Prolactin Induces IL-2 Associated TRAIL Expression on Natural Killer Cells from Chronic Hepatitis C Patients In vivo and In vitro

Author(s): Maria L.H. Medel, Gabriela G. Reyes, Luz M. Porras, Arturo R. Bernal, Jesús S. Luna, Adolfo P. Garcia, Jacqueline Cordova, Adalberto Parra, Srinivas Mummidi, David Kershenobich, Joselín Hernández*.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 19 , Issue 7 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Natural killer cells (NKC) are a major component of the innate immune response to HCV, mediating their effects through TRAIL and IFN-γ. However, their function is diminished in chronic HCV patients (HCVp). Prolactin is an immunomodulatory hormone capable of activating NKC.

Objective: The study aims to explore if hyperprolactinemia can activate NKC in HCVp.

Methods: We treated twelve chronic HCVp (confidence level =95%, power =80%) for 15 days with Levosulpiride plus Cimetidine to induce mild hyperprolactinemia. Before and after treatment, we determined TRAIL and NKG2D expression on peripheral blood NKC, along with cytokine profiles, viral loads and liver function. We also evaluated in vitro effects of prolactin and/or IL-2 on NKC TRAIL or NKG2D expression and IFN-γ levels on cultured blood mononuclear cells from 8 HCVp and 7 healthy controls.

Results: The treatment induced mild hyperprolactinemia and increased TRAIL expression on NKC as well as the secretion of IL-1ra, IL-2, PDGF and IFN-γ. Viral loads decreased in six HCVp. IL-2 and TRAIL together explained the viral load decrease. In vitro, prolactin plus IL-2 synergized to increase TRAIL and NKG2D expression on NKC from HCVp but not in controls.

Conclusion: Levosulpiride/Cimetidine treatment induced mild hyperprolactinaemia that was associated with NKC activation and Th1-type cytokine profile. Also, an increase in TRAIL and IL-2 was associated with viral load decrease. This treatment could potentially be used to reactivate NKC in HCVp.

Keywords: HCV, TRAIL, NKG2D, Viral load response, IFN-γ, hyperprolactinemia.

[1]
Thrift, A.P.; El-Serag, H.B.; Kanwal, F. Global epidemiology and burden of HCV infection and HCV-related disease. Nat. Rev. Gastroenterol. Hepatol., 2017, 14(2), 122-132.
[http://dx.doi.org/10.1038/nrgastro.2016.176] [PMID: 27924080]
[2]
Morgan, R.L.; Baack, B.; Smith, B.D.; Yartel, A.; Pitasi, M.; Falck-Ytter, Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann. Intern. Med., 2013, 158(5 Pt 1), 329-337.
[http://dx.doi.org/10.7326/0003-4819-158-5-201303050-00005] [PMID: 23460056]
[3]
Cox, A.L. MEDICINE. Global control of hepatitis C virus. Science, 2015, 349(6250), 790-791.
[http://dx.doi.org/10.1126/science.aad1302] [PMID: 26293940]
[4]
Wendt, A.; Adhoute, X.; Castellani, P.; Oules, V.; Ansaldi, C.; Benali, S.; Bourlière, M. Chronic hepatitis C: future treatment. Clin. Pharmacol., 2014, 6, 1-17.
[PMID: 24470777]
[5]
Götte, M.; Feld, J.J. Direct-acting antiviral agents for hepatitis C: structural and mechanistic insights. Nat. Rev. Gastroenterol. Hepatol., 2016, 13(6), 338-351.
[http://dx.doi.org/10.1038/nrgastro.2016.60] [PMID: 27147491]
[6]
Lauer, G.M. Immune responses to hepatitis C virus (HCV) infection and the prospects for an effective HCV vaccine or immunotherapies. J. Infect. Dis., 2013, 207(Suppl. 1), S7-S12.
[http://dx.doi.org/10.1093/infdis/jis762] [PMID: 23390305]
[7]
Sarasin-Filipowicz, M.; Oakeley, E.J.; Duong, F.H.T.; Christen, V.; Terracciano, L.; Filipowicz, W.; Heim, M.H. Interferon signaling and treatment outcome in chronic hepatitis C. Proc. Natl. Acad. Sci. USA, 2008, 105(19), 7034-7039.
[http://dx.doi.org/10.1073/pnas.0707882105] [PMID: 18467494]
[8]
Bellanti, F.; Vendemiale, G.; Altomare, E.; Serviddio, G. The impact of interferon lambda 3 gene polymorphism on natural course and treatment of hepatitis C. Clin. Dev. Immunol., 2012.2012849373
[http://dx.doi.org/10.1155/2012/849373] [PMID: 22966241]
[9]
Suppiah, V.; Gaudieri, S.; Armstrong, N.J.; O’Connor, K.S.; Berg, T.; Weltman, M.; Abate, M.L.; Spengler, U.; Bassendine, M.; Dore, G.J.; Irving, W.L.; Powell, E.; Hellard, M.; Riordan, S.; Matthews, G.; Sheridan, D.; Nattermann, J.; Smedile, A.; Müller, T.; Hammond, E.; Dunn, D.; Negro, F.; Bochud, P.Y.; Mallal, S.; Ahlenstiel, G.; Stewart, G.J.; George, J.; Booth, D.R. International Hepatitis C Genetics Consortium (IHCGC). IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European Cohort: a cross-sectional study. PLoS Med., 2011, 8(9)e1001092
[http://dx.doi.org/10.1371/journal.pmed.1001092] [PMID: 21931540]
[10]
Lunemann, S.; Schlaphoff, V.; Cornberg, M.; Wedemeyer, H. NK cells in hepatitis C: role in disease susceptibility and therapy. Dig. Dis., 2012, 30(Suppl. 1), 48-54.
[http://dx.doi.org/10.1159/000341680] [PMID: 23075868]
[11]
Glässner, A.; Eisenhardt, M.; Krämer, B.; Körner, C.; Coenen, M.; Sauerbruch, T.; Spengler, U.; Nattermann, J. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab. Invest., 2012, 92(7), 967-977.
[http://dx.doi.org/10.1038/labinvest.2012.54] [PMID: 22449797]
[12]
Ye, L.; Wang, X.; Wang, S.; Wang, Y.; Song, L.; Hou, W.; Zhou, L.; Li, H.; Ho, W. CD56+ T cells inhibit hepatitis C virus replication in human hepatocytes. Hepatology, 2009, 49(3), 753-762.
[http://dx.doi.org/10.1002/hep.22715] [PMID: 19085952]
[13]
Gao, B.; Radaeva, S. Natural killer and natural killer T cells in liver fibrosis. Biochim. Biophys. Acta, 2013, 1832(7), 1061-1069.
[http://dx.doi.org/10.1016/j.bbadis.2012.09.008] [PMID: 23022478]
[14]
Jeong, W.I.; Park, O.; Suh, Y.G.; Byun, J.S.; Park, S.Y.; Choi, E.; Kim, J.K.; Ko, H.; Wang, H.; Miller, A.M.; Gao, B. Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. Hepatology, 2011, 53(4), 1342-1351.
[http://dx.doi.org/10.1002/hep.24190] [PMID: 21480338]
[15]
Oliviero, B.; Varchetta, S.; Paudice, E.; Michelone, G.; Zaramella, M.; Mavilio, D.; De Filippi, F.; Bruno, S.; Mondelli, M.U. Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections. Gastroenterology, 2009, 137(3), 1151-1160, 1160.e1-1160.e7.,
[http://dx.doi.org/10.1053/j.gastro.2009.05.047] [PMID: 19470388]
[16]
Holder, K.A.; Stapleton, S.N.; Gallant, M.E.; Russell, R.S.; Grant, M.D. Hepatitis C virus-infected cells downregulate NKp30 and inhibit ex vivo NK cell functions. J. Immunol., 2013, 191(6), 3308-3318.
[http://dx.doi.org/10.4049/jimmunol.1300164] [PMID: 23960237]
[17]
Benedict, C.A.; Ware, C.F. TRAIL: not just for tumors anymore? J. Exp. Med., 2012, 209(11), 1903-1906.
[http://dx.doi.org/10.1084/jem.20122235] [PMID: 23091198]
[18]
Werner, J.M.; Heller, T.; Gordon, A.M.; Sheets, A.; Sherker, A.H.; Kessler, E.; Bean, K.S.; Stevens, M.; Schmitt, J.; Rehermann, B. Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection. Hepatology, 2013, 58(5), 1621-1631.
[http://dx.doi.org/10.1002/hep.26353] [PMID: 23463364]
[19]
Ahlenstiel, G.; Titerence, R.H.; Koh, C.; Edlich, B.; Feld, J.J.; Rotman, Y.; Ghany, M.G.; Hoofnagle, J.H.; Liang, T.J.; Heller, T.; Rehermann, B. Natural killer cells are polarized toward cytotoxicity in chronic hepatitis C in an interferon-alfa-dependent manner. Gastroenterology, 2010, 138(1), 325-35.e1, 2.,
[http://dx.doi.org/10.1053/j.gastro.2009.08.066] [PMID: 19747917]
[20]
Stegmann, K.A.; Björkström, N.K.; Veber, H.; Ciesek, S.; Riese, P.; Wiegand, J.; Hadem, J.; Suneetha, P.V.; Jaroszewicz, J.; Wang, C.; Schlaphoff, V.; Fytili, P.; Cornberg, M.; Manns, M.P.; Geffers, R.; Pietschmann, T.; Guzmán, C.A.; Ljunggren, H.G.; Wedemeyer, H. Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology, 2010, 138(5), 1885-1897.
[http://dx.doi.org/10.1053/j.gastro.2010.01.051] [PMID: 20334827]
[21]
Ahlenstiel, G.; Edlich, B.; Hogdal, L.J.; Rotman, Y.; Noureddin, M.; Feld, J.J.; Holz, L.E.; Titerence, R.H.; Liang, T.J.; Rehermann, B. Early changes in natural killer cell function indicate virologic response to interferon therapy for hepatitis C. Gastroenterology, 2011, 141(4), 1231-1239, 1239.e1-1239.e2.,
[http://dx.doi.org/10.1053/j.gastro.2011.06.069] [PMID: 21741920]
[22]
Ohira, M.; Ishiyama, K.; Tanaka, Y.; Doskali, M.; Igarashi, Y.; Tashiro, H.; Hiraga, N.; Imamura, M.; Sakamoto, N.; Asahara, T.; Chayama, K.; Ohdan, H. Adoptive immunotherapy with liver allograft-derived lymphocytes induces anti-HCV activity after liver transplantation in humans and humanized mice. J. Clin. Invest., 2009, 119(11), 3226-3235.
[http://dx.doi.org/10.1172/JCI38374] [PMID: 19805910]
[23]
Ishiyama, K.; Ohdan, H.; Ohira, M.; Mitsuta, H.; Arihiro, K.; Asahara, T. Difference in cytotoxicity against hepatocellular carcinoma between liver and periphery natural killer cells in humans. Hepatology, 2006, 43(2), 362-372.
[http://dx.doi.org/10.1002/hep.21035] [PMID: 16440347]
[24]
Long, E.O.; Kim, H.S.; Liu, D.; Peterson, M.E.; Rajagopalan, S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu. Rev. Immunol., 2013, 31, 227-258.
[http://dx.doi.org/10.1146/annurev-immunol-020711-075005] [PMID: 23516982]
[25]
Ma, D.; Cao, W.; Kapur, A.; Felder, M.; Scarlett, C.O.; Patankar, M.S.; Li, L. Differential expression of proteins in naïve and IL-2 stimulated primary human NK cells identified by global proteomic analysis. J. Proteomics, 2013, 91, 151-163.
[http://dx.doi.org/10.1016/j.jprot.2013.06.024] [PMID: 23806757]
[26]
Parra, A.; Ramírez-Peredo, J.; Reyes-Muñoz, E.; Ruiz-Argüelles, A.; Ruiz-Argüelles, G.J.A. Th1-Type Cytokine Named Prolactin. Facts and Hypotheses. Adv. Neuroimmune Biol., 2013, 4, 1-6.
[27]
Mavoungou, E.; Bouyou-Akotet, M.K.; Kremsner, P.G. Effects of prolactin and cortisol on natural killer (NK) cell surface expression and function of human natural cytotoxicity receptors (NKp46, NKp44 and NKp30). Clin. Exp. Immunol., 2005, 139(2), 287-296.
[http://dx.doi.org/10.1111/j.1365-2249.2004.02686.x] [PMID: 15654827]
[28]
Ishii, R.; Saito, T.; Shao, L.; Okumoto, K.; Nishise, Y.; Watanabe, H.; Makino, N.; Fukao, A.; Kitanaka, C.; Kayama, T.; Ueno, Y.; Kawata, S. Serum prolactin levels and prolactin mRNA expression in peripheral blood mononuclear cells in hepatitis C virus infection. J. Med. Virol., 2013, 85(7), 1199-1205.
[http://dx.doi.org/10.1002/jmv.23599] [PMID: 23918538]
[29]
El-Serafi, A.T.; Osama, S.; El-Zalat, H. EL-Deen, I.M. Dysregulation of male sex hormones in chronic hepatitis C patients. Andrologia, 2016, 48(1), 82-86.
[http://dx.doi.org/10.1111/and.12425] [PMID: 25912488]
[30]
Kraus, M.R.; Schäfer, A.; Bentink, T.; Scheurlen, M.; Weissbrich, B.; Al-Taie, O.; Seufert, J. Sexual dysfunction in males with chronic hepatitis C and antiviral therapy: interferon-induced functional androgen deficiency or depression? J. Endocrinol., 2005, 185(2), 345-352.
[http://dx.doi.org/10.1677/joe.1.06007] [PMID: 15845927]
[31]
Kuchay, M.S.; Mithal, A. Levosulpiride and Serum Prolactin Levels. Indian J. Endocrinol. Metab., 2017, 21(2), 355-358.
[http://dx.doi.org/10.4103/ijem.IJEM_555_16] [PMID: 28459037]
[32]
Tytgat, G.N.; Hameeteman, W.; Mulder, C.J.; Wiersinga, W.; van de Boomgaard, D.M.; Dees, J. Five-year cimetidine maintenance trial for peptic ulcer disease. A clinical and endocrinologic approach. Scand. J. Gastroenterol., 1990, 25(10), 974-980.
[http://dx.doi.org/10.3109/00365529008997622] [PMID: 2263884]
[33]
Shindoh, J.; Hasegawa, K.; Matsuyama, Y.; Inoue, Y.; Ishizawa, T.; Aoki, T.; Sakamoto, Y.; Sugawara, Y.; Makuuchi, M.; Kokudo, N. Low hepatitis C viral load predicts better long-term outcomes in patients undergoing resection of hepatocellular carcinoma irrespective of serologic eradication of hepatitis C virus. J. Clin. Oncol., 2013, 31(6), 766-773.
[http://dx.doi.org/10.1200/JCO.2012.44.3234] [PMID: 23129744]
[34]
Davis, J.M.; Knutson, K.L.; Strausbauch, M.A.; Green, A.B.; Crowson, C.S.; Therneau, T.M.; Matteson, E.L.; Gabriel, S.E. Immune response profiling in early rheumatoid arthritis: discovery of a novel interaction of treatment response with viral immunity. Arthritis Res. Ther., 2013, 15(6), R199.
[http://dx.doi.org/10.1186/ar4389] [PMID: 24267267]
[35]
Thimme, R.; Oldach, D.; Chang, K.M.; Steiger, C.; Ray, S.C.; Chisari, F.V. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J. Exp. Med., 2001, 194(10), 1395-1406.
[http://dx.doi.org/10.1084/jem.194.10.1395] [PMID: 11714747]
[36]
Thimme, R.; Bukh, J.; Spangenberg, H.C.; Wieland, S.; Pemberton, J.; Steiger, C.; Govindarajan, S.; Purcell, R.H.; Chisari, F.V. Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc. Natl. Acad. Sci. USA, 2002, 99(24), 15661-15668.
[http://dx.doi.org/10.1073/pnas.202608299] [PMID: 12441397]
[37]
Golden-Mason, L.; Rosen, H.R. Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Immunol. Rev., 2013, 255(1), 68-81.
[http://dx.doi.org/10.1111/imr.12090] [PMID: 23947348]
[38]
Missale, G.; Pilli, M.; Zerbini, A.; Penna, A.; Ravanetti, L.; Barili, V.; Orlandini, A.; Molinari, A.; Fasano, M.; Santantonio, T.; Ferrari, C. Lack of full CD8 functional restoration after antiviral treatment for acute and chronic hepatitis C virus infection. Gut, 2012, 61(7), 1076-1084.
[http://dx.doi.org/10.1136/gutjnl-2011-300515] [PMID: 22337949]
[39]
Gagnerault, M.C.; Touraine, P.; Savino, W.; Kelly, P.A.; Dardenne, M. Expression of prolactin receptors in murine lymphoid cells in normal and autoimmune situations. J. Immunol., 1993, 150(12), 5673-5681.
[PMID: 8515082]
[40]
Sun, R.; Li, A.L.; Wei, H.M.; Tian, Z.G. Expression of prolactin receptor and response to prolactin stimulation of human NK cell lines. Cell Res., 2004, 14(1), 67-73.
[http://dx.doi.org/10.1038/sj.cr.7290204] [PMID: 15040892]
[41]
Bouchard, B.; Ormandy, C.J.; Di Santo, J.P.; Kelly, P.A. Immune system development and function in prolactin receptor-deficient mice. J. Immunol., 1999, 163(2), 576-582.
[PMID: 10395643]
[42]
Carreño, P.C.; Sacedón, R.; Jiménez, E.; Vicente, A.; Zapata, A.G. Prolactin affects both survival and differentiation of T-cell progenitors. J. Neuroimmunol., 2005, 160(1-2), 135-145.
[http://dx.doi.org/10.1016/j.jneuroim.2004.11.008] [PMID: 15710466]
[43]
Matera, L.; Mori, M. Cooperation of pituitary hormone prolactin with interleukin-2 and interleukin-12 on production of interferon-gamma by natural killer and T cells. Ann. N. Y. Acad. Sci., 2000, 917, 505-513.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb05415.x] [PMID: 11268378]
[44]
Parra, A.; Reyes-Terán, G.; Ramírez-Peredo, J.; Jacquemin, B.; Quiroz, V.; Cárdenas, M.; García-Sancho, M.C.; Larrea, F. Differences in nocturnal basal and rhythmic prolactin secretion in untreated compared to treated HIV-infected men are associated with CD4+ T-lymphocytes. Immunol. Cell Biol., 2004, 82(1), 24-31.
[http://dx.doi.org/10.1111/j.1440-1711.2004.01201.x] [PMID: 14984591]
[45]
Ruiz-Extremera, A.; Muñoz-Gámez, J.A.; Abril-Molina, A.; Salmerón-Ruiz, M.A.; Muñoz-de-Rueda, P.; Pavón-Castillero, E.J.; Quiles-Pérez, R.; Carazo, A.; Gila, A.; Jimenez-Ruiz, S.M.; Casado, J.; Martín, A.B.; Sanjuán-Núñez, L.; Ocete-Hita, E.; Viota, J.L.; León, J.; Salmerón, J. Variation of transaminases, HCV-RNA levels and Th1/Th2 cytokine production during the post-partum period in pregnant women with chronic hepatitis C. PLoS One, 2013, 8(10)e75613
[http://dx.doi.org/10.1371/journal.pone.0075613] [PMID: 24130726]
[46]
Nishida, S.; Levi, D.M.; Tzakis, A.G. Liver natural killer cell inoculum for liver transplantation with hepatocellular carcinoma. Curr. Opin. Organ Transplant., 2013, 18(6), 690-694.
[http://dx.doi.org/10.1097/MOT.0000000000000024] [PMID: 24220052]
[47]
Malaguarnera, M.; Pistone, G.; Neri, S.; Romano, A.; Brogna, A.; Musumeci, S. Interleukin-2 plus ribavirin versus IFN a 2b plus ribavirin in patients with chronic HCV who did not repond to previous IFN a 2b treatment. BioDrugs, 2004, 18, 407-413.
[http://dx.doi.org/10.2165/00063030-200418060-00006] [PMID: 15571424]
[48]
Martinez, D.; Palmer, C.; Simar, D.; Cameron, B.A.; Nguyen, N.; Aggarwal, V.; Lloyd, A.R.; Zekry, A. Characterisation of the cytokine milieu associated with the up-regulation of IL-6 and suppressor of cytokine 3 in chronic hepatitis C treatment non-responders. Liver Int., 2015, 35(2), 463-472.
[http://dx.doi.org/10.1111/liv.12473] [PMID: 24461080]
[49]
Patel, K.; Remlinger, K.S.; Walker, T.G.; Leitner, P.; Lucas, J.E.; Gardner, S.D.; McHutchison, J.G.; Irving, W.; Guha, I.N. Multiplex protein analysis to determine fibrosis stage and progression in patients with chronic hepatitis C. Clin. Gastroenterol. Hepatol., 2014, 12(12), 2113-20.e1, 3.,
[http://dx.doi.org/10.1016/j.cgh.2014.04.037] [PMID: 24815325]
[50]
Mousa, N.; Eldars, W.; Eldegla, H.; Fouda, O.; Gad, Y.; Abousamra, N.; Elmasry, E.; Arafa, M. Cytokine profiles and hepatic injury in occult hepatitis C versus chronic hepatitis C virus infection. Int. J. Immunopathol. Pharmacol., 2014, 27(1), 87-96.
[http://dx.doi.org/10.1177/039463201402700111] [PMID: 24674682]
[51]
Sousa, G.M.; Oliveira, I.S.; Andrade, L.J.; Sousa-Atta, M.L.; Paraná, R.; Atta, A.M. Serum levels of Th17 associated cytokines in chronic hepatitis C virus infection. Cytokine, 2012, 60(1), 138-142.
[http://dx.doi.org/10.1016/j.cyto.2012.06.003] [PMID: 22748467]
[52]
Barnaba, V. Hepatitis C virus infection: a “liaison a trois” amongst the virus, the host, and chronic low-level inflammation for human survival. J. Hepatol., 2010, 53(4), 752-761.
[http://dx.doi.org/10.1016/j.jhep.2010.06.003] [PMID: 20673595]
[53]
Ain, R.; Canham, L.N.; Soares, M.J. Gestation stage-dependent intrauterine trophoblast cell invasion in the rat and mouse: novel endocrine phenotype and regulation. Dev. Biol., 2003, 260(1), 176-190.
[http://dx.doi.org/10.1016/S0012-1606(03)00210-0] [PMID: 12885563]
[54]
Yu-Lee, L.Y. Prolactin modulation of immune and inflammatory responses. Recent Prog. Horm. Res., 2002, 57, 435-455.
[http://dx.doi.org/10.1210/rp.57.1.435] [PMID: 12017556]
[55]
Edlich, B.; Ahlenstiel, G.; Zabaleta Azpiroz, A.; Stoltzfus, J.; Noureddin, M.; Serti, E.; Feld, J.J.; Liang, T.J.; Rotman, Y.; Rehermann, B. Early changes in interferon signaling define natural killer cell response and refractoriness to interferon-based therapy of hepatitis C patients. Hepatology, 2012, 55(1), 39-48.
[http://dx.doi.org/10.1002/hep.24628] [PMID: 21898483]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 19
ISSUE: 7
Year: 2019
Page: [975 - 984]
Pages: 10
DOI: 10.2174/1871530319666181206125545
Price: $65

Article Metrics

PDF: 19
HTML: 2