Immunomodulatory Functions of the Human Cathelicidin LL-37 (aa 13–31)-Derived Peptides are Associated with Predicted α-Helical Propensity and Hydrophobic Index

Abstract

The anti-endotoxin activity of the cationic peptide LL-37 and its derivative IG-19 is attributed to electrostatic interaction of the peptides’ positive charge with negatively charged bacterial lipopolysaccharides (LPS), and in part to the alteration of intracellular mechanisms independent of peptide binding to LPS. We examined the immunomodulatory responses induced by IG-19 and four IG-19-derived scrambled peptides (IG-19a–d), in the presence and absence of LPS, in macrophages and peripheral blood-derived mononuclear cells. All peptides had identical net charge (+5) and amino acid composition, but different hydrophobicity and α-helical propensity. Peptide IG-19 suppressed LPS-induced cytokine/chemokine production by >90%, IG-19a and IG-19b suppressed it by 40–50%, and IG-19c and IG-19d did not suppress cytokine/chemokine production at all. In silico prediction algorithms and the peptide retention time (RT) on a C18 RP HPLC column indicated a linear association between α-helical propensity and hydrophobicity with the ability of the peptides to inhibit LPS-induced responses. Peptide RT exhibited a significant correlation (>70%) between the suppression of LPS-induced cytokine/chemokine production and peptide-induced production of the anti-inflammatory cytokine IL-1RA. These results indicate that RT on a C18 column can be used as a predictor for the immunomodulatory functions of cationic peptides. Overall, we demonstrated that the immunomodulatory functions of LL-37-derived peptides with identical positive charge and amino acid composition are directly associated with the predicted α-helical propensity and hydrophobicity of the peptides.

The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP)

“…Thus, a protective role for LL‐37 in T1D has been suggested . The multifunctional nature of LL‐37 makes it of high biomedical importance and numerous studies toward the design of LL‐37‐derived peptides with antimicrobial or immunomodulatory functions have been reported …”

“…Specific partial LL‐37 sequences within its central/C‐terminal parts such as LL‐37(17(18)‐29) or LL‐37(13‐32) have been found to be sufficient for antibacterial, antiviral, or immunomodulatory activity and are thus being used for drug design . To find out whether the amyloid‐inhibition function of LL‐37 resides within specific sequence parts as well, we dissected it into the two segments: LL‐37(1‐14) and LL‐37(15‐37), which contain the N‐ and central/C‐terminal helical parts, respectively .…”

Cathelicidin and Calprotectin Are Disparately Altered in Murine Models of Inflammatory Arthritis and Airway Inflammation

“…Synthetic peptides based on CHDP sequence have been previously shown to mitigate local inflammation in chronic inflammatory disease models ( 2 ). For example, the human cathelicidin LL-37-derived peptide IG-19, which represents the minimum region of LL-37 required for immunomodulatory functions ( 21 ), can suppress pro-inflammatory cytokine secretion ( 22 , 23 ), and reduce leukocyte accumulation and control inflammatory mediators in the joints in a collagen-induced arthritis (CIA) mouse model ( 24 ). Similarly, a bovine cathelicidin-derived peptide IDR-1002 mitigates airway inflammation, controls leukocyte accumulation in the lungs, and improves airway hyper-responsiveness (AHR) in an allergen house dust mite (HDM)-challenged mouse model ( 25 ).…”

Das humane Wirtsabwehrpeptid Cathelicidin LL‐37 ist ein nanomolarer Inhibitor der amyloiden Selbstassoziation von Inselamyloid‐Polypeptid (IAPP)

“…Für LL‐37 wurde dementsprechend eine protektive Rolle beim T1D vorgeschlagen . Seine Multifunktionalität verleiht LL‐37 eine hohe biomedizinische Relevanz; so gibt es diverse Studien zum Design von LL‐37‐stämmigen Peptiden mit antimikrobiellen oder immunmodulatorischen Funktionen . Es ist zunehmend evident, dass Wechselwirkungen von amyloidogenen Polypeptiden mit anderen Polypeptiden kritische modulatorische Funktionen bei der amyloiden Selbstassoziation haben .…”

“…Spezifische partielle LL‐37‐Sequenzen innerhalb des zentral/C‐terminalen Bereichs von LL‐37 wie LL‐37(17(18)‐29) oder LL‐37(13‐32) wurden als hinreichend für die antibakteriellen, antiviralen oder immunmodulatorischen Aktivitäten von LL‐37 identifiziert und werden für den Wirkstoffentwurf eingesetzt . Wir haben gefragt, ob die amyloidinhibitorische Funktion von LL‐37 ebenfalls in solchen spezifischen Sequenzbereichen lokalisiert werden kann.…”