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Published in: BMC Immunology 1/2013

Open Access 01-12-2013 | Research article

Anti-inflammatory effect of a retrovirus-derived immunosuppressive peptide in mouse models

Authors: Martin Tolstrup, Claus Johansen, Lars Toft, Finn S Pedersen, Anne Funding, Shervin Bahrami, Lars Iversen, Lars Østergaard, Mogens Duch

Published in: BMC Immunology | Issue 1/2013

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Abstract

Background

Short dimeric or mulitmeric peptides derived from a highly conserved stretch of amino acids from gammaretroviral envelope proteins has been found to have immunosuppressive properties in vitro. Here we test the hypothesis that such immunosuppressive peptides may serve as immunomodulatory reagents for treatment of inflammatory disorders.

Results

The anti-inflammatory effect of a synthetic retrovirus-derived immunosuppressive peptide of 17 amino acids was tested in two murine skin inflammation models, a TPA-induced acute toxic contact eczema model and an oxazolone-induced allergic contact dermatitis. Overall, mice (n = 24) treated with a topically applied cream containing the dimeric immunosuppressive peptide exhibited a reduction of 28.8% in ear thickness (range 20.1-42.5), whereas the application of a scrambled peptide dimer or a monomer of the immunosuppressive peptide remained without effect (p = 0.028). Furthermore, ear biopsies from mice treated with the dimeric immunosuppressive peptide showed a significant reduction in mRNA of the pro-inflammatory cytokines TNF-α, IL-17C, and IL-6 as well as the chemokine CXCL2 compared to mice treated with control peptides.

Conclusion

Using two murine skin inflammation models, we show that an immunosuppressive retroviral peptide is capable of reducing inflammatory disorders. The results indicate that virus-derived immunosuppressive peptides capable of down-regulating several proinflammatory cytokines may represent a novel class of drugs for the treatment of excess inflammation.
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Literature
1.
go back to reference Leonardi CL, Kimball AB: Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008, 371: 1665-1674. 10.1016/S0140-6736(08)60725-4.CrossRefPubMed Leonardi CL, Kimball AB: Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008, 371: 1665-1674. 10.1016/S0140-6736(08)60725-4.CrossRefPubMed
2.
go back to reference Leonardi C, Matheson R: Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012, 366: 1190-1199. 10.1056/NEJMoa1109997.CrossRefPubMed Leonardi C, Matheson R: Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012, 366: 1190-1199. 10.1056/NEJMoa1109997.CrossRefPubMed
3.
go back to reference Valesini G, Iannuccelli C: Biological and clinical effects of anti-TNFalpha treatment. Autoimmun Rev. 2007, 7: 35-41. 10.1016/j.autrev.2007.03.003.CrossRefPubMed Valesini G, Iannuccelli C: Biological and clinical effects of anti-TNFalpha treatment. Autoimmun Rev. 2007, 7: 35-41. 10.1016/j.autrev.2007.03.003.CrossRefPubMed
4.
go back to reference Craciun FL, Schuller ER, Remick DG: Early enhanced local neutrophil recruitment in peritonitis-induced sepsis improves bacterial clearance and survival. J Immunol. 2010, 185 (11): 6930-6938. 10.4049/jimmunol.1002300.CrossRefPubMed Craciun FL, Schuller ER, Remick DG: Early enhanced local neutrophil recruitment in peritonitis-induced sepsis improves bacterial clearance and survival. J Immunol. 2010, 185 (11): 6930-6938. 10.4049/jimmunol.1002300.CrossRefPubMed
5.
go back to reference Villar J, Pérez-Méndez L: A CXCL2 polymorphism is associated with better outcomes in patients with severe sepsis. Crit Care Med. 2007, 35 (10): 2292-2297. 10.1097/01.CCM.0000284511.73556.59.CrossRefPubMed Villar J, Pérez-Méndez L: A CXCL2 polymorphism is associated with better outcomes in patients with severe sepsis. Crit Care Med. 2007, 35 (10): 2292-2297. 10.1097/01.CCM.0000284511.73556.59.CrossRefPubMed
6.
go back to reference Kim SD, Kim YK: The agonists of formyl peptide receptors prevent development of severe sepsis after microbial infection. J Immunol. 2010, 185 (7): 4302-4310. 10.4049/jimmunol.1001310.CrossRefPubMed Kim SD, Kim YK: The agonists of formyl peptide receptors prevent development of severe sepsis after microbial infection. J Immunol. 2010, 185 (7): 4302-4310. 10.4049/jimmunol.1001310.CrossRefPubMed
7.
go back to reference Hillenbrand A, Knippschild U: Sepsis induced changes of adipokines and cytokines - septic patients compared to morbidly obese patients. BMC Surg. 2010, 9: 10-26. Hillenbrand A, Knippschild U: Sepsis induced changes of adipokines and cytokines - septic patients compared to morbidly obese patients. BMC Surg. 2010, 9: 10-26.
8.
go back to reference Hamishehkar H, Beigmohammadi MT: Identification of enhanced cytokine generation following sepsis. Dream of magic bullet for mortality prediction and therapeutic evaluation. Daru. 2010, 18 (3): 155-162.PubMedCentralPubMed Hamishehkar H, Beigmohammadi MT: Identification of enhanced cytokine generation following sepsis. Dream of magic bullet for mortality prediction and therapeutic evaluation. Daru. 2010, 18 (3): 155-162.PubMedCentralPubMed
9.
go back to reference Cianciolo GJ, Lostrom ME: Murine malignant cells synthesize a 19,000-dalton protein that is physicochemically and antigenically related to the immunosuppressive retroviral protein, P15E. J Exp Med. 1983, 18 (3): 885-900.CrossRef Cianciolo GJ, Lostrom ME: Murine malignant cells synthesize a 19,000-dalton protein that is physicochemically and antigenically related to the immunosuppressive retroviral protein, P15E. J Exp Med. 1983, 18 (3): 885-900.CrossRef
10.
go back to reference Hebebrand LC, Olsen RG: Inhibition of human lymphocyte mitogen and antigen response by a 1,000-dalton protein from feline leukemia virus. Cancer Res. 1979, 39: 443-447.PubMed Hebebrand LC, Olsen RG: Inhibition of human lymphocyte mitogen and antigen response by a 1,000-dalton protein from feline leukemia virus. Cancer Res. 1979, 39: 443-447.PubMed
11.
go back to reference Cianciolo GJ, Matthews TJ: Macrophage accumulation in mice is inhibited by low molecular weight products from murine leukemia viruses. J Immunol. 1980, 124 (6): 2900-2905.PubMed Cianciolo GJ, Matthews TJ: Macrophage accumulation in mice is inhibited by low molecular weight products from murine leukemia viruses. J Immunol. 1980, 124 (6): 2900-2905.PubMed
12.
go back to reference Mangeney M, Heidmann T: Tumor cells expressing a retroviral envelope escape immune rejection in vivo. Proc Natl Acad Sci USA. 1998, 95 (25): 14920-14925. 10.1073/pnas.95.25.14920.PubMedCentralCrossRefPubMed Mangeney M, Heidmann T: Tumor cells expressing a retroviral envelope escape immune rejection in vivo. Proc Natl Acad Sci USA. 1998, 95 (25): 14920-14925. 10.1073/pnas.95.25.14920.PubMedCentralCrossRefPubMed
13.
go back to reference Mangeney M, Renard M: Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA. 2007, 104 (51): 20534-20539. 10.1073/pnas.0707873105.PubMedCentralCrossRefPubMed Mangeney M, Renard M: Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA. 2007, 104 (51): 20534-20539. 10.1073/pnas.0707873105.PubMedCentralCrossRefPubMed
14.
go back to reference Cianciolo GJ, Copeland TD: Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins. Science. 1985, 230 (4724): 453-455. 10.1126/science.2996136.CrossRefPubMed Cianciolo GJ, Copeland TD: Inhibition of lymphocyte proliferation by a synthetic peptide homologous to retroviral envelope proteins. Science. 1985, 230 (4724): 453-455. 10.1126/science.2996136.CrossRefPubMed
15.
go back to reference Cianciolo GJ, Bogerd H, Snyderman R: Human retrovirus-related synthetic peptides inhibit T lymphocyte proliferation. Immunol Lett. 1988, 19 (1): 7-13. 10.1016/0165-2478(88)90112-5.CrossRefPubMed Cianciolo GJ, Bogerd H, Snyderman R: Human retrovirus-related synthetic peptides inhibit T lymphocyte proliferation. Immunol Lett. 1988, 19 (1): 7-13. 10.1016/0165-2478(88)90112-5.CrossRefPubMed
16.
go back to reference Yaddanapudi K, Palacios G: Implication of a retrovirus-like glycoprotein peptide in the immunopathogenesis of Ebola and Marburg viruses. FASEB J. 2006, 20 (14): 2519-2530. 10.1096/fj.06-6151com.CrossRefPubMed Yaddanapudi K, Palacios G: Implication of a retrovirus-like glycoprotein peptide in the immunopathogenesis of Ebola and Marburg viruses. FASEB J. 2006, 20 (14): 2519-2530. 10.1096/fj.06-6151com.CrossRefPubMed
17.
go back to reference Bloch I, Quintana FJ: T-cell inactivation and immunosuppressive activity induced by HIV gp41 via novel interacting motif. FASEB J. 2007, 21 (2): 393-401. 10.1096/fj.06-7061com.CrossRefPubMed Bloch I, Quintana FJ: T-cell inactivation and immunosuppressive activity induced by HIV gp41 via novel interacting motif. FASEB J. 2007, 21 (2): 393-401. 10.1096/fj.06-7061com.CrossRefPubMed
18.
go back to reference Haraguchi S, Good RA: Differential modulation of Th1 and Th2 related cytokine mRNA expression by a synthetic peptide homologous to a conserved domain within retroviral envelope protein. Proc Natl Acad Sci USA. 1995, 92: 3611-3615. 10.1073/pnas.92.8.3611.PubMedCentralCrossRefPubMed Haraguchi S, Good RA: Differential modulation of Th1 and Th2 related cytokine mRNA expression by a synthetic peptide homologous to a conserved domain within retroviral envelope protein. Proc Natl Acad Sci USA. 1995, 92: 3611-3615. 10.1073/pnas.92.8.3611.PubMedCentralCrossRefPubMed
19.
go back to reference Harrell RA, Cianciolo GJ: Suppression of the respiratory burst of human monocytes by a synthetic peptide homologous to envelope proteins of human and animal retroviruses. J Immunol. 1986, 136: 3517-3520.PubMed Harrell RA, Cianciolo GJ: Suppression of the respiratory burst of human monocytes by a synthetic peptide homologous to envelope proteins of human and animal retroviruses. J Immunol. 1986, 136: 3517-3520.PubMed
20.
go back to reference Kleinerman ES, Lachman LB: A synthetic peptide homologous to the envelope proteins of retroviruses inhibits monocyte mediated killing by inactivating interleukin 1. J Immunol. 1987, 139: 2329-2337.PubMed Kleinerman ES, Lachman LB: A synthetic peptide homologous to the envelope proteins of retroviruses inhibits monocyte mediated killing by inactivating interleukin 1. J Immunol. 1987, 139: 2329-2337.PubMed
21.
go back to reference Finkelman FD, Hogan SP: Importance of cytokines in murine allergic airway disease and human asthma. J Immunol. 2010, 184 (4): 1663-1674. 10.4049/jimmunol.0902185.PubMedCentralCrossRefPubMed Finkelman FD, Hogan SP: Importance of cytokines in murine allergic airway disease and human asthma. J Immunol. 2010, 184 (4): 1663-1674. 10.4049/jimmunol.0902185.PubMedCentralCrossRefPubMed
22.
go back to reference Corren J: Cytokine inhibition in severe asthma: current knowledge and future directions. Curr Opin Pulm Med. 2011, 17 (1): 29-33. 10.1097/MCP.0b013e3283413105.CrossRefPubMed Corren J: Cytokine inhibition in severe asthma: current knowledge and future directions. Curr Opin Pulm Med. 2011, 17 (1): 29-33. 10.1097/MCP.0b013e3283413105.CrossRefPubMed
23.
go back to reference Delavallée L, Duvallet E: Anti-cytokine vaccination in autoimmune diseases. Swiss Med Wkly. 2010, 140: w13108-PubMed Delavallée L, Duvallet E: Anti-cytokine vaccination in autoimmune diseases. Swiss Med Wkly. 2010, 140: w13108-PubMed
24.
go back to reference Funding AT, Johansen C: Reduced oxazolone-induced skin inflammation in MAPKAP kinase 2 knockout mice. J Invest Dermatol. 2009, 129: 891-898. 10.1038/jid.2008.322.CrossRefPubMed Funding AT, Johansen C: Reduced oxazolone-induced skin inflammation in MAPKAP kinase 2 knockout mice. J Invest Dermatol. 2009, 129: 891-898. 10.1038/jid.2008.322.CrossRefPubMed
25.
go back to reference Lilleholt LL, Johansen C: Role of p38 mitogen-activated protein kinase isoforms in murine skin inflammation induced by 12-O-tetradecanoylphorbol 13-acetate. Acta Derm Venereol. 2011, 91: 271-278. 10.2340/00015555-1046.CrossRefPubMed Lilleholt LL, Johansen C: Role of p38 mitogen-activated protein kinase isoforms in murine skin inflammation induced by 12-O-tetradecanoylphorbol 13-acetate. Acta Derm Venereol. 2011, 91: 271-278. 10.2340/00015555-1046.CrossRefPubMed
26.
go back to reference Takahashi A, Day NK: A retroviral-derived immunosuppressive peptide activates mitogen-activated protein kinases. J Immunol. 2001, 166: 6771-6775.CrossRefPubMed Takahashi A, Day NK: A retroviral-derived immunosuppressive peptide activates mitogen-activated protein kinases. J Immunol. 2001, 166: 6771-6775.CrossRefPubMed
27.
go back to reference Cianciolo GJ, Pizzo SV: Anti-inflammatory and vasoprotective activity of a retroviral-derived peptide, homologous to human endogenous retroviruses: endothelial cell effects. PLoS One. 2012, 7 (12): e52693-10.1371/journal.pone.0052693.PubMedCentralCrossRefPubMed Cianciolo GJ, Pizzo SV: Anti-inflammatory and vasoprotective activity of a retroviral-derived peptide, homologous to human endogenous retroviruses: endothelial cell effects. PLoS One. 2012, 7 (12): e52693-10.1371/journal.pone.0052693.PubMedCentralCrossRefPubMed
28.
go back to reference Ashkenazi A, Faingold O: HIV-1 fusion protein exerts complex immunosuppressive effects. Trends Biochem Sci. 2013, 38 (7): 345-349. 10.1016/j.tibs.2013.04.003.CrossRefPubMed Ashkenazi A, Faingold O: HIV-1 fusion protein exerts complex immunosuppressive effects. Trends Biochem Sci. 2013, 38 (7): 345-349. 10.1016/j.tibs.2013.04.003.CrossRefPubMed
29.
go back to reference Morozov VA, Morozov AV: Single mutations in the transmembrane envelope protein abrogate the immunosuppressive properties of HIV-1. Retrovirology. 2012, 9: 67-10.1186/1742-4690-9-67.PubMedCentralCrossRefPubMed Morozov VA, Morozov AV: Single mutations in the transmembrane envelope protein abrogate the immunosuppressive properties of HIV-1. Retrovirology. 2012, 9: 67-10.1186/1742-4690-9-67.PubMedCentralCrossRefPubMed
30.
go back to reference Kalyan Kumar G, Dhamotharan R: Embelin reduces cutaneous TNF-α level and ameliorates skin edema in acute and chronic model of skin inflammation in mice. Eur J Pharmacol. 2011, 662: 63-69. 10.1016/j.ejphar.2011.04.037.CrossRefPubMed Kalyan Kumar G, Dhamotharan R: Embelin reduces cutaneous TNF-α level and ameliorates skin edema in acute and chronic model of skin inflammation in mice. Eur J Pharmacol. 2011, 662: 63-69. 10.1016/j.ejphar.2011.04.037.CrossRefPubMed
31.
go back to reference Papp KA, Reid C: Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severe psoriasis: results from a phase I, randomized, placebo-controlled trial. J Invest Dermatol. 2012, 132: 2466-2469. 10.1038/jid.2012.163.CrossRefPubMed Papp KA, Reid C: Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severe psoriasis: results from a phase I, randomized, placebo-controlled trial. J Invest Dermatol. 2012, 132: 2466-2469. 10.1038/jid.2012.163.CrossRefPubMed
32.
go back to reference Galloway JB, Hyrich KL: Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology. 2011, 50: 124-131. 10.1093/rheumatology/keq242.PubMedCentralCrossRefPubMed Galloway JB, Hyrich KL: Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology. 2011, 50: 124-131. 10.1093/rheumatology/keq242.PubMedCentralCrossRefPubMed
Metadata
Title
Anti-inflammatory effect of a retrovirus-derived immunosuppressive peptide in mouse models
Authors
Martin Tolstrup
Claus Johansen
Lars Toft
Finn S Pedersen
Anne Funding
Shervin Bahrami
Lars Iversen
Lars Østergaard
Mogens Duch
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2013
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/1471-2172-14-51

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