Structure-function relationship of the human antimicrobial peptide LL-37 and LL-37 fragments in the modulation of TLR responses

Biological Chemistry

Volumn 390, Issue 4, 2009, Pages 295-303

  Molhoek, E Margo ^a,b   Den Hertog, Alice L ^c   De Vries, Anne Marij B C ^a   Nazmi, Kamran ^c   Veerman, Enno C I ^c   Hartgers, Franca C ^b   Yazdanbakhsh, Maria ^b   Bikker, Floris J ^a   Van Der Kleij, Desiree ^a  

^a TNO   (Netherlands)

^b LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^c VU UNIVERSITY AMSTERDAM   (Netherlands)

Author keywords

Cathelicidins; Immunomodulation; MAP kinases; Physico chemical properties

Indexed keywords

BACTERIUM LIPOPOLYSACCHARIDE; CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; CYTOKINE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 1; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 5; TOLL LIKE RECEPTOR 6; TOLL LIKE RECEPTOR 7; TOLL LIKE RECEPTOR 8;

ANTIINFLAMMATORY ACTIVITY; ANTIMICROBIAL ACTIVITY; ARTICLE; CYTOKINE RELEASE; HUMAN; HUMAN CELL; HYDROPHOBICITY; IMMUNOMODULATION; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; STRUCTURE ACTIVITY RELATION;

AMINO ACID SEQUENCE; ANTIMICROBIAL CATIONIC PEPTIDES; CELLS, CULTURED; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CIRCULAR DICHROISM; HUMANS; LIGANDS; MOLECULAR SEQUENCE DATA; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP; TOLL-LIKE RECEPTORS;

BACTERIA (MICROORGANISMS);

EID: 64849111975     PISSN: 14316730     EISSN: 14374315     Source Type: Journal    
DOI: 10.1515/BC.2009.037     Document Type: Article

References (48)

1. Akira, S., Uematsu, S., and Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783-801.
2. Banerjee, A. and Gerondakis, S. (2007). Coordinating TLR-activated signaling pathways in cells of the immune system. Immunol. Cell Biol. 85, 420-424.
3. Bowdish, D.M., Davidson, D.J., Speert, D.P., and Hancock, R.E. (2004). The human cationic peptide LL-37 induces activation of the extracellular signal-regulated kinase and p38 kinase pathways in primary human monocytes. J. Immunol. 172, 3758-3765.
4. Bowdish, D.M., Davidson, D.J., and Hancock, R.E. (2006). Immunomodulatory properties of defensins and cathelicidins. Curr. Top. Microbiol. Immunol. 306, 27-66.
5. Braff, M.H., Hawkins, M.A., Di Nardo, A., Lopez-Garcia, B., Howell, M.D., Wong, C., Lin, K., Streib, J.E., Dorschner, R., Leung, D.Y., and Gallo, R.L. (2005). Structure-function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities. J. Immunol. 174, 4271-4278.
6. Branger, J., van den Blink, B., Weijer, S., Madwed, J., Bos, C.L., Gupta, A., Yong, C.L., Polmar, S.H., Olszyna, D.P., Hack, C.E., et al. (2002). Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J. Immunol. 168, 4070-4077.
7. Brown, K.L. and Hancock, R.E. (2006). Cationic host defense (antimicrobial) peptides. Curr. Opin. Immunol. 18, 24-30.
8. Carter, A.B., Monick, M.M., and Hunninghake, G.W. (1999). Both Erk and p38 kinases are necessary for cytokine gene transcription. Am. J. Respir. Cell Mol. Biol. 20, 751-758.
9. Ciornei, C.D., Sigurdardottir, T., Schmidtchen, A., and Bodelsson, M. (2005). Antimicrobial and chemoattractant activity, lipopolysaccharide neutralization, cytotoxicity, and inhibition by serum of analogs of human cathelicidin LL-37. Antimicrob. Agents Chemother. 49, 2845-2850.
10. Cirioni, O., Giacometti, A., Ghiselli, R., Bergnach, C., Orlando, F., Silvestri, C., Mocchegiani, F., Licci, A., Skerlavaj, B., Rocchi, M., et al. (2006). LL-37 protects rats against lethal sepsis caused by Gram-negative bacteria. Antimicrob. Agents Chemother. 50, 1672-1679.
11. Cohen, J. (2002). The immunopathogenesis of sepsis. Nature 420, 885-891.
12. den Hertog, A.L., van Marle, J., Veerman, E.C., Valentijn-Benz, M., Nazmi, K., Kalay, H., Grun, C.H., Van't Hof, W., Bolscher, J.G., and Nieuw Amerongen, A.V. (2006). The human cathelicidin peptide LL-37 and truncated variants induce segregation of lipids and proteins in the plasma membrane of Candida albicans. Biol. Chem. 387, 1495-1502.
13. Frohm, M., Agerberth, B., Ahangari, G., Stahle-Backdahl, M., Liden, S., Wigzell, H., and Gudmundsson, G.H. (1997). The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem. 272, 15258-15263.
14. Gorden, K.B., Gorski, K.S., Gibson, S.J., Kedl, R.M., Kieper, W.C., Qiu, X., Tomai, M.A., Alkan, S.S., and Vasilakos, J.P. (2005). Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J. Immunol. 174, 1259-1268.
15. Guha, M. and Mackman, N. (2001). LPS induction of gene expression in human monocytes. Cell Signal. 13, 85-94.
16. Han, J., Lee, J.D., Bibbs, L., and Ulevitch, R.J. (1994). A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808-811.
17. Hayashi, F., Smith, K.D., Ozinsky, A., Hawn, T.R., Yi, E.C., Goodlett, D.R., Eng, J.K., Akira, S., Underhill, D.M., and Aderem, A. (2001). The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099-1103.
18. Hiemstra, P.S. (2006). Defensins and cathelicidins in inflammatory lung disease: beyond antimicrobial activity. Biochem. Soc. Trans. 34, 276-278.
19. Hodges, R.S., Chen, Y., Kopecky, E., and Mant, C.T. (2004). Monitoring the hydrophilicity/hydrophobicity of amino acid side-chains in the non-polar and polar faces of amphipathic α-helices by reversed-phase and hydrophilic interaction/ cation-exchange chromatography. J. Chromatogr. A 1053, 161-172.
20. Kirikae, T., Hirata, M., Yamasu, H., Kirikae, F., Tamura, H., Kayama, F., Nakatsuka, K., Yokochi, T., and Nakano, M. (1998). Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18)-derived peptide against murine endotoxemia. Infect. Immun. 66, 1861-1868.
21. Kopp, E. and Medzhitov, R. (2003). Recognition of microbial infection by Toll-like receptors. Curr. Opin. Immunol. 15, 396-401.
22. Kurosaka, K., Chen, Q., Yarovinsky, F., Oppenheim, J.J., and Yang, D. (2005). Mouse cathelin-related antimicrobial peptide chemoattracts leukocytes using formyl peptide receptor-like 1/mouse formyl peptide receptor-like 2 as the receptor and acts as an immune adjuvant. J. Immunol. 174, 6257-6265.
23. Li, Y., Li, X., and Wang, G. (2007). On-resin cleavage of bacterially expressed fusion proteins for purification of active recombinant peptides SK-29, KR-20, LL-29, and LL-23 from human sweat or skin. Protein Exp. Purif. 55, 395-405.
24. Li, X., Li, Y., Han, H., Miller, D.W., and Wang, G. (2006). Solution structures of human LL-37 fragments and NMR-based identification of a minimal membrane-targeting antimicrobial and anticancer region. J. Am. Chem. Soc. 128, 5776-5785.
25. Mookherjee, N., Brown, K.L., Bowdish, D.M., Doria, S., Falsafi, R., Hokamp, K., Roche, F.M., Mu, R., Doho, G.H., Pistolic, J., et al. (2006). Modulation of the TLR-mediated inflammatory response by the endogenous human host defense pep-tide LL-37. J. Immunol. 176, 2455-2464.
26. Murakami, M., Lopez-Garcia, B., Braff, M., Dorschner, R.A., and Gallo, R.L. (2004). Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense. J. Immunol. 172, 3070-3077.
27. + cells. J. Immunol. 167, 3329-3338.
28. Nagaoka, I., Hirota, S., Niyonsaba, F., Hirata, M., Adachi, Y., Tamura, H., Tanaka, S., and Heumann, D. (2002). Augmentation of the lipopolysaccharide- neutralizing activities of human cathelicidin CAP18/LL-37-derived antimicrobial pep-tides by replacement with hydrophobic and cationic amino acid residues. Clin. Diagn. Lab. Immunol. 9, 972-982.
29. Nell, M.J., Tjabringa, G.S., Wafelman, A.R., Verrijk, R., Hiemstra, P.S., Drijfhout, J.W., and Grote, J.J. (2006). Development of novel LL-37 derived antimicrobial peptides with LPS and LTA neutralizing and antimicrobial activities for therapeutic application. Peptides 27, 649-660.
30. Oppenheim, J.J. and Yang, D. (2005). Alarmins: chemotactic activators of immune responses. Curr. Opin. Immunol. 17, 359-365.
31. Oren, Z., Lerman, J.C., Gudmundsson, G.H., Agerberth, B., and Shai, Y. (1999). Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. Biochem. J. 341, 501-513.
32. Peschel, A. and Sahl, H.G. (2006). The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nat. Rev. Microbiol. 4, 529-536.
33. Rosenfeld, Y., Papo, N., and Shai, Y. (2006). Endotoxin (lipopolysaccharide) neutralization by innate immunity host-defense peptides. Peptide properties and plausible modes of action. J. Biol. Chem. 281, 1636-1643.
34. Scott, M.G., Vreugdenhil, A.C., Buurman, W.A., Hancock, R.E., and Gold, M.R. (2000). Cutting edge: cationic antimicrobial peptides block the binding of lipopolysaccharide (LPS) to LPS binding protein. J. Immunol. 164, 549-553.
35. Scott, M.G., Davidson, D.J., Gold, M.R., Bowdish, D., and Hancock, R.E. (2002). The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J. Immunol. 169, 3883-3891.
36. Shibata, K., Hasebe, A., Into, T., Yamada, M., and Watanabe, T. (2000). The N-terminal lipopeptide of a 44-kDa membrane-bound lipoprotein of Mycoplasma salivarium is responsible for the expression of intercellular adhesion molecule-1 on the cell surface of normal human gingival fibroblasts. J. Immunol. 165, 6538-6544.
37. Sigurdardottir, T., Andersson, P., Davoudi, M., Malmsten, M., Schmidtchen, A., and Bodelsson, M. (2006). In silico identification and biological evaluation of antimicrobial peptides based on human cathelicidin LL-37. Antimicrob. Agents Chemother. 50, 2983-2989.
38. Sorensen, O., Arnljots, K., Cowland, J.B., Bainton, D.F., and Borregaard, N. (1997). The human antibacterial cathelicidin, hCAP-18, is synthesized in myelocytes and metamyelocytes and localized to specific granules in neutrophils. Blood 90, 2796-2803.
39. Sorensen, O.E., Follin, P., Johnsen, A.H., Calafat, J., Tjabringa, G.S., Hiemstra, P.S., and Borregaard, N. (2001). Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 97, 3951-3959.
40. Takeuchi, O., Kawai, T., Muhlradt, P.F., Morr, M., Radolf, J.D., Zychlinsky, A., Takeda, K., and Akira, S. (2001). Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int. Immunol. 13, 933-940.
41. Tossi, A., Sandri, L., and Giangaspero, A. (2000). Amphipathic, α-helical antimicrobial peptides. Biopolymers 55, 4-30.
42. Tudhope, S.J., Finney-Hayward, T.K., Nicholson, A.G., Mayer, R.J., Barnette, M.S., Barnes, P.J., and Donnelly, L.E. (2008). Different mitogen-activated protein kinase-dependent cytokine responses in cells of the monocyte lineage. J. Pharmacol. Exp. Ther. 324, 306-312.
43. van der Bruggen, T., Nijenhuis, S., van Raaij, E., Verhoef, J., and van Asbeck, B.S. (1999). Lipopolysaccharide-induced tumor necrosis factor alpha production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway. Infect. Immun. 67, 3824-3829.
44. Wang, S.W., Pawlowski, J., Wathen, S.T., Kinney, S.D., Lichenstein, H.S., and Manthey, C.L. (1999). Cytokine mRNA decay is accelerated by an inhibitor of p38-mitogen-activated protein kinase. Inflamm. Res. 48, 533-538.
45. Yang, D., Biragyn, A., Hoover, D.M., Lubkowski, J., and Oppenheim, J.J. (2004). Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu. Rev. Immunol. 22, 181-215.
46. Yu, J., Mookherjee, N., Wee, K., Bowdish, D.M., Pistolic, J., Li, Y., Rehaume, L., and Hancock, R.E. (2007). Host defense peptide LL-37, in synergy with inflammatory mediator IL-1b, augments immune responses by multiple pathways. J. Immunol. 179, 7684-7691.
47. Zanetti, M. (2004). Cathelicidins, multifunctional peptides of the innate immunity. J. Leukoc. Biol. 75, 39-48.
48. Zelezetsky, I., Pontillo, A., Puzzi, L., Antcheva, N., Segat, L., Pacor, S., Crovella, S., and Tossi, A. (2006). Evolution of the primate cathelicidin. Correlation between structural variations and antimicrobial activity. J. Biol. Chem. 281, 19861-19871.