon, So Young (Department of Biological Sciences, College of Natural Sciences, Chonnam National University) ;
  • Jeong, Soo-Yeon (Department of Biological Sciences, College of Natural Sciences, Chonnam National University) ;
  • Im, Suhn-Young (Department of Biological Sciences, College of Natural Sciences, Chonnam National University)
  • Received : 2021.10.25
  • Accepted : 2021.12.06
  • Published : 2021.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Tumor necrosis factor alpha (TNF-α) is a principal regulator of inflammation and immunity. The proinflammatory properties of TNF-α can be attributed to its ability to activate the enzyme cytosolic phospholipase A2 (cPLA2), which generates potent inflammatory lipid mediators, eicosanoids. L-glutamine (Gln) plays physiologically important roles in various metabolic processes. We have reported that Gln has a potent anti-inflammatory activity via rapid upregulation of mitogen-activated protein kinases (MAPKs) phosphatase (MKP)-1, which preferentially dephosphorylates the key proinflammatory enzymes, p38 MAPK and cytosolic phospholipase A2 (cPLA2). In this study, we have investigated whether Gln could inhibit TNF-α-induced cPLA2 activation. Gln inhibited TNF-α-induced increases in cPLA2 phosphorylation in the lungs and blood levels of the cPLA2 metabolites, leukotrine B4 (LTB4) (lipoxygenase metabolite) and prostaglandin E2 (PGE2) (cyclooxygenase metabolite). TNF-α increased p38 and cPLA2 phosphorylation and blood levels of LTB4 and PGE2, which were blocked by the p38 inhibitor SB202190. Gln inhibited TNF-α-induced p38 and cPLA2 phosphorylation and production of the cPLA2 metabolites. Such inhibitory activity of Gln was no longer observed in MKP-1 small interfering RNA-pretreated animals. Our data indicate that Gln inhibited TNF-α-induced cPLA2 phosphorylation through MKP-1 induction/p38 inhibition, and suggest that the utility of Gln in inflammatory diseases in which TNF-α plays a major role in their pathogenesis.

Keywords

Acknowledgement

This study was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (2016R1D1A3B03934457).

References

  1. Albrecht J, Sidoryk-Wegrzynowicz M, Zielinska M, Aschner M. Roles of glutamine in neurotransmission. Neuron Glia Biol. 2010. 6: 263-276. https://doi.org/10.1017/S1740925X11000093
  2. Amores-Sanchez MI, Medina MA. Glutamine, as a precursor of glutathione, and oxidative stress. Mol Genet Metab. 1999. 67: 100-105. https://doi.org/10.1006/mgme.1999.2857
  3. Ayush O, Jin ZW, Kim HK, Shin Y, Im SY, Lee HK. Glutamine up-regulates MAPK phosphatase-1 induction via activation of Ca2+ → ERK cascade pathway. Biochem Biophys Rep. 2016. 7: 10-19.
  4. Ayush O, Lee CH, Kim HK, Im SY, Cho BH, Lee HK. Glutamine suppresses dinitrofluorobenzene-induced contact dermatitis by deactivating p38 mitogen-activated protein kinase via induction of MAPK phosphatase-1. J Invest Dermatol. 2013. 133: 723-731. https://doi.org/10.1038/jid.2012.373
  5. Brondello JM, Pouyssegur J, McKenzie FR. Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science. 1999. 286: 2514-2517. https://doi.org/10.1126/science.286.5449.2514
  6. Chattopadhyay S, Machado-Pinilla R, Manguan-Garcia CManguan-Garcia C et al. MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer. Oncogene. 2006. 25: 3335-3345. https://doi.org/10.1038/sj.onc.1209364
  7. Chi H, Barry SP, Roth RJRoth RJ et al. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci USA. 2006. 103: 2274-2279. https://doi.org/10.1073/pnas.0510965103
  8. Deepak P, Sifuentes H, Sherid MD, Stobaugh D, Sadozai Y, Ehrenpreis ED. T-cell non-Hodgkin's lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 2013. 108: 99-105. https://doi.org/10.1038/ajg.2012.334
  9. Dennis EA, Cao J, Hsu YH, Magrioti V, Kokotos G. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem Rev. 2011. 111: 6130-6185. https://doi.org/10.1021/cr200085w
  10. Encarnacion S, Calderon J, Gelbard AS, Cooper AJ, Mora J. Glutamine biosynthesis and the utilization of succinate and glutamine by Rhizobium etli and Sinorhizobium meliloti. Microbiology. 1998. 144: 2629-2638. https://doi.org/10.1099/00221287-144-9-2629
  11. Feldmann M, Maini RN. Perspectives from masters in rheumatology and autoimmunity: can we get closer to a cure for rheumatoid arthritis? Arthritis Rheumatol. 2015. 67: 2283-2291. https://doi.org/10.1002/art.39269
  12. Feuerherm AJ, Dennis EA, Johansen B. Cytosolic group IVA phospholipase A2 inhibitors, AVX001 and AVX002, ameliorate collagen-induced arthritis. Arthritis Res Ther. 2019. 21: 29-41. https://doi.org/10.1186/s13075-018-1794-6
  13. Fox RE, Hopkins IB, Cabacungan ET, Tildon JT. The role of glutamine and other alternate substrates as energy sources in the fetal rat lung type II cell. Pediatr Res. 1996. 40: 135-141. https://doi.org/10.1203/00006450-199607000-00023
  14. Franklin CC, Kraft AS. Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells. J Biol Chem. 1997. 272: 16917-16923. https://doi.org/10.1074/jbc.272.27.16917
  15. Franklin CC, ikanth S Sr, Kraft AS. Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis. Proc Natl Acad Sci USA. 1998. 95: 3014-3019. https://doi.org/10.1073/pnas.95.6.3014
  16. Griffiths RD. Nutrition support in critically ill septic patients. Curr Opin Clin Nutr Metab Care. 2003. 6: 203-210. https://doi.org/10.1097/01.mco.0000058591.27240.4e
  17. Griffiths RD, Jones C, Palmer TE. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutrition. 1997. 13: 295-302. https://doi.org/10.1016/S0899-9007(97)00017-8
  18. Hammer M, Mages J, Dietrich HDietrich H et al. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. J Exp Med. 2006. 203: 15-20. https://doi.org/10.1084/jem.20051753
  19. Hirabayashi T, Shimizu T. Localization and regulation of cytosolic phospholipase A2. Biochim Biophys Acta. 2000. 1488: 124-138. https://doi.org/10.1016/S1388-1981(00)00115-3
  20. Hoeck WG, Ramesha CS, Chang DJ, Fan N, Heller RA. Cytoplasmic phospholipase A2 activity and gene expression are stimulated by tumor necrosis factor: dexamethasone blocks the induced synthesis. Proc Natl Acad Sci USA. 1993. 90: 4475-4479. https://doi.org/10.1073/pnas.90.10.4475
  21. Im YN, Jeong SY, Youm JY, Lee HK, Im SY. L-glutamine attenuates DSS-induced Colitis via induction of MAPK phosphatase-1. Nutrients. 2018. 10: 288-297. https://doi.org/10.3390/nu10030288
  22. Jia Z, Babu PV, Si HSi H et al. Genistein inhibits TNF-α-induced endothelial inflammation through the protein kinase pathway A and improves vascular inflammation in C57BL/6 mice. Int J Cardiol. 2013. 168: 2637-2645. https://doi.org/10.1016/j.ijcard.2013.03.035
  23. Jeong SY, Im SY. Estrogen induces CK2a activation via generation of reactive oxygen species. Biomed Sci Letters. 2019. 25: 23-31. https://doi.org/10.15616/bsl.2019.25.1.23
  24. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016. 12: 49-62. https://doi.org/10.1038/nrrheum.2015.169
  25. Keyse SM, Emslie EA. Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature. 1992. 359: 644-647. https://doi.org/10.1038/359644a0
  26. Kim JM, Im YN, Chung YJ, et al. Glutamine deficiency shifts the asthmatic state toward neutrophilic airway inflammation. Allergy. 2021. Oct 3. doi: 10.1111/all.15121. Online ahead of print.
  27. Kim YS, Kim GY, Kim JHKim JH et al. Glutamine inhibits lipopolysaccharide-induced cytoplasmic phospholipase A2 activation and protects against endotoxin shock in mouse. Shock. 2006. 25: 290-294. https://doi.org/10.1097/01.shk.0000194041.18699.6f
  28. Ko HM, Kang NI, Kim YSKim YS et al. Glutamine preferentially inhibits T-helper type 2 cell-mediated airway inflammation and late airway hyperresponsiveness through the inhibition of cytosolic phospholipase A2 activity in a murine asthma model. Clin Exp Allergy. 2008. 38: 357-364. https://doi.org/10.1111/j.1365-2222.2007.02900.x
  29. Ko HM, Oh SH, Bang HSBang HS et al. Glutamine protects mice from lethal endotoxic shock via a rapid induction of MAPK phosphatase-1. J Immunol. 2009. 182: 7957-7962. https://doi.org/10.4049/jimmunol.0900043
  30. Lee CH, Kim HK, Kim JMKim JM et al. Glutamine suppresses airway neutrophilia by blocking cytosolic phospholipase A(2) via an induction of MAPK phosphatase-1. J Immunol. 2012. 189: 5139-5146. https://doi.org/10.4049/jimmunol.1201599
  31. Lee IT, Lin CC, Cheng SE, Hsiao LD, Hsiao YC, Yang CM. TNF-α induces cytosolic phospholipase A2 expression in human lung epithelial cells via JNK1/2- and p38 MAPK-dependent AP-1 activation. PLoS One. 2013. 8: e72783-72793. https://doi.org/10.1371/journal.pone.0072783
  32. Leslie CC. Cytosolic phospholipase A2: physiological function and role in disease. J Lipid Res. 2015. 56: 1386-1402. https://doi.org/10.1194/jlr.R057588
  33. Li J, Gorospe M, Hutter D, Barnes J, Keyse SM, Liu Y. Transcriptional induction of MKP-1 in response to stress is associated with histone H3 phosphorylation-acetylation. Mol Cell Biol. 2001. 21: 8213-8224. https://doi.org/10.1128/MCB.21.23.8213-8224.2001
  34. Lin CC, Lin WN, Cho RL, Wang CY, Hsiao LD, Yang CM. TNF-α-induced cPLA2 expression via NADPH oxidase/reactive oxygen species-dependent NF-κB cascade on human pulmonary alveolar epithelial cells. Front Pharmacol. 2016. 7: 447-462.
  35. Lin YW, Yang JL. Cooperation of ERK and SCFSkp2 for MKP-1 destruction provides a positive feedback regulation of proliferating signaling. J Biol Chem. 2006. 281: 915-926. https://doi.org/10.1074/jbc.M508720200
  36. Marusic S, Thakker P, Pelker JWPelker JW et al. Blockade of cytosolic phospholipase A2 alpha prevents experimental autoimmune encephalomyelitis and diminishes development of Th1 and Th17 responses. J Neuroimmunol. 2008. 204: 29-37. https://doi.org/10.1016/j.jneuroim.2008.08.012
  37. Misra-Press A, Rim CS, Yao H, Roberson MS, Stork PJ. A novel mitogen-activated protein kinase phosphatase: structure, expression, and regulation. J Biol Chem. 1995. 270: 14587-14596. https://doi.org/10.1074/jbc.270.24.14587
  38. Monaco C, Nanchahal J, Taylor P, Feldmann M. Anti-TNF therapy: past, present and future. Int Immunol. 2015. 27: 55-62. https://doi.org/10.1093/intimm/dxu102
  39. Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med. 2002. 30: 2022-2029. https://doi.org/10.1097/00003246-200209000-00011
  40. Omland SH, Habicht A, Damsbo P, Wilms J, Johansen B, Gniadecki RJ. A randomized, double-blind, placebo-controlled, dose-escalation first-in-man study (phase 0) to assess the safety and efficacy of topical cytosolic phospholipase A2 inhibitor, AVX001, in patients with mild to moderate plaque psoriasis. Eur Acad Dermatol Venereol. 2017. 7: 1161-1167.
  41. Rosengarten M, Hadad N, Solomonov Y, Lamprecht S, Levy R. Cytosolic phospholipase A2 has a crucial role in the pathogenesis of DSS-induced colitis in mice. Eur J Immunol. 2016. 46: 400-408. https://doi.org/10.1002/eji.201545848
  42. Sapirstein A, Bonventre JV. Specific physiological roles of cytosolic phospholipase A2 as defined by gene knockouts. Biochim Biophys Acta. 2000. 1488: 139-148. https://doi.org/10.1016/S1388-1981(00)00116-5
  43. Smith JA, Kauffman CA. Endemic fungal infections in patients receiving tumour necrosis factor-α inhibitor therapy. Drugs. 2009. 69: 1403-1415. https://doi.org/10.2165/00003495-200969110-00002
  44. Su B, Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol. 1996. 8: 402-411. https://doi.org/10.1016/S0952-7915(96)80131-2
  45. Sun H, Charles CH, Lau LF, Tonks NK. MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. Cell. 1993. 75: 487-493. https://doi.org/10.1016/0092-8674(93)90383-2
  46. Taylor P, Williams R, Feldmann M. Tumour necrosis factor as a therapeutic target for immune-mediated inflammatory diseases. Curr Opin Biotechnol. 2004. 15: 557-563. https://doi.org/10.1016/j.copbio.2004.09.005
  47. Wang J, Yin DP, Liu YX, Baer R, Yin Y. Dual specificity phosphatase 1/CL100 is a direct transcriptional target of E2F-1 in the apoptotic response to oxidative stress. Cancer Res. 2007. 67: 6737-6744. https://doi.org/10.1158/0008-5472.CAN-06-4402
  48. Wang Z, Xu J, Zhou JY, Liu Y, Wu GS. Mitogen-activated protein kinase phosphatase-1 is required for cisplatin resistance. Cancer Res. 2006. 66: 8870-8877. https://doi.org/10.1158/0008-5472.CAN-06-1280
  49. Wischmeyer PE, Lynch J, Liedel JLiedel J et al. Glutamine administration reduces Gram-negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control. Crit Care Med. 2001. 29: 2075-2080. https://doi.org/10.1097/00003246-200111000-00006
  50. Yang D, Ji HF, Zhang XMZhang XM et al. Protective effect of cytosolic phospholipase A2 inhibition against inflammation and degeneration by promoting regulatory T cells in rats with experimental autoimmune encephalomyelitis. Mediators Inflamm. 2014. 2014: 890139-890146.
  51. Zhao Q, Wang X, Nelin LDNelin LD et al. MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J Exp Med. 2006. 203: 131-140. https://doi.org/10.1084/jem.20051794