The hLF1–11 peptide comprising the first 11 N-terminal residues of human lactoferrin exerts antimicrobial activity in vivo, enhances the inflammatory response of monocytes and directs monocyte-macrophage differentiation toward cells with enhanced antimicrobial properties. In this study, we investigated the effects of hLF1–11 on human monocyte-dendritic cell (DC) differentiation and subsequent T cell activation. Results revealed that – compared to control (peptide-incubated) DCs – hLF1–11-differentiated DCs displayed enhanced expression of HLA class II antigens and dectin-1, and increased phagocytosis of Candida albicans. In addition, hLF1–11-differentiated DCs produced enhanced amounts of reactive oxygen species, IL-6 and IL-10, but not IL-12p40 and TNF-α, upon stimulation with C. albicans. Moreover, 6-day-cultured hLF1–11-differentiated DCs and control (peptide-incubated) DCs that had been stimulated with a Th17-inducing mix of antigens (including C. albicans) for 24 h were cocultured with autologous CD4+ T cells for 72 h and then the levels of IL-10, IL-17 and IFN-γ production and the percentage of cytokine-producing T cells were assessed. The results revealed that the hLF1–11-differentiated DCs induced an enhanced IL-17, but reduced IFN-γ, production by T cells as compared to control (peptide-incubated) DCs. Collectively, the hLF1–11 peptide drives monocyte-DC differentiation toward DCs that promote antifungal responses and enhance Th17 polarization.

Keywords:
Dendritic cell, Polarization, Candida albicans, Monocytes, Antimicrobial peptide, T lymphocyte
1.
Zasloff M: Antimicrobial peptides of multicellular organisms. Nature 2002;415:389–395.
2.
Brogden KA: Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 2005;3:238–250.
3.
Nibbering PH, Ravensbergen E, Welling MM, van Berkel LA, van Berkel PH, Pauwels EK, Nuijens JH: Human lactoferrin and peptides derived from its N terminus are highly effective against infections with antibiotic-resistant bacteria. Infect Immun 2001;69:1469–1476.
4.
Konopka K, Dorocka-Bobkowska B, Gebremedhin S, Duzgunes N: Susceptibility of Candida biofilms to histatin 5 and fluconazole. Antonie Van Leeuwenhoek 2010;97:413–417.
5.
Lupetti A, Brouwer CP, Bogaards SJ, Welling MM, de Heer E, Campa M, van Dissel JT, Friesen RH, Nibbering PH: Human lactoferrin-derived peptide’s antifungal activities against disseminated Candida albicans infection. J Infect Dis 2007;196:1416–1424.
6.
van der Does AM, Bogaards SJ, Ravensbergen B, Beekhuizen H, van Dissel JT, Nibbering PH: Antimicrobial peptide hLF1– 11 directs granulocyte-macrophage colony-stimulating factor-driven monocyte differentiation toward macrophages with enhanced recognition and clearance of pathogens. Antimicrob Agents Chemother 2010;54:811–816.
7.
Bowdish DM, Davidson DJ, Scott MG, Hancock RE: Immunomodulatory activities of small host defense peptides. Antimicrob Agents Chemother 2005;49:1727–1732.
8.
Jenssen H, Hancock RE: Therapeutic potential of HDPS as immunomodulatory agents. Methods Mol Biol 2010;618:329–347.
9.
Hale JD, Hancock RE: Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. Expert Rev Anti Infect Ther 2007;5:951–959.
10.
Hancock RE, Sahl HG: Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat Biotechnol 2006;24:1551–1557.
11.
Scott MG, Dullaghan E, Mookherjee N, Glavas N, Waldbrook M, Thompson A, Wang A, Lee K, Doria S, Hamill P, Yu JJ, Li Y, Donini O, Guarna MM, Finlay BB, North JR, Hancock RE: An anti-infective peptide that selectively modulates the innate immune response. Nat Biotechnol 2007;25:465–472.
12.
Nijnik A, Madera L, Ma S, Waldbrook M, Elliott MR, Easton DM, Mayer ML, Mullaly SC, Kindrachuk J, Jenssen H, Hancock RE: Synthetic cationic peptide IDR-1002 provides protection against bacterial infections through chemokine induction and enhanced leukocyte recruitment. J Immunol 2010;184:2539–2550.
13.
van der Does AM, Beekhuizen H, Ravensbergen B, Vos T, Ottenhoff TH, van Dissel JT, Drijfhout JW, Hiemstra PS, Nibbering PH: LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature. J Immunol 2010;185:1442–1449.
14.
Davidson DJ, Currie AJ, Reid GS, Bowdish DM, MacDonald KL, Ma RC, Hancock RE, Speert DP: The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J Immunol 2004;172:1146–1156.
15.
Mookherjee N, Lippert DN, Hamill P, Falsafi R, Nijnik A, Kindrachuk J, Pistolic J, Gardy J, Miri P, Naseer M, Foster LJ, Hancock RE: Intracellular receptor for human host defense peptide LL-37 in monocytes. J Immunol 2009;183:2688–2696.
16.
Kandler K, Shaykhiev R, Kleemann P, Klescz F, Lohoff M, Vogelmeier C, Bals R: The antimicrobial peptide LL-37 inhibits the activation of dendritic cells by TLR ligands. Int Immunol 2006;18:1729–1736.
17.
Dijkshoorn L, Brouwer CP, Bogaards SJ, Nemec A, van den Broek PJ, Nibbering PH: The synthetic N-terminal peptide of human lactoferrin, hLF(1–11), is highly effective against experimental infection caused by multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2004;48:4919–4921.
18.
van der Does AM, Bogaards SJ, Jonk L, Wulferink M, Velders MP, Nibbering PH: The human lactoferrin-derived peptide hLF1–11 primes monocytes for an enhanced TLR-mediated immune response. Biometals 2010;23:493–505.
19.
Zenaro E, Donini M, Dusi S. Induction of Th1/Th17 immune response by Mycobacterium tuberculosis: role of dectin-1, mannose receptor, and DC-SIGN. J Leukoc Biol 2009;86:1393–1401.
20.
Bettelli E, Korn T, Oukka M, Kuchroo VK: Induction and effector functions of TH17 cells. Nature 2008;453:1051–1057.
21.
Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, Scheinberg P, Price DA, Hage CA, Kholi LM, Khoruts A, Frank I, Else J, Schacker T, Silvestri G, Douek DC: Differential Th17 CD4 t-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 2008;112:2826–2835.
22.
Louten J, Boniface K, de Waal Malefyt R: Development and function of Th17 cells in health and disease. J Allergy Clin Immunol 2009;123:1004–1011.
23.
Roy KC, Bandyopadhyay G, Rakshit S, Ray M, Bandyopadhyay S: IL-4 alone without the involvement of GM-CSF transforms human peripheral blood monocytes to a CD1adim, CD83+ myeloid dendritic cell subset. J Cell Sci 2004;117:3435–3445.
24.
Conti HR, Gaffen SL: Host responses to Candida albicans: Th17 cells and mucosal candidiasis. Microbes Infect 2010;12:518–527.
25.
Eyerich K, Foerster S, Rombold S, Seidl HP, Behrendt H, Hofmann H, Ring J, Traidl-Hoffmann C: Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J Invest Dermatol 2008;128:2640–2645.
26.
Iwakura Y, Nakae S, Saijo S, Ishigame H: The roles of IL-17α in inflammatory immune responses and host defense against pathogens. Immunol Rev 2008;226:57–79.
27.
Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, Magorien JE, Blauvelt A, Kolls JK, Cheung AL, Cheng G, Modlin RL, Miller LS: IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Invest 2010;120:1762–1773.
28.
Onishi RM, Gaffen SL: Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease. Immunology 2010;129:311–321.
29.
Yu JJ, Gaffen SL: Interleukin-17: a novel inflammatory cytokine that bridges innate and adaptive immunity. Front Biosci 2008;13:170–177.
30.
Bouguermouh S, Fortin G, Baba N, Rubio M, Sarfati M: CD28 co-stimulation down regulates Th17 development. PLoS One 2009;4:e5087.
31.
Hamad M: Antifungal immunotherapy and immunomodulation: a double-hitter approach to deal with invasive fungal infections. Scand J Immunol 2008;67:533–543.
32.
Presicce P, Giannelli S, Taddeo A, Villa ML, Della Bella S: Human defensins activate monocyte-derived dendritic cells, promote the production of proinflammatory cytokines, and up-regulate the surface expression of CD91. J Leukoc Biol 2009;86:941–948.
© 2012 S. Karger AG, Basel
2012
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