Modulation of the TLR-Mediated Inflammatory Response by the Endogenous Human Host Defense Peptide LL-37

Abstract

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-α 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-κB in the presence of LPS, including NFκB1 (p105/p50) and TNF-α-induced protein 2 (TNFAIP2). In contrast, LL-37 did not significantly inhibit LPS-induced genes that antagonize inflammation, such as TNF-α-induced protein 3 (TNFAIP3) and the NF-κB inhibitor, NFκBIA, or certain chemokine genes that are classically considered proinflammatory. Nuclear translocation, in LPS-treated cells, of the NF-κB 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-κB pathway. LL-37 almost completely prevented the release of TNF-α and other cytokines by human PBMC following stimulation with LPS and other TLR2/4 and TLR9 agonists, but not with cytokines TNF-α or IL-1β. 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.

Cathelicidin Antimicrobial Peptides Block Dendritic Cell TLR4 Activation and Allergic Contact Sensitization

“…Much work using cell culture models has shown that cathelicidins can alter host immune responses including stimulating proinflammatory events (5, 8 -10), and recent evidence mediating potentially anti-inflammatory events (11). The complexity of cell types studied, the culture conditions used and opposite effects observed from the same laboratory (11), have made it difficult to draw conclusions regarding the inflammatory function of cathelicidins in vivo.…”

“…The complexity of cell types studied, the culture conditions used and opposite effects observed from the same laboratory (11), have made it difficult to draw conclusions regarding the inflammatory function of cathelicidins in vivo. Our data are clear-cathelicidin possesses potent anti-inflammatory activity, inhibiting allergic contact dermatitis.…”

“…The human cathelicidin peptide LL-37 has been shown to be chemotactic for monocytes, T lymphocytes, neutrophils and mast cells (5,8,9). Under cell culture conditions LL-37 has also been shown to stimulate chemokine and cytokine secretion from monocytes, dendritic cells (DC), 3 and epithelial keratinocytes (10), but recent data have also shown that LL-37 can inhibit LPS induced cytokine release from monocytes (11). Given that 1) LL-37 could mediate both proinflammatory and anti-inflammatory effects in vitro and 2) the degree of proteolytic processing (12,13) of cathelicidin peptides in tissue dictates function (10), it has remained unclear what effects cathelicidins or other antimicrobial peptides may have on inflammation in vivo.…”

cAMP Stringently Regulates Human Cathelicidin Antimicrobial Peptide Expression in the Mucosal Epithelial Cells by Activating cAMP-response Element-binding Protein, AP-1, and Inducible cAMP Early Repressor

“…It has direct microbicidal activities against a wide range of bacteria, viruses, fungi, and protozoa in vitro (5)(6)(7)(8)(9)(10). In addition, its antimicrobial functions in vivo are significantly contributed by multiple immunomodulatory properties (11)(12)(13). The physiological importance of cathelicidin in host defense is underscored by the increased susceptibility of the knock-out animals, whereas the transgenics develop resistance to various infections (14 -18).…”

LL-37 attenuates inflammatory impairment via mTOR signaling-dependent mitochondrial protection

“…For example, LL-37 dramatically suppresses tumor necrosis factor ␣ (TNF-␣) production induced by the stimulation of human monocytes or macrophage cell lines with lipopolysaccharide (LPS) or lipoteichoic acid (LTA) in vitro (Mookherjee et al, 2006;Scott et al, 2000). LL-37 also reduces LPS and interferon ␥ (IFN-␥) responses in human peripheral blood mononuclear cells (PBMCs) and mouse splenic B cells .…”