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- Hoffmann, MH, et al.
(författare)
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The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats
- 2013
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 72:7, s. 1239-1248
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Tidskriftsartikel (refereegranskat)abstract
- In rheumatoid arthritis (RA), neutrophil granulocytes fuel inflammation and damage tissue in the joint by releasing cytotoxic agents, antimicrobial peptides, proteases and other inflammatory mediators. The human cathelicidin LL-37 has recently been implicated in the development of systemic lupus erythematosus and psoriasis.ObjectiveTo elucidate if antimicrobial peptides (AMPs) contribute to the pathogenesis of arthritis.MethodsExpression of LL-37 was determined in synovial membranes from patients with arthritis and control subjects. Expression of the rat cathelicidin rCRAMP and defensins was characterised in joints, blood and secondary lymphoid organs during pristane-induced arthritis (PIA) in rats and in a transfer model of PIA induced by CD4 T cells. Serum samples of rats with arthritis were tested for IgG and IgM autoantibodies against rCRAMP by immunoblot and for interferon (IFNα) by ELISA.ResultsCathelicidins are strongly upregulated in RA synovial membranes and in joints from rats with arthritis as compared with healthy joints. Expression was most prominent in neutrophil granulocytes and macrophages/osteoclasts. Cathelicidin expression is also upregulated in the blood and spleen of pristane-injected rats, with strongest expression detected in activated CD62L− cells coexpressing granulocyte and monocyte markers. Pristane injection caused accumulation of low-density granulocytes in the blood. After pristane injection, the increased expression of rCRAMP coincided with higher levels of cell death, raised levels of interferon (IFN)α and development of autoantibodies.ConclusionsOur results show strong upregulation of cathelicidins and β-defensins coinciding with pathological events of arthritis. Higher expression and release of AMPs might contribute to development and/or maintenance of disease by systemic or local mechanisms.
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- Cederlund, A, et al.
(författare)
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Label-free quantitative mass spectrometry reveals novel pathways involved in LL-37 expression
- 2014
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Ingår i: Journal of innate immunity. - : S. Karger AG. - 1662-8128 .- 1662-811X. ; 6:3, s. 365-376
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Tidskriftsartikel (refereegranskat)abstract
- Antimicrobial peptides are important for a healthy host-microbe homeostasis. In infections characterized by low levels of the human cathelicidin, LL-37, induction of its expression increases clearance of pathogens. Our aim was to discover signaling pathways and compounds capable of affecting the expression of LL-37. We recently observed a synergistic induction of LL-37 expression by stimulating the colonic epithelial cell-line HT-29 with lactose and phenylbutyrate (PBA). Here, we studied regulatory circuits mediating this synergism in HT-29 cells stimulated with lactose (60 g/l) and PBA (2 m<smlcap>M</smlcap>) for 24 h by using mass spectrometry and pathway analyses. Selected pathways were evaluated for their involvement in LL-37 regulation in a <i>CAMP</i> gene-luciferase reporter system. Three pathways were examined in detail: thyroid hormone receptor and retinoid X receptor (TR/RXR) activation, eicosanoid signaling and steroid biosynthesis. Induced expression of LL-37 was observed upon stimulation with triiodothyronine (T3, 2.5 n<smlcap>M</smlcap>-1 µ<smlcap>M</smlcap> for 3-30 h) and thyroxine (T4, 2.5-10 n<smlcap>M</smlcap> for 24 h). Furthermore, the synergism of lactose and PBA was reduced in cells coincubated with inhibitors of phospholipase A2, cyclooxygenase 2 or HMG-CoA reductase. Based on these results, we conclude that proteomics and pathway analyses are valuable tools for dissecting the regulatory networks involved in LL-37 expression.
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- Cederlund, A, et al.
(författare)
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Specificity in killing pathogens is mediated by distinct repertoires of human neutrophil peptides
- 2010
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Ingår i: Journal of innate immunity. - : S. Karger AG. - 1662-8128 .- 1662-811X. ; 2:6, s. 508-521
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil-derived antimicrobial peptides and proteins (AMPs) play an important role in the defense against microbes. Absence of defense is illustrated by neutropenic patients with frequent bacterial and fungal infections. However, the specificity of the antimicrobial effects has not been adequately described. We set out to determine the specific antimicrobial pattern of polypeptides in neutrophils (polymorphonuclear leukocytes, PMNs) against 4 potential human pathogens: <i>Moraxella catarrhalis, Staphylococcus aureus, Haemophilus influenzae </i>and <i>Candida albicans</i>. Protein extracts of human PMNs were separated using high-performance liquid chromatography and fractions were assayed for antimicrobial activity. Fractions displaying antimicrobial activity were separated on SDS-PAGE and characterized using MALDI-MS. Depletion experiments were utilized to determine the contribution of each AMP to the antimicrobial effect. Among the identified AMPs, α-defensins 1–3, azurocidin, LL-37, lysozyme, calprotectin and lactotransferrin were studied in detail. We found a divergent pattern of killing, that is, certain peptides and proteins exhibited selective activity against specific pathogens, while others displayed a broader antimicrobial activity. α-Defensins, LL-37 and calprotectin were active against all species, while lactotransferrin exclusively inhibited growth of <i>S. aureus</i>. Conversely, azurocidin was active against all species except <i>S. aureus</i>. Our observations may shed light on bacterial resistance to AMPs and on the elimination of specific bacterial communities on mucosal surfaces.
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- Kienhöfer, D, et al.
(författare)
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No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:12, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP-/-) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP-/- mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP-/- mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP-/- mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins.
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- Nylen, F, et al.
(författare)
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Boosting innate immunity: development and validation of a cell-based screening assay to identify LL-37 inducers
- 2014
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Ingår i: Innate immunity. - : SAGE Publications. - 1753-4267 .- 1753-4259. ; 20:4, s. 364-376
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Tidskriftsartikel (refereegranskat)abstract
- Innate immunity, the front line of our defence against pathogens, relies, to a great extent, on the production of antimicrobial peptides (AMPs). These peptides exhibit antimicrobial activity and immunomodulatory properties. In humans, AMPs include the defensins (α- and β-families) and the cathelicidin, LL-37. Bacterial resistance against antibiotics is a growing concern, and novel antimicrobial strategies are needed urgently. Hence, the concept of strengthening immune defences against infectious microbes by inducing AMP expression may represent novel or complementary pharmaceutical interventions in the treatment or prevention of infections. We have developed and validated a robust cell-based reporter assay for LL-37 expression, which serves as a marker for a healthy epithelial barrier. This reporter assay can be a powerful tool for high-throughput screenings. We first employed our assay to screen a panel of histone deacetylase inhibitors and derivatives, and then the Prestwick Chemical Library of Food and Drug Administration-approved compounds. After hit confirmation and independent validation in the parental cell line we identified five novel inducers of LL-37. This reporter assay will help to identify novel drug candidates for the treatment and prevention of infections. Importantly, the pattern of hits obtained may suggest cellular pathways and key mediators involved in the regulation of AMP expression.
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