Host Defense Peptide LL-37, in Synergy with Inflammatory Mediator IL-1β, Augments Immune Responses by Multiple Pathways

Abstract

The human cathelicidin LL-37 is a cationic host defense peptide and serves as an important component of innate immunity. It has been demonstrated to be a multifunctional modulator of innate immune responses, although the mechanism(s) underlying this have not been well characterized. In this study, it was demonstrated that LL-37 synergistically enhanced the IL-1β-induced production of cytokines (IL-6, IL-10) and chemokines such as macrophage chemoattractant proteins (MCP-1, MCP-3) in human PBMC, indicating a role in enhancing certain innate immune responses. Similarly, LL-37 synergistically enhanced chemokine production in the presence of GM-CSF, but IFN-γ, IL-4, or IL-12 addition led to antagonism, indicating that the role of LL-37 in reinforcing specific immune responses is selective and restricted to particular endogenous immune mediators. The inhibition of G protein-coupled receptors and PI3K substantially suppressed the ability of IL-1β and LL-37 to synergistically enhance the production of chemokine MCP-3. Consistent with this, the combination of IL-1β and LL-37 enhanced the activation/phosphorylation of kinase Akt and the transcription factor CREB. The role of transcription factor NF-κB was revealed through the demonstration of enhanced phosphorylation of IκBα and the consequent nuclear translocation of NF-κB subunits p50 and p65, as well as the antagonistic effects of an inhibitor of IκBα phosphorylation. These results together indicate that the human host defense peptide LL-37 can work in synergy with the endogenous inflammatory mediator IL-1β to enhance the induction of specific inflammatory effectors by a complex mechanism involving multiple pathways, thus reinforcing certain innate immune responses.

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

“…As shown in Fig. 5B, the MAPKs MEK-1 (upstream of ERK1/2) and p38, PI3K, and the NF-kB signaling pathway were all essential for IDR-1002 activity, mirroring previous findings for peptides IDR-1 and LL-37 (16,(38)(39)(40). In contrast, inhibition of the JAK-STAT pathway with inhibitor AG490, JNK with SP600125, protein kinase A with amide 6-22, or Ca 2+ /calmodulin-dependent protein kinase II with KN-93 did not have significant effects on IDR-1002 activity (Supplemental Fig.…”

“…6). This suggests that the protective activity of IDR-1002 was likely mediated through enhanced leukocyte recruitment to the site of infection rather than through direct effects of the peptide on the microbicidal activities of the recruited leukocytes; however, we cannot rule out that additional activities of IDR-1002 not detected in our studies may emerge in vivo as a result of synergy with the action of bacterial compounds or other host mediators, as exemplified by the synergy in the various immunomodulatory properties of natural and synthetic cationic peptides with IL-1b, GM-CSF, and CpG oligonucleotides (38,39,46,47).…”

“…Of these inhibitors, AG490 and amide 6-22 were previously shown to have no inhibitory effects on LL-37 activity (40), and AG490 and SP600125 had no inhibitory effects on IDR-1 (16). These findings further suggest a strong overlap among the signaling pathways used IDR-1002, IDR-1 (16), and natural immunomodulatory peptides like human cathelicidin LL-37 (38,39) despite the lack of any obvious sequence similarities. Interestingly, the microtubule assembly inhibitor nocodazole and actin polymerization inhibitor cytochalasin D also abolished chemokine induction by peptide IDR-1002 (Fig.…”

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

“…LL-37 can indirectly promote the recruitment of inflammatory cells by inducing bronchial epithelial cells to release interleukin-8 (IL-8) (Filewod et al, 2009). LL-37 can also augment the secretion of IL-6 and IL-10 induced by the proinflammatory cytokine IL-1␤ in myeloid cells (Yu et al, 2007).…”

Antimicrobial peptides

“…Besides direct elimination of microbes, AMPs have been shown to possess several immuno-modulatory functions such as modification of host gene expression, 88,89 induction of cell death in other plants, 90 association with epigenetic somaclonal variation events, 91 conferring zinc tolerance, 92 playing as chemokines, 93,94 and/or induction of chemokine production, 95 inhibition of proinflammatory cytokine production induced by LPS, 96 wound healing promotion, 97 inhibitory activities toward tumor cells and HIV-1 reverse transcriptase, 98 and modulation of adaptive immune responses, e.g., by activation of human plasmacytoid dendritic cells in some auto-immune diseases. 4,5 Modulation of different cascades of immune system in relevant transgenic plants.…”