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* Department of Microbiology and Immunology and
British Columbia Research Institute for Child and Family Health, University of British Columbia, Vancouver, British Columbia, Canada
The role of LL-37, a human cationic antimicrobial peptide, in the
immune system is not yet clearly understood. It is a widely expressed
peptide that can be up-regulated during an immune response. In this
report, we demonstrate that LL-37 is a potent antisepsis agent with the
ability to inhibit macrophage stimulation by bacterial components such
as LPS, lipoteichoic acid, and noncapped lipoarabinomannan. We also
demonstrate that LL-37 protects mice against lethal endotoxemia. In
addition to preventing macrophage activation by bacterial components,
we hypothesized the LL-37 may also have direct effects on macrophage
function. We therefore used gene expression profiling to identify
macrophage functions that might be modulated by LL-37. These studies
revealed that LL-37 directly up-regulates 29 genes and down-regulated
another 20 genes. Among the genes predicted to be up-regulated by LL-37
were those encoding chemokines and chemokine receptors. Consistent with
this, LL-37 up-regulated the expression of chemokines in macrophages
and the mouse lung (monocyte chemoattractant protein 1), human
A549 epithelial cells (IL-8), and whole human blood (monocyte
chemoattractant protein 1 and IL-8), without stimulating the
proinflammatory cytokine, TNF
. LL-37 also up-regulated the chemokine
receptors CXCR-4, CCR2, and IL-8RB. These findings indicate that LL-37
may contribute to the immune response by limiting the damage caused by
bacterial products and by recruiting immune cells to the site of
infection so that they can clear the infection.
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 Y. E. Lau, D. M. E. Bowdish, C. Cosseau, R. E. W. Hancock, and D. J. Davidson Apoptosis of Airway Epithelial Cells: Human Serum Sensitive Induction by the Cathelicidin LL-37 Am. J. Respir. Cell Mol. Biol., April 1, 2006; 34(4): 399 - 409. [Abstract] [Full Text] [PDF]
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N. Mookherjee, K. L. Brown, D. M. E. Bowdish, S. Doria, R. Falsafi, K. Hokamp, F. M. Roche, R. Mu, G. H. Doho, J. Pistolic, et al. Modulation of the TLR-Mediated Inflammatory Response by the Endogenous Human Host Defense Peptide LL-37 J. Immunol., February 15, 2006; 176(4): 2455 - 2464. [Abstract] [Full Text] [PDF]
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B. Deslouches, K. Islam, J. K. Craigo, S. M. Paranjape, R. C. Montelaro, and T. A. Mietzner Activity of the De Novo Engineered Antimicrobial Peptide WLBU2 against Pseudomonas aeruginosa in Human Serum and Whole Blood: Implications for Systemic Applications Antimicrob. Agents Chemother., August 1, 2005; 49(8): 3208 - 3216. [Abstract] [Full Text] [PDF]
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 D. M.E. Bowdish and R. E.W. Hancock Anti-endotoxin properties of cationic host defence peptides and proteins Innate Immunity, August 1, 2005; 11(4): 230 - 236. [Abstract] [PDF]
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C. D. Ciornei, T. Sigurdardottir, A. Schmidtchen, and M. Bodelsson Antimicrobial and Chemoattractant Activity, Lipopolysaccharide Neutralization, Cytotoxicity, and Inhibition by Serum of Analogs of Human Cathelicidin LL-37 Antimicrob. Agents Chemother., July 1, 2005; 49(7): 2845 - 2850. [Abstract] [Full Text] [PDF]
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 A. F. Gombart, N. Borregaard, and H. P. Koeffler Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3 FASEB J, July 1, 2005; 19(9): 1067 - 1077. [Abstract] [Full Text] [PDF]
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K. Kurosaka, Q. Chen, F. Yarovinsky, J. J. Oppenheim, and D. Yang 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., May 15, 2005; 174(10): 6257 - 6265. [Abstract] [Full Text] [PDF]
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D. M. E. Bowdish, D. J. Davidson, M. G. Scott, and R. E. W. Hancock Immunomodulatory Activities of Small Host Defense Peptides Antimicrob. Agents Chemother., May 1, 2005; 49(5): 1727 - 1732. [Abstract] [Full Text] [PDF]
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J. Oliaro, S. Dudal, J. Liautard, J.-B. Andrault, J.-P. Liautard, and V. Lafont V{gamma}9V{delta}2 T cells use a combination of mechanisms to limit the spread of the pathogenic bacteria Brucella J. Leukoc. Biol., May 1, 2005; 77(5): 652 - 660. [Abstract] [Full Text] [PDF]
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M. Iimura, R. L. Gallo, K. Hase, Y. Miyamoto, L. Eckmann, and M. F. Kagnoff Cathelicidin Mediates Innate Intestinal Defense against Colonization with Epithelial Adherent Bacterial Pathogens J. Immunol., April 15, 2005; 174(8): 4901 - 4907. [Abstract] [Full Text] [PDF]
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D. M. E. Bowdish, D. J. Davidson, Y. E. Lau, K. Lee, M. G. Scott, and R. E. W. Hancock Impact of LL-37 on anti-infective immunity J. Leukoc. Biol., April 1, 2005; 77(4): 451 - 459. [Abstract] [Full Text] [PDF]
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N. Borregaard, K. Theilgaard-Monch, J. B. Cowland, M. Stahle, and O. E. Sorensen Neutrophils and keratinocytes in innate immunity--cooperative actions to provide antimicrobial defense at the right time and place J. Leukoc. Biol., April 1, 2005; 77(4): 439 - 443. [Abstract] [Full Text] [PDF]
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S. van Wetering, G. S. Tjabringa, and P. S. Hiemstra Interactions between neutrophil-derived antimicrobial peptides and airway epithelial cells J. Leukoc. Biol., April 1, 2005; 77(4): 444 - 450. [Abstract] [Full Text] [PDF]
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M. H. Braff, M. A. Hawkins, A. D. Nardo, B. Lopez-Garcia, M. D. Howell, C. Wong, K. Lin, J. E. Streib, R. Dorschner, D. Y. M. Leung, et al. Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities J. Immunol., April 1, 2005; 174(7): 4271 - 4278. [Abstract] [Full Text] [PDF]
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T. D. Starner, B. Agerberth, G. H. Gudmundsson, and P. B. McCray Jr. Expression and Activity of {beta}-Defensins and LL-37 in the Developing Human Lung J. Immunol., February 1, 2005; 174(3): 1608 - 1615. [Abstract] [Full Text] [PDF]
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Y. E. Lau, A. Rozek, M. G. Scott, D. L. Goosney, D. J. Davidson, and R. E. W. Hancock Interaction and Cellular Localization of the Human Host Defense Peptide LL-37 with Lung Epithelial Cells Infect. Immun., January 1, 2005; 73(1): 583 - 591. [Abstract] [Full Text] [PDF]
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D. Yang, Q. Chen, H. F. Rosenberg, S. M. Rybak, D. L. Newton, Z. Y. Wang, Q. Fu, V. T. Tchernev, M. Wang, B. Schweitzer, et al. Human Ribonuclease A Superfamily Members, Eosinophil-Derived Neurotoxin and Pancreatic Ribonuclease, Induce Dendritic Cell Maturation and Activation J. Immunol., November 15, 2004; 173(10): 6134 - 6142. [Abstract] [Full Text] [PDF]
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O. Levy Antimicrobial proteins and peptides: anti-infective molecules of mammalian leukocytes J. Leukoc. Biol., November 1, 2004; 76(5): 909 - 925. [Abstract] [Full Text] [PDF]
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T.-T. Wang, F. P. Nestel, V. Bourdeau, Y. Nagai, Q. Wang, J. Liao, L. Tavera-Mendoza, R. Lin, J. H. Hanrahan, S. Mader, et al. Cutting Edge: 1,25-Dihydroxyvitamin D3 Is a Direct Inducer of Antimicrobial Peptide Gene Expression J. Immunol., September 1, 2004; 173(5): 2909 - 2912. [Abstract] [Full Text] [PDF]
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D. M. E. Bowdish, D. J. Davidson, D. P. Speert, and R. E. W. Hancock The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes J. Immunol., March 15, 2004; 172(6): 3758 - 3765. [Abstract] [Full Text] [PDF]
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 D. M. Shasby and P. McCray Sepsis and Innate Immunity Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 144 - 145. [Full Text] [PDF]
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D. J. Davidson, A. J. Currie, G. S. D. Reid, D. M. E. Bowdish, K. L. MacDonald, R. C. Ma, R. E. W. Hancock, and D. P. Speert The Cationic Antimicrobial Peptide LL-37 Modulates Dendritic Cell Differentiation and Dendritic Cell-Induced T Cell Polarization J. Immunol., January 15, 2004; 172(2): 1146 - 1156. [Abstract] [Full Text] [PDF]
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M. Zanetti Cathelicidins, multifunctional peptides of the innate immunity J. Leukoc. Biol., January 1, 2004; 75(1): 39 - 48. [Abstract] [Full Text] [PDF]
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G. S. Tjabringa, J. Aarbiou, D. K. Ninaber, J. W. Drijfhout, O. E. Sorensen, N. Borregaard, K. F. Rabe, and P. S. Hiemstra The Antimicrobial Peptide LL-37 Activates Innate Immunity at the Airway Epithelial Surface by Transactivation of the Epidermal Growth Factor Receptor J. Immunol., December 15, 2003; 171(12): 6690 - 6696. [Abstract] [Full Text] [PDF]
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A. Di Nardo, A. Vitiello, and R. L. Gallo Cutting Edge: Mast Cell Antimicrobial Activity Is Mediated by Expression of Cathelicidin Antimicrobial Peptide J. Immunol., March 1, 2003; 170(5): 2274 - 2278. [Abstract] [Full Text] [PDF]
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