Skip to main content
Top
Published in: Virology Journal 1/2014

Open Access 01-12-2014 | Short report

E5564 inhibits immunosuppressive cytokine IL-10 induction promoted by HIV-1 Tat protein

Authors: Elmostafa Bahraoui, Laurence Briant, Nathalie Chazal

Published in: Virology Journal | Issue 1/2014

Login to get access

Abstract

Background

In HIV-1 infected patients, production of interleukin-10 (IL-10), a highly immunosuppressive cytokine, is associated with progression of infection toward AIDS. HIV-1 Tat protein, by interacting with TLR4-MD2 at the membrane level, induces IL-10 production by primary human monocytes and macrophages. In the present study we evaluated the effect of the TLR4 antagonist Eritoran tetrasodium (E5564) on HIV-1 Tat-induced IL-10 production.

Findings

Here, we confirm that the recombinant HIV-1 Tat protein and the GST-Tat 1–45 fusion protein efficiently stimulate IL-10 production by primary monocytes and macrophages and that this stimulation is inhibited by blocking anti-TLR4 mAbs. We show that a similar inhibition is observed by preincubating the cells with the TLR4 antagonist E5564.

Conclusion

This study provides compelling data showing for the first time that the TLR4 antagonist E5564 inhibits the immunosuppressive cytokine IL-10 production by primary human monocytes and macrophages incubated in the presence of HIV-1 Tat protein.
Appendix
Available only for authorised users
Literature
1.
go back to reference Clerici M, Shearer GM: A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today 1993, 14: 107-111. 10.1016/0167-5699(93)90208-3PubMedCrossRef Clerici M, Shearer GM: A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today 1993, 14: 107-111. 10.1016/0167-5699(93)90208-3PubMedCrossRef
2.
go back to reference Clerici M, Sarin A, Coffman RL, Wynn TA, Blatt SP, Hendrix CW, Wolf SF, Shearer GM, Henkart PA: Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis. Proc Natl Acad Sci U S A 1994, 91: 11811-11815. 10.1073/pnas.91.25.11811PubMedPubMedCentralCrossRef Clerici M, Sarin A, Coffman RL, Wynn TA, Blatt SP, Hendrix CW, Wolf SF, Shearer GM, Henkart PA: Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis. Proc Natl Acad Sci U S A 1994, 91: 11811-11815. 10.1073/pnas.91.25.11811PubMedPubMedCentralCrossRef
3.
go back to reference Emilie D, Fior R, Llorente L, Marfaing-Koka A, Peuchmaur M, Devergne O, Jarrousse B, Wijdenes J, Boue F, Galanaud P: Cytokines from lymphoid organs of HIV-infected patients: production and role in the immune disequilibrium of the disease and in the development of B lymphomas. Immunol Rev 1994, 140: 5-34. 10.1111/j.1600-065X.1994.tb00863.xPubMedCrossRef Emilie D, Fior R, Llorente L, Marfaing-Koka A, Peuchmaur M, Devergne O, Jarrousse B, Wijdenes J, Boue F, Galanaud P: Cytokines from lymphoid organs of HIV-infected patients: production and role in the immune disequilibrium of the disease and in the development of B lymphomas. Immunol Rev 1994, 140: 5-34. 10.1111/j.1600-065X.1994.tb00863.xPubMedCrossRef
4.
go back to reference Graziosi C, Pantaleo G, Fauci AS: Comparative analysis of constitutive cytokine expression in peripheral blood and lymph nodes of HIV-infected individuals. Res Immunol 1994, 145: 602-605. discussion 605–607 10.1016/S0923-2494(05)80040-9PubMedCrossRef Graziosi C, Pantaleo G, Fauci AS: Comparative analysis of constitutive cytokine expression in peripheral blood and lymph nodes of HIV-infected individuals. Res Immunol 1994, 145: 602-605. discussion 605–607 10.1016/S0923-2494(05)80040-9PubMedCrossRef
5.
go back to reference Alfano M, Poli G: The cytokine network in HIV infection. Curr Mol Med 2002, 2: 677-689. 10.2174/1566524023361925PubMedCrossRef Alfano M, Poli G: The cytokine network in HIV infection. Curr Mol Med 2002, 2: 677-689. 10.2174/1566524023361925PubMedCrossRef
6.
go back to reference Clerici M, Wynn TA, Berzofsky JA, Blatt SP, Hendrix CW, Sher A, Coffman RL, Shearer GM: Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest 1994, 93: 768-775. 10.1172/JCI117031PubMedPubMedCentralCrossRef Clerici M, Wynn TA, Berzofsky JA, Blatt SP, Hendrix CW, Sher A, Coffman RL, Shearer GM: Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest 1994, 93: 768-775. 10.1172/JCI117031PubMedPubMedCentralCrossRef
7.
go back to reference Goldstein G: HIV-1 Tat protein as a potential AIDS vaccine. Nat Med 1996, 2: 960-964. 10.1038/nm0996-960PubMedCrossRef Goldstein G: HIV-1 Tat protein as a potential AIDS vaccine. Nat Med 1996, 2: 960-964. 10.1038/nm0996-960PubMedCrossRef
8.
go back to reference Westendorp MO, Shatrov VA, Schulze-Osthoff K, Frank R, Kraft M, Los M, Krammer PH, Droge W, Lehmann V: HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. The EMBO journal 1995, 14: 546-554.PubMedPubMedCentral Westendorp MO, Shatrov VA, Schulze-Osthoff K, Frank R, Kraft M, Los M, Krammer PH, Droge W, Lehmann V: HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. The EMBO journal 1995, 14: 546-554.PubMedPubMedCentral
9.
go back to reference Xiao H, Neuveut C, Tiffany HL, Benkirane M, Rich EA, Murphy PM, Jeang KT: Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc Natl Acad Sci U S A 2000, 97: 11466-11471. 10.1073/pnas.97.21.11466PubMedPubMedCentralCrossRef Xiao H, Neuveut C, Tiffany HL, Benkirane M, Rich EA, Murphy PM, Jeang KT: Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc Natl Acad Sci U S A 2000, 97: 11466-11471. 10.1073/pnas.97.21.11466PubMedPubMedCentralCrossRef
10.
go back to reference Bennasser Y, Badou A, Tkaczuk J, Bahraoui E: Signaling pathways triggered by HIV-1 Tat in human monocytes to induce TNF-alpha. Virology 2002, 303: 174-180. 10.1006/viro.2002.1676PubMedCrossRef Bennasser Y, Badou A, Tkaczuk J, Bahraoui E: Signaling pathways triggered by HIV-1 Tat in human monocytes to induce TNF-alpha. Virology 2002, 303: 174-180. 10.1006/viro.2002.1676PubMedCrossRef
11.
go back to reference Leghmari K, Contreras X, Moureau C, Bahraoui E: HIV-1 Tat protein induces TNF-alpha and IL-10 production by human macrophages: differential implication of PKC-betaII and -delta isozymes and MAP kinases ERK1/2 and p38. Cell Immunol 2008, 254: 46-55. 10.1016/j.cellimm.2008.06.011PubMedCrossRef Leghmari K, Contreras X, Moureau C, Bahraoui E: HIV-1 Tat protein induces TNF-alpha and IL-10 production by human macrophages: differential implication of PKC-betaII and -delta isozymes and MAP kinases ERK1/2 and p38. Cell Immunol 2008, 254: 46-55. 10.1016/j.cellimm.2008.06.011PubMedCrossRef
12.
go back to reference Rubartelli A, Poggi A, Sitia R, Zocchi MR: HIV-I Tat: a polypeptide for all seasons. Immunol Today 1998, 19: 543-545. 10.1016/S0167-5699(98)01351-6PubMedCrossRef Rubartelli A, Poggi A, Sitia R, Zocchi MR: HIV-I Tat: a polypeptide for all seasons. Immunol Today 1998, 19: 543-545. 10.1016/S0167-5699(98)01351-6PubMedCrossRef
13.
go back to reference Albini A, Ferrini S, Benelli R, Sforzini S, Giunciuglio D, Aluigi MG, Proudfoot AE, Alouani S, Wells TN, Mariani G, Rabin RL, Farber JM, Noonan DM: HIV-1 Tat protein mimicry of chemokines. Proc Natl Acad Sci U S A 1998, 95: 13153-13158. 10.1073/pnas.95.22.13153PubMedPubMedCentralCrossRef Albini A, Ferrini S, Benelli R, Sforzini S, Giunciuglio D, Aluigi MG, Proudfoot AE, Alouani S, Wells TN, Mariani G, Rabin RL, Farber JM, Noonan DM: HIV-1 Tat protein mimicry of chemokines. Proc Natl Acad Sci U S A 1998, 95: 13153-13158. 10.1073/pnas.95.22.13153PubMedPubMedCentralCrossRef
14.
go back to reference Ben Haij N, Leghmari K, Planes R, Thieblemont N, Bahraoui E: HIV-1 Tat protein binds to TLR4-MD2 and signals to induce TNF-alpha and IL-10. Retrovirology 2013, 10: 123. 10.1186/1742-4690-10-123PubMedPubMedCentralCrossRef Ben Haij N, Leghmari K, Planes R, Thieblemont N, Bahraoui E: HIV-1 Tat protein binds to TLR4-MD2 and signals to induce TNF-alpha and IL-10. Retrovirology 2013, 10: 123. 10.1186/1742-4690-10-123PubMedPubMedCentralCrossRef
15.
go back to reference Mullarkey M, Rose JR, Bristol J, Kawata T, Kimura A, Kobayashi S, Przetak M, Chow J, Gusovsky F, Christ WJ, Rossignol DP: Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther 2003, 304: 1093-1102. 10.1124/jpet.102.044487PubMedCrossRef Mullarkey M, Rose JR, Bristol J, Kawata T, Kimura A, Kobayashi S, Przetak M, Chow J, Gusovsky F, Christ WJ, Rossignol DP: Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther 2003, 304: 1093-1102. 10.1124/jpet.102.044487PubMedCrossRef
16.
go back to reference Wittebole X, Castanares-Zapatero D, Laterre PF: Toll-like receptor 4 modulation as a strategy to treat sepsis. Mediat Inflamm 2010, 2010: 568396.CrossRef Wittebole X, Castanares-Zapatero D, Laterre PF: Toll-like receptor 4 modulation as a strategy to treat sepsis. Mediat Inflamm 2010, 2010: 568396.CrossRef
17.
go back to reference Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, Demeyer I, Sainati S, Amlot N, Cao C, Ii M, Matsuda H, Mouri K, Cohen J: A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med 2010, 38: 1685-1694. 10.1097/CCM.0b013e3181e7c5c9PubMedCrossRef Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, Demeyer I, Sainati S, Amlot N, Cao C, Ii M, Matsuda H, Mouri K, Cohen J: A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med 2010, 38: 1685-1694. 10.1097/CCM.0b013e3181e7c5c9PubMedCrossRef
18.
go back to reference Roger T, Froidevaux C, Le Roy D, Reymond MK, Chanson AL, Mauri D, Burns K, Riederer BM, Akira S, Calandra T: Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proc Natl Acad Sci U S A 2009, 106: 2348-2352. 10.1073/pnas.0808146106PubMedPubMedCentralCrossRef Roger T, Froidevaux C, Le Roy D, Reymond MK, Chanson AL, Mauri D, Burns K, Riederer BM, Akira S, Calandra T: Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proc Natl Acad Sci U S A 2009, 106: 2348-2352. 10.1073/pnas.0808146106PubMedPubMedCentralCrossRef
19.
go back to reference Hawkins LD, Christ WJ, Rossignol DP: Inhibition of endotoxin response by synthetic TLR4 antagonists. Curr Top Med Chem 2004, 4: 1147-1171. 10.2174/1568026043388123PubMedCrossRef Hawkins LD, Christ WJ, Rossignol DP: Inhibition of endotoxin response by synthetic TLR4 antagonists. Curr Top Med Chem 2004, 4: 1147-1171. 10.2174/1568026043388123PubMedCrossRef
20.
go back to reference Menghini R, Campia U, Tesauro M, Marino A, Rovella V, Rodia G, Schinzari F, Tolusso B, di Daniele N, Federici M, Zoli A, Ferraccioli G, Cardillo C: Toll-Like Receptor 4 Mediates Endothelial Cell Activation Through NF-kappaB but Is Not Associated with Endothelial Dysfunction in Patients with Rheumatoid Arthritis. PLoS One 2014, 9: e99053. 10.1371/journal.pone.0099053PubMedPubMedCentralCrossRef Menghini R, Campia U, Tesauro M, Marino A, Rovella V, Rodia G, Schinzari F, Tolusso B, di Daniele N, Federici M, Zoli A, Ferraccioli G, Cardillo C: Toll-Like Receptor 4 Mediates Endothelial Cell Activation Through NF-kappaB but Is Not Associated with Endothelial Dysfunction in Patients with Rheumatoid Arthritis. PLoS One 2014, 9: e99053. 10.1371/journal.pone.0099053PubMedPubMedCentralCrossRef
21.
go back to reference Badou A, Bennasser Y, Moreau M, Leclerc C, Benkirane M, Bahraoui E: Tat protein of human immunodeficiency virus type 1 induces interleukin-10 in human peripheral blood monocytes: implication of protein kinase C-dependent pathway. J Virol 2000, 74: 10551-10562. 10.1128/JVI.74.22.10551-10562.2000PubMedPubMedCentralCrossRef Badou A, Bennasser Y, Moreau M, Leclerc C, Benkirane M, Bahraoui E: Tat protein of human immunodeficiency virus type 1 induces interleukin-10 in human peripheral blood monocytes: implication of protein kinase C-dependent pathway. J Virol 2000, 74: 10551-10562. 10.1128/JVI.74.22.10551-10562.2000PubMedPubMedCentralCrossRef
22.
go back to reference Bennasser Y, Bahraoui E: HIV-1 Tat protein induces interleukin-10 in human peripheral blood monocytes: involvement of protein kinase C-betaII and -delta. FASEB J 2002, 16: 546-554. 10.1096/fj.01-0775comPubMedCrossRef Bennasser Y, Bahraoui E: HIV-1 Tat protein induces interleukin-10 in human peripheral blood monocytes: involvement of protein kinase C-betaII and -delta. FASEB J 2002, 16: 546-554. 10.1096/fj.01-0775comPubMedCrossRef
23.
go back to reference Contreras X, Bennasser Y, Bahraoui E: IL-10 production induced by HIV-1 Tat stimulation of human monocytes is dependent on the activation of PKC beta(II) and delta isozymes. Microbes and infection/Institut Pasteur 2004, 6: 1182-1190. 10.1016/j.micinf.2004.06.008PubMedCrossRef Contreras X, Bennasser Y, Bahraoui E: IL-10 production induced by HIV-1 Tat stimulation of human monocytes is dependent on the activation of PKC beta(II) and delta isozymes. Microbes and infection/Institut Pasteur 2004, 6: 1182-1190. 10.1016/j.micinf.2004.06.008PubMedCrossRef
24.
go back to reference Rallabhandi P, Phillips RL, Boukhvalova MS, Pletneva LM, Shirey KA, Gioannini TL, Weiss JP, Chow JC, Hawkins LD, Vogel SN, Blanco JC: Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2. mBio 2012, 3(4). doi: 10.1128/mBio.00218-12. Rallabhandi P, Phillips RL, Boukhvalova MS, Pletneva LM, Shirey KA, Gioannini TL, Weiss JP, Chow JC, Hawkins LD, Vogel SN, Blanco JC: Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2. mBio 2012, 3(4). doi: 10.1128/mBio.00218-12.
25.
go back to reference Neal MD, Jia H, Eyer B, Good M, Guerriero CJ, Sodhi CP, Afrazi A, Prindle T Jr, Ma C, Branca M, Ozolek J, Brodsky JL, Wipf P, Hackam DJ: Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors. PLoS One 2013, 8: e65779. 10.1371/journal.pone.0065779PubMedPubMedCentralCrossRef Neal MD, Jia H, Eyer B, Good M, Guerriero CJ, Sodhi CP, Afrazi A, Prindle T Jr, Ma C, Branca M, Ozolek J, Brodsky JL, Wipf P, Hackam DJ: Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors. PLoS One 2013, 8: e65779. 10.1371/journal.pone.0065779PubMedPubMedCentralCrossRef
26.
go back to reference Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM, Karp CL, McAlees J, Gioannini TL, Weiss J, Chen WH, Ernst RK, Rossignol DP, Gusovsky F, Blanco JC, Vogel SN: The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 2013, 497: 498-502. 10.1038/nature12118PubMedPubMedCentralCrossRef Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM, Karp CL, McAlees J, Gioannini TL, Weiss J, Chen WH, Ernst RK, Rossignol DP, Gusovsky F, Blanco JC, Vogel SN: The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 2013, 497: 498-502. 10.1038/nature12118PubMedPubMedCentralCrossRef
27.
go back to reference Barochia A, Solomon S, Cui X, Natanson C, Eichacker PQ: Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin Drug Metab Toxicol 2011, 7: 479-494. 10.1517/17425255.2011.558190PubMedPubMedCentralCrossRef Barochia A, Solomon S, Cui X, Natanson C, Eichacker PQ: Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin Drug Metab Toxicol 2011, 7: 479-494. 10.1517/17425255.2011.558190PubMedPubMedCentralCrossRef
Metadata
Title
E5564 inhibits immunosuppressive cytokine IL-10 induction promoted by HIV-1 Tat protein
Authors
Elmostafa Bahraoui
Laurence Briant
Nathalie Chazal
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2014
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-014-0214-z

Other articles of this Issue 1/2014

Virology Journal 1/2014 Go to the issue