The Human Cationic Peptide LL-37 Induces Activation of the Extracellular Signal-Regulated Kinase and p38 Kinase Pathways in Primary Human Monocytes

Abstract

LL-37 is a cationic peptide that is found in the granules of neutrophils and is secreted by epithelial cells from a variety of tissues. Levels of LL-37 in vivo increase upon infection, and its production and secretion are increased upon stimulation with proinflammatory mediators. It has been postulated that LL-37 modulates the immune response by interacting with the effector cells of innate immunity; however, the mechanism of this interaction is unknown. LL-37 induced phosphorylation and activation of the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) and p38, in human peripheral blood-derived monocytes and a human bronchial epithelial cell line, but not in B or T lymphocytes. Phosphorylation was not dependent on the G protein-coupled formyl peptide-like receptor 1, which was previously proposed to be the receptor for LL-37-induced chemotaxis on human monocytes and T cells. Activation of ERK1/2 and p38 was markedly increased by the presence of GM-CSF, but not M-CSF. Exposure to LL-37 also led to the activation of Elk-1, a transcription factor that is downstream of and activated by phosphorylated ERK1/2, the up-regulation of various Elk-1-controlled genes, and the transcription and secretion of IL-8. Inhibition of either p38 or ERK1/2 kinases led to a reduction in LL-37-induced IL-8 secretion and inhibition of the transcription of various chemokine genes. The ability of LL-37 to signal through these pathways has broad implications in immunity, monocyte activation, proliferation, and differentiation.

Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities

“…Similarly, FPRL-1 expression was not seen in cultured keratinocytes or in whole skin by immunostaining. This result agrees with recent studies demonstrating that FPRL-1 is not involved in LL-37-induced activation of epithelial cells (21) or monocytes (23).…”

“…Previous investigations showed that cell activation and signaling by LL-37 can be G i protein dependent (19) or independent (23). Therefore, the IL-8 response was evaluated after treatment of keratinocytes with the G i inhibitor, pertussis toxin (PTX), in the presence or the absence of LL-37 or D-LL-37.…”

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

“…Cathelicidin has been suggested to stimulate leukocyte recruitment and cytokine release in a receptor-specific manner (5,21,22). Thus, if a high-stringency receptor interaction was required to inhibit LPS activation of DC, structural modifications would be expected to eliminate this response.…”

Neutrophil-derived azurocidin alarms the immune system

“…For example, human neutrophil peptides (HNPs; ␣-defensins) are chemotactic for resting, naïve CD4 T cells, CD8 T cells, and immature dendritic cells (DCs), whereas cathelicidins [LL-37 in the human; mouse cathelinrelated antimicrobial peptide (mCRAMP) in the mouse] are chemotactic for PMN, monocytes/macrophages, and T cells [10,11]. Cathelicidins also activate MAPK pathways in monocytes/macrophages, promoting the in vitro differentiation of precursor monocytes into DCs [12,13]. Finally, alarmins exhibit potent in vivo-immunoenhancing activity.…”