Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter August 11, 2016

Glutathione and glutathione derivatives in immunotherapy

  • Alessandra Fraternale EMAIL logo , Serena Brundu and Mauro Magnani
From the journal Biological Chemistry

Abstract

Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment, which is important for several cellular functions. Altered intracellular GSH levels are observed in a wide range of pathologies, including several viral infections, as well as in aging, all of which are also characterized by an unbalanced Th1/Th2 immune response. A central role in influencing the immune response has been ascribed to GSH. Specifically, GSH depletion in antigen-presenting cells (APCs) correlates with altered antigen processing and reduced secretion of Th1 cytokines. Conversely, an increase in intracellular GSH content stimulates IL-12 and/or IL-27, which in turn induces differentiation of naive CD4+ T cells to Th1 cells. In addition, GSH has been shown to inhibit the replication/survival of several pathogens, i.e. viruses and bacteria. Hence, molecules able to increase GSH levels have been proposed as new tools to more effectively hinder different pathogens by acting as both immunomodulators and antimicrobials. Herein, the new role of GSH and its derivatives as immunotherapeutics will be discussed.

Acknowledgments

This work was supported by PRIN (Research projects of National interest) 2010-2011-prot. 2010PHT9NF_004 granted to Fraternale. Funding organization: Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR).

References

Afkarian, M., Sedy, J.R., Yang, J., Jacobson, N.G., Cereb, N., Yang, S.Y., Murphy, T.L., and Murphy, K.M. (2002). T-bet is a STAT1-induced regulator for IL-12R expression in naïve CD4+ T cells. Nat. Immunol. 3, 549–557.10.1038/ni794Search in Google Scholar

Aggarwal, B.B. (1998). Human Cytokines (London: Blackwell Science).Search in Google Scholar

Alam, K., Ghousunnissa, S., Nair, S., Valluri, V.L., and Mukhopadhyay, S. (2010). Glutathione-redox balance regulates c-rel-driven IL-12 production in macrophages: possible implications in antituberculosis immunotherapy. J. Immunol. 184, 2918–2929.10.4049/jimmunol.0900439Search in Google Scholar

Allan, E.R., Tailor, P., Balce, D.R., Pirzadeh, P., McKenna, N.T., Renaux, B., Warren, A.L., Jirik, F.R., and Yates, R.M. (2014). NADPH oxidase modifies patterns of MHC class II-restricted epitopic repertoires through redox control of antigen processing. J. Immunol. 192, 4989–5001.10.4049/jimmunol.1302896Search in Google Scholar

Allen, M., Bailey, C., Cahatol, I., Dodge, L., Yim, J., Kassissa, C., Luong, J., Kasko, S., Pandya, S., and Venketaraman V. (2015). Mechanisms of control of Mycobacterium tuberculosis by NK cells: role of glutathione. Front. Immunol. 6, 508.10.3389/fimmu.2015.00508Search in Google Scholar

Anderberg, S.J., Newton, G.L., and Fahey, R.C. (1998). Micothiol biosynthesis and metabolism; cellular levels of potential intermediates in the biosynthesis and degradation of mycothiol in Mycobacterium smegmatis. J. Biol. Chem. 273, 30391–30397.10.1074/jbc.273.46.30391Search in Google Scholar

Anderson, M.E., Powrie, F., Puri, R.N., and Meister, A. (1985). Glutathione monoethyl ester: preparation, uptake by tissues, and conversion to glutathione. Arch. Biochem. Biophys. 239, 538–548.10.1016/0003-9861(85)90723-4Search in Google Scholar

Anderson, M.E., Nilsson, M., and Sims, N.R. (2004). Glutathione monoethyl ester prevents mitochondrial glutathione depletion during focal cerebral ischemia. Neurochem. Int. 44, 153–159.10.1016/S0197-0186(03)00133-5Search in Google Scholar

Aquilano, K., Baldelli, S., and Ciriolo, M.R. (2014). Glutathione: new roles in redox signaling for an old antioxidant. Front. Pharmacol. 5, 196.10.3389/fphar.2014.00196Search in Google Scholar PubMed PubMed Central

Arango, D.G. and Descoteaux, A. (2014). Macrophage cytokines: involvement in immunity and infectious diseases. Front. Immunol. 5, 491.10.3389/fimmu.2014.00491Search in Google Scholar PubMed PubMed Central

Ates, B., Abraham, L., and Ercal, N. (2008). Antioxidant and free radical scavenging properties of Nacetylcysteine amide (NACA) and comparison with N-acetylcysteine (NAC). Free Radic. Res. 42, 372–377.10.1080/10715760801998638Search in Google Scholar PubMed

Aukrust, P., Müller, F., Svardal, A.M., Ueland, T., Berge, R.K., and Froland, S.S. (2003). Disturbed glutathione metabolism and decreased antioxidant levels in human immunodeficiency virus-infected patients during highly active antiretroviral therapy-potential immunomodulatory effects of antioxidants. J. Infect. Dis. 188, 232–238.10.1086/376459Search in Google Scholar

Aw, D., Silva, A.B., and Palmer, D.B. (2007). Immunosenescence: emerging challenges for an ageing population. Immunology 120, 435–446.10.1111/j.1365-2567.2007.02555.xSearch in Google Scholar

Balikò, Z., Szereday, L., and Szekeres-Bartho, J. (1998). Th2 biased immune response in cases with active M. tb infection and tuberculin anergy. FEMS Immunol. Med. Microbiol. 22, 199–204.10.1016/S0928-8244(98)00089-3Search in Google Scholar

Balkwill, F. (2000). The Cytokine Network (Oxford: Oxford University Press).Search in Google Scholar

Ballatori, N., Krance, S.M., Notenboom, S., Shi, S., Tieu, K., and Hammond, C.L. (2009). Glutathione dysregulation and the etiology and progression of human diseases. Biol. Chem. 390, 191–214.10.1515/BC.2009.033Search in Google Scholar

Bermudez, L.E., Wu, M., and Young, L.S. (1995). Interleukin-12-stimulated natural killer cells can activate human macrophages to inhibit growth of Mycobacterium avium. Infect. Immun. 63, 4099–4104.10.1128/iai.63.10.4099-4104.1995Search in Google Scholar

Biswas, S., Chida, A.S., and Rahman, I. (2006). Redox modifications of protein-thiols: emerging roles in cell signaling. Biochem. Pharmacol. 71, 551–564.10.1016/j.bcp.2005.10.044Search in Google Scholar

Buhl, R., Jaffe, H.A., Holroyd, K.J., Wells, F.B., Mastrangeli, A., Saltini, C., Cantin, A.M., and Crystal, R.G. (1989). Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet 2, 1294–1298.10.1016/S0140-6736(89)91909-0Search in Google Scholar

Cacciatore, I., Cornacchia, C., Pinnen, F., Mollica, A., and Di Stefano, A. (2010). Prodrug approach for increasing cellular glutathione levels. Molecules 15, 1242–1264.10.3390/molecules15031242Search in Google Scholar

Cai, J., Chen, Y., Seth, S., Furukawa, S., Compans, R.W., and Jones, D.P. (2003). Inhibition of influenza infection by glutathione. Free Radic. Biol. Med. 34, 928–936.10.1016/S0891-5849(03)00023-6Search in Google Scholar

Cappiello, M., Amodeo, P., Mendez, B.L., Scaloni, A., Vilardo, P.G., Cecconi, I., Dal Monte, M., Banditelli, S., Talamo, F., Micheli, V., et al. (2001). Modulation of aldose reductase activity through S-thiolation by physiological thiols. Chem. Biol. Interact. 130132, 597–608.10.1016/S0009-2797(00)00286-6Search in Google Scholar

Ciriolo, M.R., Palamara, A.T., Incerpi, S., Lafavia, E., Buè, M.C., De Vito, P., Garaci, E., and Rotilio, G. (1997). Loss of GSH, oxidative stress, and decrease of intracellular pH as sequential steps in viral infection. J. Biol. Chem. 272, 2700–2708.10.1074/jbc.272.5.2700Search in Google Scholar

Cresswell, P., Ackerman, A.L., Giodini, A., Peaper, D.R., and Wearsch, P.A. (2005). Mechanisms of MHC class I-restricted antigen processing and cross-presentation. Immunol. Rev. 207, 145–157.10.1111/j.0105-2896.2005.00316.xSearch in Google Scholar

Crotzer, V.L. and Blum, J.S. (2009). Autophagy and its role in MHC-mediated antigen presentation. J. Immunol. 182, 3335–3341.10.4049/jimmunol.0803458Search in Google Scholar

Denis, M. (1994). Interleukin-12 (IL-12) augments cytolytic activity of natural killer cells toward Mycobacterium tuberculosis-infected human monocytes. Cell. Immunol. 156, 529–536.10.1006/cimm.1994.1196Search in Google Scholar

Desideri, E., Filomeni, G., and Ciriolo, M.R. (2012). Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells. Autophagy 8, 1769–1781.10.4161/auto.22037Search in Google Scholar

Djuretic, I.M., Levanon, D., Negreanu, V., Groner, Y., Rao, A., and Ansel, K.M. (2007). Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat. Immunol. 8, 145–153.10.1038/ni1424Search in Google Scholar

Dobashi, K., Aihara, M., Araki, T., Shimizu, Y., Utsugi, M., Iizuka, K., Murata, Y., Hamuro, J., Nakazawa, T., and Mori, M. (2001). Regulation of LPS induced IL-12 production by IFN-γ and IL-4 through intracellular glutathione status in human alveolar macrophages. Clin. Exp. Immunol. 124, 290–296.10.1046/j.1365-2249.2001.01535.xSearch in Google Scholar

Dröge, W. (2002). Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants. Exp. Gerontol. 37, 1333–1345.10.1016/S0531-5565(02)00175-4Search in Google Scholar

Duh, E.J., Maury, W.J., Folks, T.M., Fauci, A.S., and Rabson, A.B. (1989). Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-κB sites in the long terminal repeat. Proc. Natl. Acad. Sci. USA 86, 5974–5978.10.1073/pnas.86.15.5974Search in Google Scholar PubMed PubMed Central

Ensoli, F., Cafaro, A., Casabianca, A., Tripiciano, A., Bellino, S., Longo, O., Francavilla, V., Picconi, O., Sgadari, C., Moretti, S., et al. (2015). HIV-1 Tat immunization restores immune homeostasis and attacks the HAART-resistant blood HIV DNA: results of a randomized phase II exploratory clinical trial. Retrovirology 12, 33.10.1186/s12977-015-0151-ySearch in Google Scholar PubMed PubMed Central

Farrar, J.D., Asnagli, H., and Murphy, K.M. (2002). T helper subset development: roles of instruction, selection, and transcription. J. Clin. Invest. 109, 431–435.10.1172/JCI0215093Search in Google Scholar

Fraternale, A., Casabianca, A., Orlandi, C., Cerasi, A., Chiarantini, L., Brandi, G., and Magnani, M. (2002). Macrophage protection by addition of glutathione (GSH)-loaded erythrocytes to AZT and DDI in a murine AIDS model. Antiviral Res. 56, 263–272.10.1016/S0166-3542(02)00128-6Search in Google Scholar

Fraternale, A., Paoletti, M.F., Casabianca, A., Orlandi, C., Schiavano, G.F., Chiarantini, L., Clayette, P., Oiry, J., Vogel, J.U., Cinatl, J.Jr., et al. (2008). Inhibition of murine AIDS by pro-glutathione (GSH) molecules. Antiviral Res. 77, 120–127.10.1016/j.antiviral.2007.11.004Search in Google Scholar

Fraternale, A., Paoletti, M.F., Casabianca, A., Nencioni, L., Garaci, E., Palamara, A.T., and Magnani, M. (2009). GSH and analogs in antiviral therapy. Mol. Aspects Med. 30, 99–110.10.1016/j.mam.2008.09.001Search in Google Scholar

Fraternale, A., Paoletti, M.F., Dominici, S., Caputo, A., Castaldello, A., Millo, E., Brocca-Cofano, E., Smietana, M., Clayette, P., Oiry, J., et al. (2010). The increase in intra-macrophage thiols induced by new pro-GSH molecules directs the Th1 skewing in ovalbumin immunized mice. Vaccine 28, 7676–7682.10.1016/j.vaccine.2010.09.033Search in Google Scholar

Fraternale, A., Paoletti, M.F, Dominici, S., Buondelmonte, C., Caputo, A., Castaldello, A., Tripiciano, A., Cafaro, A., Palamara, A.T., Sgarbanti, R., et al. (2011). Modulation of Th1/Th2 immune responses to HIV-1 Tat by new pro-GSH molecules. Vaccine 29, 6823–6829.10.1016/j.vaccine.2011.07.101Search in Google Scholar

Fraternale, A., Crinelli, R., Casabianca, A., Paoletti, M.F., Orlandi, C., Carloni, E., Smietana, M., Palamara, A.T., and Magnani, M. (2013). Molecules altering the intracellular thiol content modulate NF-κB and STAT-1/IRF-1 signalling pathways and IL-12 p40 and IL-27 p28 production in murine macrophages. PLoS One 8, e57866.10.1371/journal.pone.0057866Search in Google Scholar

Fraternale, A., Brundu, S., and Magnani, M. (2015). Polarization and repolarization of macrophages. J. Clin. Cell. Immunol. 6, 319.Search in Google Scholar

Frosch, S., Bonifas, U., Eck, H.P., Bockstette, M., Droege, W., Rüde, E., and Reske-Kunz A.B. (1993). The efficient bovine insulin presentation capacity of bone marrow-derived macrophages activated by granulocyte-macrophage colony-stimulating factor correlates with a high level intracellular reducing thiols. Eur. J. Immunol. 23, 1430–1434.10.1002/eji.1830230704Search in Google Scholar

Gainey, D., Short, S., and McCoy, K. (1996). Intracellular location of cysteine transport activity correlates with productive-processing of antigen disulfide. J. Cell. Physiol. 168, 248–254.10.1002/(SICI)1097-4652(199608)168:2<248::AID-JCP3>3.0.CO;2-PSearch in Google Scholar

Garaci, E., Palamara, A.T., Di Francesco, P., Favalli, C., Ciriolo, M.R., and Rotilio, G. (1992). Glutathione inhibits replication and expression of viral proteins in cultured cells infected with Sendai virus. Biochem. Biophys. Res. Commun. 188, 1090–1096.10.1016/0006-291X(92)91343-OSearch in Google Scholar

Garaci, E., Palamara, A.T., Ciriolo, M.R., D’Agostini, C., Abdel-Latif, M.S., Aquaro, S., Lafavia, E., and Rotilio, G. (1997). Intracellular GSH content and HIV replication in human macrophages. J. Leukoc. Biol. 62, 54–59.10.1002/jlb.62.1.54Search in Google Scholar

Giral, P., Jacob, N., Dourmap, C., Hansel, B., Carrié, A., Bruckert, E., Girerd, X., and Chapman, M.J. (2008). Elevated gammaglutamyltransferase activity and perturbed thiol profile are associated with features of metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 28, 587–593.10.1161/ATVBAHA.107.157891Search in Google Scholar

Grinberg, L., Fibach, E., Amer, J., and Atlas, D. (2005). N-acetylcysteine amide, a novel cell-permeating thiol, restores cellular glutathione and protects human red blood cells from oxidative stress. Free Radic. Biol. Med. 38, 136–145.10.1016/j.freeradbiomed.2004.09.025Search in Google Scholar

Grubeck-Loebenstein, B. and Wick, G. (2002). The ageing of the immune system. Adv. Immunol. 80, 243–284.10.1016/S0065-2776(02)80017-7Search in Google Scholar

Grubeck-Loebenstein, B., Della Bella, S., Iorio, A.M., Michel, J.P., Pawelec, G., and Solana, R. (2009). Immunosenescence and vaccine failure in the elderly. Aging Clin. Exp. Res. 21, 201–209.10.1007/BF03324904Search in Google Scholar PubMed

Guerra, C., Morris, D., Sipin, A., Kung, S., Franklin, M., Gray, D., Tanzil, M., Guilford, F., Khasawneth, F.T., and Venketaraman, V. (2011). Glutathione and adaptive immune responses against Mycobacterium tuberculosis infection in healthy and HIV infected individuals. PloS One 6, e28378.10.1371/journal.pone.0028378Search in Google Scholar PubMed PubMed Central

Hadzic, T., Li, L., Cheng, N., Walsh, S.A., Spitz, D.R., and Knudson, C.M. (2005). The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion. J. Immunol. 175, 7965–7972.10.4049/jimmunol.175.12.7965Search in Google Scholar PubMed

Hamuro, J., Murata, Y., and Suzuki, M. (1999). The triggering and healing of tumor stromal inflammatory reactions regulated by oxidative and reductive macrophages. Gann. Monograph Cancer Res. 48, 153–164.Search in Google Scholar

Haque, M.A., Hawes, J.W., and Blum, J.S. (2001). Cysteinylation of MHC Class II ligands: peptide endocytosis and reduction within APC influences T cell recognition. J. Immunol. 166, 4543–4551.10.4049/jimmunol.166.7.4543Search in Google Scholar PubMed

Hassan, M.Q., Hadi, R.A., Al-Rawi, Z.S., Padron, V.A., and Stohs, S.J. (2001). The glutathione defense system in the pathogenesis of rheumatoid arthritis. J. Appl. Toxicol. 21, 69–73.10.1002/jat.736Search in Google Scholar PubMed

Hayes, J.D. and McLellan, L.I. (1999). Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic. Res. 31, 273–300.10.1080/10715769900300851Search in Google Scholar PubMed

Hodgson, K., Morris, J., Bridson, T., Govan, B., Rush, C., and Ketheesan, N. (2015). Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections. Immunology 144, 171–185.10.1111/imm.12394Search in Google Scholar PubMed PubMed Central

Hwang, E.S., Szabo, S.J., Schwartzberg, P.L., and Glimcher, L.H. (2005). T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307, 430–433.10.1126/science.1103336Search in Google Scholar PubMed

Incze, K., Farkas, J., Mihalyi, V., and Zukal, E. (1974). Antibacterial effect of cysteine-nitrosothiol and possible percursors thereof. Appl. Microbiol. 27, 202–205.10.1128/am.27.1.202-205.1974Search in Google Scholar PubMed PubMed Central

Jensen, P.E. (1995). Antigen unfolding and disulfide reduction in antigen presenting cells. Semin. Immunol. 7, 347–353.10.1006/smim.1995.0039Search in Google Scholar PubMed

Kaiko, G.E., Horvat, J.C., Beagley, K.W, and Hansbro, P.M. (2007). Immunological decision-making: how does the immune system decide to mount a helper T-cell response? Immunology 123, 326–338.10.1111/j.1365-2567.2007.02719.xSearch in Google Scholar PubMed PubMed Central

Kalebic, T., Kinter, A., Poli, G., Anderson, M.E., Meister, A., and Fauci A.S. (1991). Suppression of human immunodeficiency virus expression in chronically infected monocytic cells by glutathione, glutathione ester, and N-acetylcysteine. Proc. Natl. Acad. Sci. USA 88, 986–990.10.1073/pnas.88.3.986Search in Google Scholar PubMed PubMed Central

Kamide, Y., Utsugi, M., Dobashi, K., Ono, A., Ishizuka, T., Hisada, T., Koga, Y., Uno, Y., Hamuro, J., and Mori, M. (2011). Intracellular glutathione redox status in human dendritic cells regulates IL-27 production and T-cell polarization. Allergy 66, 1183–1192.10.1111/j.1398-9995.2011.02611.xSearch in Google Scholar PubMed

Kato, T., Oikawa, S.T., Takahashi, K., Saito, K., Wang, L., Nishio, A., Hakamada-Taguchi, R., Kawanishi, S., and Kuribayashi, K. (2006). Endocrine disruptors that deplete glutathione levels in APC promote Th2 polarization in mice leading to the exacerbation of airway inflammation. Eur. J. Immunol. 36, 1199–1209.10.1002/eji.200535140Search in Google Scholar PubMed

Kato, C., Mikami, M., and Natsuno, T. (2008). Participation of glutathione in the elimination of Porphyromonas gingivalis in vivo. Oral. Microbiol. Immunol. 23, 441–448.10.1111/j.1399-302X.2008.00436.xSearch in Google Scholar PubMed

Khan, N., Alam, K., Mande, S.C., Valluri, V.L., Hasnain, S.E., and Mukhopadhyay, S. (2008). Mycobacterium tuberculosis heat shock protein 60 modulates immune response to PPD by manipulating the surface expression of TLR2 on macrophages. Cell. Microbiol. 10, 1711–1722.10.1111/j.1462-5822.2008.01161.xSearch in Google Scholar PubMed

Koike, Y., Hisada, T., Utsugi, M., Ishizuka, T., Shimizu, Y., Ono, A., Murata, Y., Hamuro, J., Mori, M., and Dobashi, K. (2007). Glutathione redox regulates airway hyperresponsiveness and airway inflammation in mice. Am. J. Respir. Cell. Mol. Biol. 37, 322–329.10.1165/rcmb.2006-0423OCSearch in Google Scholar

Lagman, M., Ly, J., Saing, T., Kaur, S.M., Tudela, E.V., Morris, D., Chi, P.-T., Ochoa, C., Sathananthan, A., and Venketaraman, V. (2015). Investigating the causes for decreased levels of glutathione in individuals with type II diabetes. PLoS One 10, e0118436.10.1371/journal.pone.0118436Search in Google Scholar

Linehan, E. and Fitzgerald, D.C. (2015). Ageing and the immune system: focus on macrophages. Eur. J. Microbiol. Immunol. 5, 14–24.10.1556/EuJMI-D-14-00035Search in Google Scholar

Lu, S.C. (2009). Regulation of glutathione synthesis. Mol. Asp. Med. 30, 42–59.10.1016/S0070-2137(01)80004-2Search in Google Scholar

Lucas, S., Ghilardi, N., Li, J., and de Sauvage F.J. (2003). IL-27 regulates IL-12 responsiveness of naïve CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc. Natl. Acad. Sci. USA 100, 15047–15052.10.1073/pnas.2536517100Search in Google Scholar PubMed PubMed Central

Luckheeram, V.R., Zhou, R., Verma, A.D., and Bing, X. (2012). CD4+ T cells: differentiation and functions. Clin. Dev. Immunol. 2012, 925135.10.1155/2012/925135Search in Google Scholar PubMed PubMed Central

Lugo-Villarino, G., Maldonado-López, R., Possemato, R., Peñaranda, C., and Glimcher, L.H. (2003). T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells. Proc. Nat. Acad. Sci. USA 100, 7749–7754.10.1073/pnas.1332767100Search in Google Scholar PubMed PubMed Central

Lushchak, V.I. (2012). Glutathione homeostasis and functions: potential targets for medical interventions. J. Amino Acids 2012, 736837.10.1155/2012/736837Search in Google Scholar PubMed PubMed Central

Ly, J., Lagman, M., Saing, T., Singh, M.K., Tudela, E.V., Morris, D., Anderson, J., Daliva, J., Ochoa, C., Patel, N., et al. (2015). Liposomal glutathione supplementation restores TH1 cytokine response to Mycobacterium tuberculosis infection in HIV-infected individuals. J. Interferon Cytokine Res. 35, 875–887.10.1089/jir.2014.0210Search in Google Scholar PubMed PubMed Central

Maher, P. (2005). The effects of stress and ageing on glutathione metabolism. Ageing Res. Rev. 4, 288–314.10.1016/j.arr.2005.02.005Search in Google Scholar PubMed

Mantovani, A., Sica, A., Sozzani, S., Allavena, P., Vecchi, A., and Locati, M. (2004). The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686.10.1016/j.it.2004.09.015Search in Google Scholar

Martinez, F.O. and Gordon, S. (2014). The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13.10.12703/P6-13Search in Google Scholar

Matthias, L.J., Yam, P.T., Jiang, X.M., Vandegraaff, N., Li, P., Poumbourios, P., Donoghue, N., and Hogg, P.J. (2002). Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1. Nat. Immunol. 3, 727–732.10.1038/ni815Search in Google Scholar

Mori, I., Komatsu, T., Takeuchi, K., Nakakuki, K., Sudo, M., and Kimura, Y. (1995). In vivo induction of apoptosis by influenza virus. J. Gen. Virol. 76, 2869–2873.10.1099/0022-1317-76-11-2869Search in Google Scholar

Morris, D., Guerra, C., Donohue, C., Oh, H., Khurasany, M., and Venketaraman, V. (2012). Unveiling the mechanisms for decreased glutathione in individuals with HIV infection. Clin. Dev. Immunol. 2012, 734125.10.1155/2012/734125Search in Google Scholar

Morris, D., Khurasany, M., Nguyen, T., Kim, J., Guilford, F., Mehta, R., Gray, D., Saviola, B., and Venketaraman, V. (2013a). Glutathione and infection. Biochim. Biophys. Acta 1830, 3329–3349.10.1016/j.bbagen.2012.10.012Search in Google Scholar

Morris, D., Guerra, C., Khurasany, M., Guilford, F., Saviola, B., Huang, Y., and Venketaraman, V. (2013b). Glutathione supplementation improves macrophage functions in HIV. J. Interferon Cytokine Res. 33, 270–279.10.1089/jir.2012.0103Search in Google Scholar

Muraille, E., Oberdan, L., and Moser, M. (2014). Th1/Th2 paradigm extended: macrophage polarization as an appreciated pathogen-driven escape mechanism? Front. Immunol. 5, 603.10.3389/fimmu.2014.00603Search in Google Scholar

Murata, Y., Amao, M., Yoneda, J., and Hamuro, J. (2002). Intracellular thiol redox status of macrophages directs the Th1 skewing in thioredoxin transgenic mice during aging. Mol. Immunol. 38, 747–757.10.1016/S0161-5890(01)00111-0Search in Google Scholar

Murphy, K.M., Ouyang, W., Farrar, J.D., Yang, J., Ranganath, S., Asnagli, H., Afkarian, M., and Murphy, T.L. (2000). Signaling and transcription in T helper development. Annu. Rev. Immunol. 18, 451–494.10.1146/annurev.immunol.18.1.451Search in Google Scholar PubMed

Murray, P.J., Allen, J.E., Biswas, S.K., Fisher, E.A., Gilroy D.W., Goerdt, S., Gordon, S., Hamilton, J.A., Ivashkiv, L.B., Lawrence, T., et al. (2014). Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20.10.1016/j.immuni.2014.06.008Search in Google Scholar

Nencioni, L., Iuvara, A., Aquilano, K., Ciriolo, M.R., Cozzolino, F., Rotilio, G., Garaci, E., and Palamara, A.T. (2003). Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2. FASEB J. 17, 758–760.10.1096/fj.02-0508fjeSearch in Google Scholar

Nencioni, L., De Chiara, G., Sgarbanti, R., Amatore, D., Aquilano, K., Marcocci, M.E., Serafino, A., Torcia, M., Cozzolino, F., Ciriolo, M.R., et al. (2009). Bcl-2 expression and p38MAPK activity in cells infected with influenza A virus: impact on virally induced apoptosis and viral replication. J. Biol. Chem. 284, 16004–16015.10.1074/jbc.M900146200Search in Google Scholar

Oiry, J., Mialocq, P., Puy, J.Y., Fretier, P., Clayette, P., Dormont, D., and Imbach, J.L. (2001). NAC/MEA conjugate: a new potent antioxidant which increases the GSH level in various cell lines. Bioorg. Med. Chem. Lett. 11, 1189–1191.10.1016/S0960-894X(01)00171-8Search in Google Scholar

Oiry, J., Mialocq, P., Puy, J.Y., Fretier, P., Dereuddre-Bosquet, N., Dormont, D., Imbach, J.L., and Clayette, P. (2004). Synthesis and biological evaluation in human monocyte-derived macrophages of N-(N-acetyl-l-cysteinyl)-Sacetylcysteamine analogues with potent antioxidant and anti-HIV activities. J. Med. Chem. 47, 1789–1795.10.1021/jm030374dSearch in Google Scholar

Palamara, A.T., Perno, C.F., Ciriolo, M.R., Dini, L., Balestra, E., D’Agostini, C., Di Francesco, P., Favalli, C., Rotilio, G., and Garaci, E. (1995). Evidence for antiviral activity of glutathione: in vitro inhibition of herpes simplex virus type 1 replication. Antiviral Res. 27, 237–253.10.1016/0166-3542(95)00008-ASearch in Google Scholar

Palamara, A.T., Brandi, G., Rossi, L., Millo, E., Benatti, U., Nencioni, L., Iuvara, A., Garaci, E., and Magnani, M. (2004). New synthetic glutathione derivatives with increased antiviral activities. Antivir. Chem. Chemother. 15, 83–91.10.1177/095632020401500204Search in Google Scholar PubMed

Perl, A., Gergely, P.Jr., Nagy, G., Koncz, A., and Banki, K. (2004). Mitochondrial hyperpolarization: a checkpoint of T cell life, death and autoimmunity. Trends Immunol. 25, 360–367.10.1016/j.it.2004.05.001Search in Google Scholar PubMed PubMed Central

Peterson, J.D., Herzenberg, L.A., Vasquez, K., and Waltenbaugh, C. (1998). Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns. Proc. Natl. Acad. Sci. USA 95, 3071–3076.10.1073/pnas.95.6.3071Search in Google Scholar PubMed PubMed Central

Podinovskaia, M., Lee, W., Caldwell, S., and Russell, D.G. (2013). Infection of macrophages with Mycobacterium tuberculosis induces global modifications to phagosomal function. Cell. Microbiol. 15, 843–859.10.1111/cmi.12092Search in Google Scholar PubMed PubMed Central

Ponnappan, S. and Ponnappan, U. (2011). Ageing and immune function: molecular mechanisms to interventions. Antioxid. Redox. Signal. 14, 1551–1585.10.1089/ars.2010.3228Search in Google Scholar

Ray, P.D., Huang, B.-W., and Tsuji, Y. (2012). Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell. Signal. 24, 981–990.10.1016/j.cellsig.2012.01.008Search in Google Scholar

Rizzoli, V., Schiappelli, P., Moretto, C., and Galzigna, L. (1995). S-acetyl and S-phenylacethyl-glutathione in rat brain tissue. Eur. J. Lab. Med. 3, 11–13.Search in Google Scholar

Rushworth, G.F. and Megson, I.L. (2014). Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol. Ther. 41, 150–159.10.1016/j.pharmthera.2013.09.006Search in Google Scholar

Scherz-Shouval, R., Shvets, E., Fass, E., Shorer, H., Gil, L., and Zvulun, E. (2007). Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26, 1749–1760.10.1038/sj.emboj.7601623Search in Google Scholar

Sgarbanti, R., Nencioni, L., Amatore, D., Coluccio, P., Fraternale, A., Sale, P., Mammola, C.L., Carpino, G., Gaudio, E., Magnani, M., et al. (2011). Redox regulation of the influenza hemagglutinin maturation process: a new cell-mediated strategy for anti-influenza therapy. Antioxid. Redox Signal. 15, 593–606.10.1089/ars.2010.3512Search in Google Scholar

Short, S., Merkel, B.J., Caffrey, R., and McCoy, K.L. (1996). Defective antigen processing correlates with a low level of intracellular glutathione. Eur. J. Immunol. 26, 3015–3020.10.1002/eji.1830261229Search in Google Scholar

Sido, B., Hack, V., Hochlehnert, A., Lipps, H., Herfarth, C., and Droge, W. (1998). Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease. Gut 42, 485–492.10.1136/gut.42.4.485Search in Google Scholar

Spallholz, J.E. (1987). Glutathione: is it an evolutionary vestige of the penicillins? Med. Hypotheses 23, 253–257.10.1016/0306-9877(87)90016-8Search in Google Scholar

Staal, F.J. (1998). Glutathione and HIV infection: reduced reduced, or increased oxidized? Eur. J. Clin. Invest. 28, 194–196.10.1046/j.1365-2362.1998.00268.xSearch in Google Scholar PubMed

Staal, F.J., Roederer, M., Herzenberg, L.A., and Herzenberg, L.A. (1990). Intracellular thiols regulate activation of nuclear factor kappa B and transcription of human immunodeficiency virus. Proc. Natl. Acad. Sci. USA 87, 9943–9947.10.1073/pnas.87.24.9943Search in Google Scholar PubMed PubMed Central

Tan, K.S., Lee, K.O., Low, K.C., Gamage, A.M., Liu, Y., Tan, G.Y., Koh, H.Q., Alonso, S., and Gan, Y.H. (2012). Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria. J. Clin. Invest. 122, 2289–2300.10.1172/JCI57817Search in Google Scholar

Thierfelder, W.E., Van Deursen, J.M., Yamamoto, K., Tripp, R.A., Sarawar, S.R., Carson, R.T., Sangster, M.Y., Vignali, D.A., Doherty, P.C., Grosveld, G.C., et al. (1996). Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382, 171–174.10.1038/382171a0Search in Google Scholar

Tiwari, G., Tiwari, R., Sriwastawa, S., Bhati, L., Pandey, S., Pandey, P., and Bannerjee, S.K. (2012). Drug delivery systems: an updated review. Int. J. Pharm. Investig. 2, 2–11.10.4103/2230-973X.96920Search in Google Scholar

Trinchieri, G., Pflanz, S., and Kastelein, R.A. (2003). The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19, 641–644.10.1016/S1074-7613(03)00296-6Search in Google Scholar

Utsugi, M., Dobashi, K., Ishizuka, T., Endou, K., Hamuro, J., Murata, Y., Nakazawa, T., and Mori, M. (2003). c-Jun N-Termianl kinase negatively regulates lipopolysaccharide-induced IL-12 production in human macrophages: role of mitogen-activated protein kinase in glutathione redox regulation of IL-12 production. J. Immunol. 171, 628–635.10.4049/jimmunol.171.2.628Search in Google Scholar PubMed

Venketaraman, V., Dayaram, Y.K., Talaue, M.T., and Connell, N.D. (2005). Glutathione and nitrosoglutathione in macrophage defense against Mycobacterium tuberculosis. Infect. Immun. 73, 1886–1889.10.1128/IAI.73.3.1886-1889.2005Search in Google Scholar PubMed PubMed Central

Venketaraman, V., Millman, A., Salman, M., Swaminathan, S., Goetz, M., Lardizabal, A., Hom, D., and Connell, N.D. (2008). Glutathione levels and immune responses in tuberculosis patients. Microb. Pathog. 44, 255–261.10.1016/j.micpath.2007.09.002Search in Google Scholar PubMed

Vogel, J.U., Cinatl, J., Dauletbaev, N., Buxbaum, S., Treusch, G., Cinatl, J.Jr., Gerein, V., and Doerr, H.W. (2005). Effects of S-acetylglutathione in cell and animal model of herpes simplex virus type 1 infection. Med. Microbiol. Immunol. 194, 55–59.10.1007/s00430-003-0212-zSearch in Google Scholar PubMed

Vyas, J.M., Van der Veen A.G., and Ploegh, H.L. (2008). The known unknowns of antigen processing and presentation. Nat. Rev. Immunol. 8, 607–618.10.1038/nri2368Search in Google Scholar PubMed PubMed Central

Walsh, A.C., Michaud, S.G., Malossi, J.A., and Lawrence, D.A. (1995). Glutathione depletion in human T lymphocytes: analysis of activation-associated gene expression and the stress response. Toxicol. Appl. Pharmacol. 133, 249–261.10.1006/taap.1995.1149Search in Google Scholar PubMed

Watson, W.H., Chen, Y., and Jones, D.P. (2003). Redox state of glutathione and thioredoxin in differentiation and apoptosis. BioFactors 17, 307–314.10.1002/biof.5520170130Search in Google Scholar PubMed

Weiskopf, D., Schwanninger, A., Weinberger, B., Almanzar, G., Parson, W., Buus, S., Lindner, H., and Grubeck-Loebenstein, B. (2010). Oxidative stress can alter the antigenicity of immunodominant peptides. J. Leuk. Biol. 87, 165–172.10.1189/jlb.0209065Search in Google Scholar PubMed

Zargari, M., Allameh, A., Sanati, M.H., Tiraihi, T., Lavasani, S., and Emadyan, O. (2007). Relationship between the clinical scoring and demyelination in central nervous system with total antioxidant capacity of plasma during experimental autoimmune encephalomyelitis development in mice. Neurosci. Lett. 412, 24–28.10.1016/j.neulet.2006.08.033Search in Google Scholar PubMed

Zhu, J., Yamane, H., Cote-Sierra, J., Guo, L., and Paul, W.E. (2006). GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res. 16, 3–10.10.1038/sj.cr.7310002Search in Google Scholar PubMed

Received: 2016-5-6
Accepted: 2016-8-3
Published Online: 2016-8-11
Published in Print: 2017-2-1

©2017 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 30.3.2024 from https://www.degruyter.com/document/doi/10.1515/hsz-2016-0202/html
Scroll to top button