Host Defense Peptide LL-37 Selectively Reduces Proinflammatory Macrophage Responses

Brown, Kelly L.; Poon, Grace F. T.; Birkenhead, Darlene; Pena, Olga M.; Falsafi, Reza; Dahlgren, Cláes; Karlsson, Anna; Bylund, Johan; Hancock, Robert E. W.; Johnson, Pauline

doi:10.4049/jimmunol.1002508

Cited by 137 publications

(114 citation statements)

References 45 publications

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“…LL-37 also reduces LPS and interferon ␥ (IFN-␥) responses in human peripheral blood mononuclear cells (PBMCs) and mouse splenic B cells . LL-37 selectively reduces proinflammatory macrophage responses (Brown et al, 2011) and inhibits dsRNA/TLR3-induced TNF-␣ and IL-8 in keratinocytes (Chen et al, 2013). Consistent with these suppressive effects in vitro, LL-37 is protective in mouse models of LPS-induced sepsis (Scott et al, 2002).…”

Section: Introductionmentioning

confidence: 69%

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

Sun

Zheng

et al. 2014

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tThe human cationic antimicrobial protein LL-37 is a multifunctional host defense peptide with a wide range of immunomodulatory activities. Previous work has shown that LL-37 exerts both pro-and antiinflammatory effects. The role of mitochondria in the skin inflammatory effects of LL-37 has not been well studied. Therefore, our aim was to investigate the immunomodulatory effect of LL-37 in HaCaT cells and to delineate the underlying mechanisms related to mitochondrial function. Immunohistochemistry results from tissue microarrays showed strong cytoplasmic LL-37 staining in inflammatory cells in chronic dermatic inflammation. Using exogenous LL-37 stimulation and LL-37 knockdown and overexpression, LL-37 was demonstrated to dramatically reduce the mRNA levels and protein secretion of inflammatory cytokines including IL-6, IL-8, IL-1␣ and tumor necrosis factor-␣ (TNF-␣), which are induced by lipopolysaccharides (LPS). The anti-inflammatory effects of LL-37 are dependent upon its ability to increase mitochondrial biogenesis and to maintain mitochondrial homeostasis. Furthermore, we observed that LL-37 enhances the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and mammalian target of rapamycin (mTOR). The mTOR inhibitor rapamycin can neutralize the protective effects of LL-37 on mitochondria. In conclusion, these results suggest that high LL-37 expression levels correlate with chronic skin inflammation; mitochondrial dysfunction occurs in HaCaT cells during inflammation; and LL-37 attenuates inflammatory impairment by stimulating mitochondrial biogenesis and protecting mitochondrial function, which are dependent upon mTOR signaling. These findings provide new insights into targeting mitochondria with LL-37 to prevent skin inflammatory reactions.

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Section: Introductionmentioning

confidence: 69%

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

Sun

Zheng

et al. 2014

The International Journal of Biochemistry & Cell Biology

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“…Clinically used antibiotics can lead to the release of endotoxin that increases the inflammatory response (8). In addition to direct antibacterial activity, most AMPs have immunomodulatory activity (7,37). Therefore, OH-CATH30 may play a role in the immunomodulatory activity against infections.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant Bacteria In Vitro and in Mouse Models

Lee

Zhang

2012

Antimicrob Agents Chemother

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bAntimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacy in vivo hamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activity in vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteria in vitro and in vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 g/ml against drug-resistant clinical isolates of several pathogenic species, including Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killed E. coli quickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD 50 ) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistant E. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drugresistant bacteria.

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“…Importantly, our results show that in the presence of IL-13, vitamin D exposure results in higher expression of hCAP18/LL-37. This cathelicidin displays broad-spectrum antimicrobial activity, affects inflammation and immunity, and stimulates wound repair (10,45). Therefore, increased cathelicidin expression in asthma may contribute to increased host defense and wound repair.…”

Section: Figmentioning

confidence: 99%

Interleukin 13 Exposure Enhances Vitamin D-Mediated Expression of the Human Cathelicidin Antimicrobial Peptide 18/LL-37 in Bronchial Epithelial Cells

et al. 2012

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25D 3 ), by CYP27B1. Low circulating vitamin D levels in childhood asthma are associated with more-severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2-driven inflammation mediated by cytokines such as interleukin 4 (IL-4) and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP18/LL-37 expression is unknown. Therefore, we investigated this with well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D 3 , and expression of hCAP18/LL-37, CYP27B1, the 1,25D 3 -inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D 3 to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas vitamin D receptor (VDR) expression was not significantly affected. The enhancing effect of IL-13 on 25D 3 -mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western blotting and immunofluorescence staining.In conclusion, we demonstrate that IL-13 induces vitamin D-dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.T he upper respiratory tract is continuously exposed to pathogens. Epithelial cells function as the front line of host defense in the lung by preventing microbes from entering the bloodstream through the physical barrier provided by the tight junctions (24) and mucociliary clearance (36). Furthermore, epithelial cells secrete antimicrobial peptides and proteins (AMPs), such as lysozyme, lactoferrin and defensins, reactive oxygen and nitrogen species, interferons, and chemokines and cytokines, which eliminate pathogens directly or indirectly via attraction of phagocytic leukocytes (23, 55). In the lung, the AMP human cathelicidin (hCAP18/LL-37) is mainly secreted by neutrophils and epithelial cells, and the active peptide LL-37 displays broad-spectrum antimicrobial activity against bacteria, fungi, and viruses. It also contributes to microbial clearance by other mechanisms, including attraction of phagocytes (21, 48).In epithelial cells, a variety of stimuli, including proinflammatory cytokines (17, 22), microbial products (35), injury (15), endoplasmic reticulum (ER) stress (39), and butyrate, a short-chain fatty acid produced by resident colonic bacteria (41,44,44), have been shown to increase expression of hCAP18/LL-37. Recent studies also showed that vitamin D is an important regulator of hCAP18/LL-37 expression in epithelial cells and macrophages (56,58). Other studies showed that microbial exposures may also increase vitamin D-mediated expression of hCAP18/LL-37 through the induction of 25-hydroxy-vitamin D-1-␣-hydroxylase (CYP27B1), which converts 25-hydroxy-vitamin D 3 (25D 3 ) into the active 1,25(OH) 2 -vitaminD 3 (1,25D 3 ) (25,33).One of the well-established functions of vitamin D is mediating calcium ...

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Host Defense Peptide LL-37 Selectively Reduces Proinflammatory Macrophage Responses

Cited by 137 publications

References 45 publications

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

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

Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant Bacteria In Vitro and in Mouse Models

Interleukin 13 Exposure Enhances Vitamin D-Mediated Expression of the Human Cathelicidin Antimicrobial Peptide 18/LL-37 in Bronchial Epithelial Cells

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