Effects of the cathelicidin LL-37 on intestinal epithelial barrier integrity

Otte, Jan-Michel; Zdebik, Anna-Elisabeth; Brand, Stephan; Chromik, Ansgar M.; Strauß, Sarah; Schmitz, Frank; Steinstraesser, Lars; Schmidt, Wolfgang E.

doi:10.1016/j.regpep.2009.03.009

Cited by 80 publications

(72 citation statements)

References 57 publications

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“…As examples, pulmonary surfactant protein D has roles in surfactant lipid homeostasis and some antimicrobial peptides (e.g., LL-37) have roles in wound healing and epithelial barrier function [108,109]. Also, as with other innate defense mediators, there is evidence that extracellular histones can contribute to cell injury, harmful inflammation and activation of thrombosis.…”

Section: Resultsmentioning

confidence: 99%

Histones as Mediators of Host Defense, Inflammation and Thrombosis

et al. 2016

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Histones are known for their ability to bind to and regulate expression of DNA. However, histones are also present in cytoplasm and extracellular fluids where they serve host defense functions and promote inflammatory responses. Histones are a major component of neutrophil extracellular traps that contribute to bacterial killing but also to inflammatory injury. Histones can act as antimicrobial peptides and directly kill bacteria, fungi, parasites and viruses, in vitro and in a variety of animal hosts. In addition, histones can trigger inflammatory responses in some cases acting through Toll-like receptors or inflammasome pathways. Extracellular histones mediate organ injury (lung, liver), sepsis physiology, thrombocytopenia and thrombin generation and some proteins can bind histones and reduce these potentially harmful effects.

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Section: Resultsmentioning

confidence: 99%

Histones as Mediators of Host Defense, Inflammation and Thrombosis

et al. 2016

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“…Intrarectal administration of synthetic cathelin-related peptide or mCRAMP-expressing plasmid ameliorated DSS-induced colitis in mice genetically deficient in cathelicidin by preserving mucus thickness and inducing the expression of Muc1, Muc3, Muc4, and, in particular, Muc2 mucin genes (29,39). Further studies showed that LL-37 stimulated mucus synthesis and the expression of MUC1 and MUC2 via the MAPK pathway (40,41).…”

Section: Discussionmentioning

confidence: 99%

MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis

et al. 2017

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Embedded in the colonic mucus are cathelicidins, small cationic peptides secreted by colonic epithelial cells. Humans and mice have one cathelicidin-related antimicrobial peptide (CRAMP) each, LL-37/hCAP-18 and Cramp, respectively, with related structure and functions. Altered production of MUC2 mucin and antimicrobial peptides is characteristic of intestinal amebiasis. The interactions between MUC2 mucin and cathelicidins in conferring innate immunity against Entamoeba histolytica are not well characterized. In this study, we quantified whether MUC2 expression and release could regulate the expression and secretion of cathelicidin LL-37 in colonic epithelial cells and in the colon. The synthesis of LL-37 was enhanced with butyrate (a product of bacterial fermentation) and interleukin-1␤ (IL-1␤) (a proinflammatory cytokine in colitis) in the presence of exogenously added purified MUC2. The LL-37 responses to butyrate and IL-1␤ were higher in high-MUC2-producing cells than in lentivirus short hairpin RNA (shRNA) MUC2-silenced cells. Activation of cyclic adenylyl cyclase (AMP) and mitogen-activated protein kinase (MAPK) signaling pathways was necessary for the simultaneous expression of MUC2 and cathelicidins. In Muc2 mucin-deficient (Muc2 Ϫ/Ϫ ) mice, murine cathelicidin (Cramp) was significantly reduced compared to that in Muc2 ϩ/Ϫ and Muc2 ϩ/ϩ littermates. E. histolyticainduced acute inflammation in colonic loops stimulated high levels of cathelicidin in Muc2 ϩ/ϩ but not in Muc2 Ϫ/Ϫ littermates. In dextran sodium sulfate (DSS)-induced colitis in Muc2 ϩ/ϩ mice, which depletes the mucus barrier and goblet cell mucin, Cramp expression was significantly enhanced during restitution. These studies demonstrate regulatory mechanisms between MUC2 and cathelicidins in the colonic mucosa where an intact mucus barrier is essential for expression and secretion of cathelicidins in response to E. histolytica-and DSS-induced colitis. KEYWORDS Entamoeba histolytica, MUC2, antimicrobial peptides, mucinT he innate defenses of the colon and first barrier against pathogens include glycosylated MUC2 mucin secreted by goblet cells that forms an inner sterile layer firmly attached to the epithelium and an outer layer with an expanded volume and that is colonized by bacteria (1). Embedded in colonic mucus are cathelicidins, small cationic peptides (23 to 37 amino acids) secreted by neutrophils and epithelial cells, including colonic epithelium, with broad antimicrobial activity (2, 3). The only cathelicidin described in humans is LL-37/hCAP-18, which is homologous to mouse cathelicidinrelated antimicrobial peptide (CRAMP) (2, 3). Both LL-37 and CRAMP have related structure and antimicrobial and chemotactic functions (2, 3). Sodium butyrate pro-

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“…The human cathelicidin, LL-37, is involved in innate immune responses, angiogenesis and wound healing. It was suggested that LL-37 stimulated migration of the human colon cell line, Caco-2, via P2X7 receptors [499] affecting intestinal epithelial barrier integrity [533].…”

Section: Receptor Identificationmentioning

confidence: 99%

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

Burnstock

2013

Purinergic Signalling

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Purinergic signalling plays major roles in the physiology and pathophysiology of digestive organs. Adenosine 5′-triphosphate (ATP), together with nitric oxide and vasoactive intestinal peptide, is a cotransmitter in nonadrenergic, non-cholinergic inhibitory neuromuscular transmission. P2X and P2Y receptors are widely expressed in myenteric and submucous enteric plexuses and participate in sympathetic transmission and neuromodulation involved in enteric reflex activities, as well as influencing gastric and intestinal epithelial secretion and vascular activities. Involvement of purinergic signalling has been identified in a variety of diseases, including inflammatory bowel disease, ischaemia, diabetes and cancer. Purinergic mechanosensory transduction forms the basis of enteric nociception, where ATP released from mucosal epithelial cells by distension activates nociceptive subepithelial primary afferent sensory fibres expressing P2X3 receptors to send messages to the pain centres in the central nervous system via interneurons in the spinal cord. Purinergic signalling is also involved in salivary gland and bile duct secretion.

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Effects of the cathelicidin LL-37 on intestinal epithelial barrier integrity

Cited by 80 publications

References 57 publications

Histones as Mediators of Host Defense, Inflammation and Thrombosis

Histones as Mediators of Host Defense, Inflammation and Thrombosis

MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis

Purinergic signalling in the gastrointestinal tract and related organs in health and disease

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