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* Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, and
Department of Statistics and Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada; and
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
The sole human cathelicidin peptide, LL-37, has been demonstrated to protect animals against endotoxemia/sepsis. Low, physiological concentrations of LL-37 (
1 µg/ml) were able to modulate inflammatory responses by inhibiting the release of the proinflammatory cytokine TNF-
in LPS-stimulated human monocytic cells. Microarray studies established a temporal transcriptional profile and identified differentially expressed genes in LPS-stimulated monocytes in the presence or absence of LL-37. LL-37 significantly inhibited the expression of specific proinflammatory genes up-regulated by NF-
B in the presence of LPS, including NFB1 (p105/p50) and TNF--induced protein 2 (TNFAIP2). In contrast, LL-37 did not significantly inhibit LPS-induced genes that antagonize inflammation, such as TNF--induced protein 3 (TNFAIP3) and the NF-B inhibitor, NFBIA, or certain chemokine genes that are classically considered proinflammatory. Nuclear translocation, in LPS-treated cells, of the NF-B subunits p50 and p65 was reduced 
50% in the presence of LL-37, demonstrating that the peptide altered gene expression in part by acting directly on the TLR-to-NF-B pathway. LL-37 almost completely prevented the release of TNF- and other cytokines by human PBMC following stimulation with LPS and other TLR2/4 and TLR9 agonists, but not with cytokines TNF- or IL-1
. Biochemical and inhibitor studies were consistent with a model whereby LL-37 modulated the inflammatory response to LPS/endotoxin and other agonists of TLR by a complex mechanism involving multiple points of intervention. We propose that the natural human host defense peptide LL-37 plays roles in the delicate balancing of inflammatory responses in homeostasis as well as in combating sepsis induced by certain TLR agonists.
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