Identification of the first antagonist peptide that inhibits biological effects of interleukin-15

Alicia Santos; Osvaldo Reyes; Ania Cabrales; Yunier Rodríguez; Haydee Gerónimo; Hilda E Garay; Celia A Arrieta; Miriam Ojeda; Ana C Machado; José Suárez; Julio A Ancisar; Mariela Vázquez; Gerardo Guillén; Araceli Chico; Miguel Estévez; Alexey Llopiz; Jesús Noda; Aniel Sánchez; Lorenzo Silengo; Fiorella Altruda; Silvio Perea

2013, Number 4

Biotecnol Apl 2013; 30 (4)

Identification of the first antagonist peptide that inhibits biological effects of interleukin-15

Santos A, Reyes O, Cabrales A, Rodríguez Y, Geronimo H, Garay HE, Arrieta CA, Ojeda M, Machado AC, Suarez J, Ancisar JA, Vázquez M, Guillén G, Chico A, Estévez M, Llopiz A, Noda J, Sánchez A, Silengo L, Altruda F, Perea S

Full text

How to cite this article

Language: English
References: 24
Page: 317-319
PDF size: 197.62 Kb.

ABSTRACT

Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is expressed in several autoimmune and inflammatory diseases. We have identifi ed the 36-45 sequence KVTAMKCFLL on human IL-15 that is recognized by a soluble form of recombinant hIL-15Rα-Fc fusion protein. This sequence synthesized as a 10 aa. peptide binds to the IL-15Rα and was able to block the biological activity of IL-15 in two IL-15 dependent cells lines. Using alanine scan strategy we identified a more active peptide by replacing the second Lys in the sequence for the polar non-charged amino acid threonine. Moreover, soluble IL-15Rα was quantitated by a newly developed enzyme-linked immunosorbent assay (ELISA) using the P8 peptide as capture in samples of synovial fluid from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). This research won the 2012 Award of the Cuban National Academy of Sciences.

REFERENCES

McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429-42.
Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;11 Suppl 1:S1.
Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Annu Rev Med. 2000;51:207-29.
McInnes IB, Liew FY. Cytokine networks- towards new therapies for rheumatoid arthritis. Nat Clin Pract Rheumatol. 2005;1(1):31-9.
McInnes IB, al-Mughales J, Field M, Leung BP, Huang FP, Dixon R, et al. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med. 1996;2(2):175-82.
Carroll HP, Paunovic V, Gadina M. Signalling, inflammation and arthritis: Crossed signals: the role of interleukin-15 and -18 in autoimmunity. Rheumatology (Oxford). 2008;47(9):1269-77.
McInnes IB, Gracie JA, Harnett M, Harnett W, Liew FY. New strategies to control infl ammatory synovitis: interleukin 15 and beyond. Ann Rheum Dis. 2003;62 Suppl 2:ii51-4.
Oppenheimer-Marks N, Brezinschek RI, Mohamadzadeh M, Vita R, Lipsky PE. Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells In vitro and in the SCID mouse-human rheumatoid arthritis model In vivo. J Clin Invest. 1998;101(6):1261-72.
McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY. Interleukin-15 mediates T celldependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med. 1997;3(2):189-95.
Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifi lieff A. IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol. 2003;170(4):2106-12.
Verri WA Jr, Cunha TM, Ferreira SH, Wei X, Leung BP, Fraser A, et al. IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production. Eur J Immunol. 2007;37(12):3373-80.
Ogata Y, Kukita A, Kukita T, Komine M, Miyahara A, Miyazaki S, et al. A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2. J Immunol. 1999;162(5):2754-60.
Miranda-Carus ME, Benito-Miguel M, Balsa A, Cobo-Ibanez T, Perez de Ayala C, Pascual-Salcedo D, et al. Peripheral blood T lymphocytes from patients with early rheumatoid arthritis express RANKL and interleukin-15 on the cell surface and promote osteoclastogenesis in autologous monocytes. Arthritis Rheum. 2006;54(4):1151-64.
Budagian V, Bulanova E, Orinska Z, Pohl T, Borden EC, Silverman R, et al. Reverse signaling through membrane-bound interleukin-15. J Biol Chem. 2004;279(40):42192-201.
Neely GG, Epelman S, Ma LL, Colarusso P, Howlett CJ, Amankwah EK, et al. Monocyte surface- bound IL-15 can function as an activating receptor and participate in reverse signaling. J Immunol. 2004;172(7):4225-34.
Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity. 2002;17(5):537-47.
Baslund B, Tvede N, Danneskiold-Samsoe B, Petersen J, Petersen LJ, Schuurman J, et al. A novel human monoclonal antibody against IL-15 (humax-IL15) in patients with active rheumatoid arthritis (RA): results of a doubleblind, placebocontrolled phase I/II trial. Arthritis Rheum. 2003;48 Suppl 9:S1706.
Kim YS, Maslinski W, Zheng XX, Stevens AC, Li XC, Tesch GH, et al. Targeting the IL-15 receptor with an antagonist IL-15 mutant/Fc gamma2a protein blocks delayedtype hypersensitivity. J Immunol. 1998; 160(12):5742-8.
Ruchatz H, Leung BP, Wei XQ, McInnes IB, Liew FY. Soluble IL-15 receptor alpha-chain administration prevents murine collageninduced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J Immunol. 1998;160(11):5654-60.
Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD, et al. Converting IL-15 to a superagonist by binding to soluble IL-15Ralpha. Proc Natl Acad Sci USA. 2006;103(24):9166-71.
Mortier E, Quemener A, Vusio P, Lorenzen I, Boublik Y, Grotzinger J, et al. Soluble interleukin- 15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins. J Biol Chem. 2006;281(3):1612-9.
Santos A, Cabrales A, Reyes O, Gerónimo H, Rodríguez Y, Garay H, Arrieta C, Silva R, Guillen G. Identifi cation of an interleukin-15 antagonist peptide that binds to IL-15Rα. Biotecnol Apl. 2008;25(4):320-4.
Savio AS, Acosta OR, Perez HG, Alvarez YR, Chico A, Ojeda MO, et al. Enhancement of the inhibitory effect of an IL-15 antagonist peptide by alanine scanning. J Pept Sci. 2012; 18(1):25-9.
Machado Diaz AC, Chico Capote A, Arrieta Aguero CA, Rodriguez Alvarez Y, Garcia Del Barco Herrera D, Estevez Del Toro M, et al. Proinfl ammatory soluble interleukin-15 receptor alpha is increased in rheumatoid arthritis. Arthritis. 2012;2012:943156.