RESUMEN
RATIONALE: Recently a frequent exacerbator phenotype has been described in bronchiectasis, but the underlying biological mechanisms are unknown. Antimicrobial peptides (AMPs) are important in host defence against microbes but can be proinflammatory in chronic lung disease. OBJECTIVES: To determine pulmonary and systemic levels of AMP and their relationship with disease severity and future risk of exacerbations in bronchiectasis. METHODS: A total of 135 adults with bronchiectasis were prospectively enrolled at three European centres. Levels of cathelicidin LL-37, lactoferrin, lysozyme and secretory leucocyte protease inhibitor (SLPI) in serum and sputum were determined at baseline by ELISA. Patients were followed up for 12 months. We examined the ability of sputum AMP to predict future exacerbation risk. MEASUREMENTS AND MAIN RESULTS: AMP levels were higher in sputum than in serum, suggesting local AMP release. Patients with more severe disease at baseline had dysregulation of airway AMP. Higher LL-37 and lower SLPI levels were associated with Bronchiectasis Severity Index, lower FEV1 (forced expiratory volume in 1 s) and Pseudomonas aeruginosa infection. Low SLPI levels were also associated with the exacerbation frequency at baseline. During follow-up, higher LL-37 and lower SLPI levels were associated with a shorter time to the next exacerbation, whereas LL-37 alone predicted exacerbation frequency over the next 12 months. CONCLUSIONS: Patients with bronchiectasis showed dysregulated sputum AMP levels, characterised by elevated LL-37 and reduced SLPI levels in the frequent exacerbator phenotype. Elevated LL-37 and reduced SLPI levels are associated with Pseudomonas aeruginosa infection and can predict future risk of exacerbations in bronchiectasis.
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Péptidos Catiónicos Antimicrobianos/inmunología , Bronquiectasia/inmunología , Anciano , Biomarcadores/metabolismo , Progresión de la Enfermedad , Europa (Continente) , Femenino , Humanos , Lactoferrina/inmunología , Masculino , Muramidasa/inmunología , Fenotipo , Estudios Prospectivos , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Índice de Severidad de la Enfermedad , Esputo/metabolismo , CatelicidinasRESUMEN
PURPOSE: To evaluate cervical mucus secretory leukocyte protease inhibitor (SLPI) concentrations in patients with high-risk human papillomavirus (hrHPV) 16 or 18 positive and low-grade squamous intraepithelial lesions (LGSIL) or high-grade squamous intraepithelial lesions (HGSIL). METHOD: Patients with HPV 16 or 18 positive from 30 to 45 years of age whose cervical cancer screening results reported cytologically LGSIL or HGSIL were included in the study. In the control group, we included participants in the same age with cytology negative and HPV-negative healthy women. All cytological LGSIL or HGSIL results were histopathologically confirmed with colposcopic biopsy specimens. Finally, the study consisted of a total of 3 groups each containing 25 participants as follows: (1) Pap smear and HPV-negative control group, (2) HPV 16 or HPV 18 and LGSIL-positive participants, and (3) HPV 16 or 18 and HGSIL-positive participants. Cervical mucus SLPI levels were analyzed using the enzyme-linked immunosorbent assay method. RESULTS: The mean cervical mucus SLPI levels were 32.94 ng/mL (range: 23-41.29 ng/mL) in the hrHPV + LGSIL group, 29.40 ng/mL (range: 21.03-38.95 ng/mL) in the hrHPV + HGSIL, and 18.75 ng/mL (range: 13.58-29.24 ng/mL) in the healthy control group. Cervical mucus SLPI levels were found to be significantly higher in the hrHPV + LGSIL and hrHPV + HGSIL groups compared to the control group ( P < .001). CONCLUSIONS: The data from the present study indicate that SLPI seems to be one of the important immunomodulatory proteins that provide local immune response in cervical mucosa.
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Moco del Cuello Uterino/inmunología , Infecciones por Papillomavirus/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/inmunología , Adulto , Cuello del Útero/metabolismo , Cuello del Útero/patología , Femenino , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 18/inmunología , Papillomavirus Humano 18/aislamiento & purificación , Humanos , Prueba de Papanicolaou , Infecciones por Papillomavirus/virología , Inhibidor Secretorio de Peptidasas Leucocitarias/análisis , Lesiones Intraepiteliales Escamosas de Cuello Uterino/virología , Neoplasias del Cuello Uterino/prevención & control , Neoplasias del Cuello Uterino/virología , Frotis VaginalRESUMEN
We identified diminished levels of the natural inhibitor of neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), in myeloid cells and plasma of patients with severe congenital neutropenia (CN). We further found that downregulation of SLPI in CD34(+) bone marrow (BM) hematopoietic progenitors from healthy individuals resulted in markedly reduced in vitro myeloid differentiation accompanied by cell-cycle arrest and elevated apoptosis. Reciprocal regulation of SLPI by NE is well documented, and we previously demonstrated diminished NE levels in CN patients. Here, we found that transduction of myeloid cells with wild-type NE or treatment with exogenous NE increased SLPI messenger RNA and protein levels, whereas transduction of mutant forms of NE or inhibition of NE resulted in downregulation of SLPI. An analysis of the mechanisms underlying the diminished myeloid differentiation caused by reduced SLPI levels revealed that downregulation of SLPI with short hairpin RNA (shRNA) upregulated nuclear factor κB levels and reduced phospho-extracellular signal-regulated kinase (ERK1/2)-mediated phosphorylation and activation of the transcription factor lymphoid enhancer-binding factor-1 (LEF-1). Notably, microarray analyses revealed severe defects in signaling cascades regulating the cell cycle, including c-Myc-downstream signaling, in myeloid cells transduced with SLPI shRNA. Taken together, these results indicate that SLPI controls the proliferation, differentiation, and cell cycle of myeloid cells.
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Granulocitos/citología , Granulocitos/metabolismo , Granulocitos/patología , Neutropenia/congénito , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Células de la Médula Ósea/citología , Diferenciación Celular/inmunología , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Regulación de la Expresión Génica/inmunología , Células HEK293 , Humanos , Elastasa de Leucocito/antagonistas & inhibidores , Elastasa de Leucocito/genética , Elastasa de Leucocito/metabolismo , Sistema de Señalización de MAP Quinasas/inmunología , Células Mieloides/citología , Células Mieloides/metabolismo , FN-kappa B/metabolismo , Neutropenia/metabolismo , Neutropenia/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Células MadreRESUMEN
SLPI acts as a modulator of the innate immune responses of macrophages, neutrophils and odontoblasts, and LPS-inducible anti-inflammatory cytokine to suppress the production of pro-inflammatory products by macrophages. Many studies have revealed the effects of light emitting diodes (LEDs) on the tissue repair and inflammatory responses. Although the anti-inflammatory mechanisms of irradiation with LEDs in gingival fibroblasts are known, the effects of 660 nm red LEDs on the inflammation remain unclear. Moreover, there is no report regarding the molecular mechanism for the relationship between SLPI and biological effects of LEDs. The effects of 660 nm red LEDs on inflammation with SLPI were investigated by examining the effects of 660 nm LED on the SLPI expression of RAW264.7 cells after LPS stimulation. This paper reports that the 660 nm red LED induced SLPI expression or reduced the LPS response, and inhibited NF-κB activation directly, leading to the suppression of pro-inflammatory cytokines, such as TNF-α and IL-1ß, suggesting that it might be a useful wavelength LED for inflammation therapy.
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Inflamación/inmunología , Activación de Macrófagos/inmunología , Activación de Macrófagos/efectos de la radiación , Macrófagos/inmunología , Macrófagos/efectos de la radiación , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Animales , Línea Celular , Color , Relación Dosis-Respuesta en la Radiación , Inflamación/inducido químicamente , Inflamación/prevención & control , Luz , Iluminación , Lipopolisacáridos , Ratones , Dosis de Radiación , SemiconductoresRESUMEN
Secretory leukocyte proteinase inhibitor (SLPI) is a well-established inhibitor of serine proteases such as human neutrophil elastase (HNE) and a NF-κB regulatory agent in immune cells. In this paper, we report that SLPI plays a previously uncharacterized role in regulating activation of plasmacytoid dendritic cells (pDCs). As the main source of IFN type I (IFNI), pDCs are crucial contributors to inflammatory and likely wound-healing responses associated with psoriasis. The mechanisms responsible for activation of pDCs in psoriatic skin are therefore of substantial interest. We demonstrate that in lesional skin of psoriasis patients, SLPI together with its enzymatic target HNE and DNA, is a component of neutrophil extracellular traps (NETs). Whereas SLPI(+) neutrophils and NETs were found to colocalize with pDCs in psoriatic skin, a mixture of SLPI with neutrophil DNA and HNE induced a marked production of IFNI by pDCs. IFNI synthesis by stimulated pDCs was dependent on intracellular DNA receptor TLR9. Thus, SLPI may contribute to psoriasis by enabling pDCs to sense extracellular DNA and produce IFNI.
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ADN/inmunología , Células Dendríticas/inmunología , Psoriasis/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Interferón Tipo I/inmunología , Elastasa de Leucocito/inmunología , MasculinoRESUMEN
Lysozyme, secretory leukocyte proteinase inhibitor (SLPI) and glycoprotein 340 (gp340) are important effectors of the innate immune system in sinonasal mucosa. Bacterial biofilms (BBF) are highly organized bacterial communities resistant to host defense systems. The aim of this study was to investigate the expression of lysozyme, SLPI and gp340 in sinus mucosa from chronic rhinosinusitis (CRS) patients with different BBF status. In this prospective cohort study, 63 CRS patients undergoing endoscopic sinus surgery and 20 controls were enrolled and their mucosal samples from ethmoid sinus were obtained. Biofilms were examined by confocal scanning laser microscopy (CSLM), and the expressions of lysozyme, SLPI and gp340 in mRNA and protein levels were detected using reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and Western blot assay, respectively. As a result, 35/63 (55.6%) of the patients were BBF positive in the CRS group and none in controls. Both mRNA and protein levels of lysozyme, SLPI and gp340 in patients with CRS were significantly higher than those in controls. When sub-classified according to BBF status, the CRS patients with BBF revealed the significantly enhanced mRNA and protein levels of lysozyme, SLPI and gp340. In conclusion, our study demonstrates that lysozyme, SLPI and gp340 are constitutively expressed in sinus mucosa and their up-regulated expressions on both the mRNA and protein levels are associated with BBF in CRS patients. These findings may offer an insight into the interaction between BBF and the innate immune system.
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Biopelículas , Senos Etmoidales/metabolismo , Muramidasa/genética , ARN Mensajero/genética , Receptores Inmunológicos/genética , Mucosa Respiratoria/metabolismo , Rinitis/genética , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Sinusitis/genética , Adulto , Estudios de Casos y Controles , Enfermedad Crónica , Senos Etmoidales/inmunología , Senos Etmoidales/microbiología , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunidad Innata/inmunología , Masculino , Microscopía Confocal , Persona de Mediana Edad , Muramidasa/inmunología , Muramidasa/metabolismo , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/metabolismo , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/microbiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rinitis/inmunología , Rinitis/microbiología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Sinusitis/inmunología , Sinusitis/microbiología , Adulto JovenRESUMEN
BACKGROUND: Secretory leukocyte protease inhibitor (SLPI) is responsible for regulating inflammatory damage to and innate and adaptive immune responses in the vaginal mucosa. Depressed cervicovaginal SLPI levels have been correlated with both Trichomonas vaginalis infection and poor reproductive health outcomes. METHODS: We measured levels of SLPI in 215 vaginal specimens collected from adolescent and young adult females aged 14-22 years. Log-transformed SLPI values were compared by analysis of variance or by an unpaired t test before and after adjustment for confounding effects through the propensity score method. RESULTS: Females receiving hormonal contraceptives and those with an abnormal vaginal pH had lower SLPI levels as compared to their peers. After propensity score adjustment for race, behavioral factors, hormonal use, and other sexually transmitted infections (STIs), SLPI levels were lower in females with a positive T. vaginalis antigen test result, a vaginal pH >4.5, vaginal leukocytosis, and recurrent (vs initial) T. vaginalis infection, with the lowest levels observed in those with the highest T. vaginalis loads. CONCLUSIONS: The SLPI level was reduced by >50% in a T. vaginalis load-dependent manner. Future research should consider whether identifying and treating females with low levels of T. vaginalis infection (before they become wet mount positive) would prevent the loss of SLPI and impaired vaginal immunity. The SLPI level could be used as a vaginal-health marker to evaluate interventions and vaginal products.
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Biomarcadores/análisis , Infecciones del Sistema Genital/inmunología , Infecciones del Sistema Genital/parasitología , Inhibidor Secretorio de Peptidasas Leucocitarias/análisis , Trichomonas vaginalis/patogenicidad , Vagina/inmunología , Vagina/parasitología , Adolescente , Femenino , Humanos , Carga de Parásitos , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Trichomonas vaginalis/inmunología , Adulto JovenRESUMEN
The peculiarities of cytokines as compounds of immunogenesis are shown in the patients having acute (A) and chronic (Ch) pyelonephritis (PN). The combination of antibacterial therapy with Nukleinat and Galavit promotes the positive changes of cytokin-producing ability of immunocompetent cells and decrease in the level of proinflammation cytokines in blood and urine, secretory leucocyte protease inhibitor (SLPI) in urine. In children with PN and adult patients with diagnostically elevated titres of antibodies (IgG) to Herpes simplex virus, Cytomegalovirus are shown the positive effects of Kanephron® H and Proteflazidum, accordingly. Clinico-immunological effects of immunomodulators testify to the expediency of this usage in complex therapy with the aim to modulate the cytokine link of immunity for improvement of the effective treatment in APN and the protection against aggravation of kidney functioning in ChPN.
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Infecciones Bacterianas/tratamiento farmacológico , Infecciones por Citomegalovirus/tratamiento farmacológico , Herpes Simple/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Inductores de Interferón/uso terapéutico , Pielonefritis/tratamiento farmacológico , Enfermedad Aguda , Adulto , Antibacterianos/uso terapéutico , Antioxidantes/uso terapéutico , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Niño , Enfermedad Crónica , Citocinas/genética , Citocinas/inmunología , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Femenino , Expresión Génica , Herpes Simple/complicaciones , Herpes Simple/inmunología , Herpes Simple/virología , Humanos , Riñón/efectos de los fármacos , Riñón/inmunología , Riñón/patología , Luminol/análogos & derivados , Luminol/uso terapéutico , Masculino , Persona de Mediana Edad , Ácidos Nucleicos/uso terapéutico , Preparaciones de Plantas/uso terapéutico , Pielonefritis/complicaciones , Pielonefritis/inmunología , Pielonefritis/microbiología , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunologíaRESUMEN
BACKGROUND: This study investigated whether the increase in serum prostate specific antigen (PSA) typically seen during male urinary tract infection (UTI) is incidental or reflects an innate defence mechanism of the prostate. The protective roles of the whey-acid-motif-4-disulphide core (WFDC) proteins, secretory leukoproteinase inhibitor (SLPI) and WFDC2, in the prostate were also examined. METHODS: UTI recurrence was assessed retrospectively in men following initial UTI by patient interview. PSA, SLPI, and WFDC2 gene expression were assessed using biopsy samples. LNCaP and DU145 in vitro prostate cell models were utilized to assess the effects of an Escherichia coli challenge on PSA and WFDC gene expression, and bacterial invasion of the prostate epithelium. The effects of PSA on WFDC antimicrobial properties were studied using recombinant peptides and time-kill assays. RESULTS: Men presenting with PSA >4 ng/ml at initial UTI were less likely to have recurrent (r) UTI than those with PSA <4 ng/ml [2/15 (13%) vs. 7/10 (70%), P < 0.01]. Genes encoding PSA, SLPI and WFDC2, were expressed in prostatic epithelium, and the PSA and SLPI proteins co-localized in vivo. Challenging LNCaP (PSA-positive) cells with E. coli increased PSA, SLPI, and WFDC2 gene expression (P < 0.05), and PSA synthesis (P < 0.05), and reduced bacterial invasion. Pre-incubation of DU145 (PSA-negative) cells with PSA also decreased bacterial invasion. In vitro incubation of recombinant SLPI and WFDC2 with PSA resulted in peptide proteolysis and increased E. coli killing. CONCLUSIONS: Increased PSA during UTI appears protective against rUTI and in vitro is linked to proteolysis of WFDC proteins supporting enhanced prostate innate defences.
Asunto(s)
Infecciones por Escherichia coli , Escherichia coli , Antígeno Prostático Específico , Próstata/inmunología , Infecciones Urinarias , Anciano , Epitelio/inmunología , Escherichia coli/aislamiento & purificación , Escherichia coli/fisiología , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/fisiopatología , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Masculino , Persona de Mediana Edad , Proteínas de la Leche/inmunología , Antígeno Prostático Específico/genética , Antígeno Prostático Específico/inmunología , Proteínas/inmunología , Recurrencia , Estudios Retrospectivos , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Infecciones Urinarias/inmunología , Infecciones Urinarias/microbiología , Infecciones Urinarias/fisiopatología , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAPRESUMEN
Although periodontal tissue is continually challenged by microbial plaque, it is generally maintained in a healthy state. To understand the basis for this, we investigated innate antiviral immunity in human periodontal tissue. The expression of mRNA encoding different antiviral proteins, myxovirus resistance A (MxA), protein kinase R (PKR), oligoadenylate synthetase (OAS), and secretory leukocyte protease inhibitor (SLPI) were detected in both healthy tissue and that with periodontitis. Immunostaining data consistently showed higher MxA protein expression in the epithelial layer of healthy gingiva as compared with tissue with periodontitis. Human MxA is thought to be induced by type I and III interferons (IFNs) but neither cytokine type was detected in healthy periodontal tissues. Treatment in vitro of primary human gingival epithelial cells (HGECs) with α-defensins, but not with the antimicrobial peptides ß-defensins or LL-37, led to MxA protein expression. α-defensin was also detected in healthy periodontal tissue. In addition, MxA in α-defensin-treated HGECs was associated with protection against avian influenza H5N1 infection and silencing of the MxA gene using MxA-targeted-siRNA abolished this antiviral activity. To our knowledge, this is the first study to uncover a novel pathway of human MxA induction, which is initiated by an endogenous antimicrobial peptide, namely α-defensin. This pathway may play an important role in the first line of antiviral defense in periodontal tissue.
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Células Epiteliales/inmunología , Proteínas de Unión al GTP/inmunología , Regulación de la Expresión Génica/inmunología , Encía/inmunología , alfa-Defensinas/inmunología , 2',5'-Oligoadenilato Sintetasa , Péptidos Catiónicos Antimicrobianos/inmunología , Péptidos Catiónicos Antimicrobianos/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Proteínas de Unión al GTP/biosíntesis , Encía/citología , Encía/metabolismo , Humanos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Subtipo H5N1 del Virus de la Influenza A/metabolismo , Gripe Humana/inmunología , Gripe Humana/metabolismo , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Proteínas de Resistencia a Mixovirus , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , alfa-Defensinas/metabolismo , beta-Defensinas/inmunología , beta-Defensinas/metabolismo , CatelicidinasRESUMEN
There are numerous defense proteins present in the saliva. Although some of these molecules are present in rather low concentrations, their effects are additive and/or synergistic, resulting in an efficient molecular defense network of the oral cavity. Moreover, local concentrations of these proteins near the mucosal surfaces (mucosal transudate), periodontal sulcus (gingival crevicular fluid) and oral wounds and ulcers (transudate) may be much greater, and in many cases reinforced by immune and/or inflammatory reactions of the oral mucosa. Some defense proteins, like salivary immunoglobulins and salivary chaperokine HSP70/HSPAs (70 kDa heat shock proteins), are involved in both innate and acquired immunity. Cationic peptides and other defense proteins like lysozyme, bactericidal/permeability increasing protein (BPI), BPI-like proteins, PLUNC (palate lung and nasal epithelial clone) proteins, salivary amylase, cystatins, prolin-rich proteins, mucins, peroxidases, statherin and others are primarily responsible for innate immunity. In this paper, this complex system and function of the salivary defense proteins will be reviewed.
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Inmunidad Adaptativa/inmunología , Inmunidad Innata/inmunología , Mucosa Bucal/inmunología , Saliva/inmunología , Proteínas y Péptidos Salivales/inmunología , Adrenomedulina/inmunología , Catelicidinas/inmunología , Defensinas/inmunología , Proteínas HSP70 de Choque Térmico/inmunología , Histatinas/inmunología , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina M/inmunología , Lactoferrina/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunologíaRESUMEN
We have demonstrated previously that the inoculation of murine mammary tumor cells genetically modified to express high levels of secretory leukocyte protease inhibitor (2C1) do not develop tumors in immunocompetent mice and these cells are more prone to apoptosis than control cells. The aim of the present study was to evaluate the role of the adaptive immune response in the lack of tumor growth of 2C1 cells and the possibility of using these cells for immunotherapy. The s.c. administration of mock transfected F3II cells induces tumor in BALB/c and Nude mice. However, the inoculation of 2C1 cells develops tumor in Nude but not in BALB/c mice. The inoculation of mock transfected F3II cells to 2C1 immunized BALB/c mice by repeated administration of 2C1 cells (once a week for 3 weeks) developed significantly smaller tumors than those observed in non-immunized mice. Remarkably, survival of tumor-bearing immunized mice was higher than non-immunized animals. Herein, we demonstrate that an immunotherapy with SLPI over-expressing non-irradiated tumor cells which do not develop tumor in immunocompetent mice, partially restrain the tumor growth induced by F3II cells and increase the survival of the mice.
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Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/terapia , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Animales , Procesos de Crecimiento Celular/inmunología , Femenino , Inmunoterapia , Inmunoterapia Adoptiva/métodos , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , TransfecciónRESUMEN
Despite tremendous advances in our understanding of HIV/AIDS since the first cases were reported 30 years ago, we are still a long way from understanding critical steps of HIV acquisition, pathogenesis and correlates of protection. Our new understanding of the importance of the mucosa as a target for HIV infection, as well as our recent observations showing that altered expression and responses of innate pattern recognition receptors are significantly associated with pathogenesis and resistance to HIV infection, indicate that correlates of immunity to HIV are more likely to be associated with mucosal and innate responses. Most of the heterosexual encounters do not result in productive HIV infection, suggesting that the female genital tract is protected against HIV by innate defence molecules, such as antiproteases, secreted mucosally. The present review highlights the role and significance of the serine protease inhibitors SLPI (secretory leucocyte protease inhibitor), trappin-2, elafin and ps20 (prostate stromal protein 20 kDa) in HIV susceptibility and infection. Interestingly, in contrast with SLPI, trappin-2 and elafin, ps20 has been shown to enhance HIV infectivity. Thus understanding the balance and interaction of these factors in mucosal fluids may significantly influence HIV infection.
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Elafina/inmunología , Infecciones por VIH/inmunología , VIH/inmunología , Proteínas de la Leche/inmunología , Proteínas/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Femenino , Genitales Femeninos/inmunología , Humanos , Inmunidad Mucosa/inmunología , Inhibidores de Proteasas/inmunologíaRESUMEN
WAP (whey acidic protein) is an important whey protein present in milk of mammals. This protein has characteristic domains, rich in cysteine residues, called 4-DSC (four-disulfide core domain). Other proteins, mainly present at mucosal surfaces, have been shown to also possess these characteristic WAP-4-DSC domains. The present review will focus on two WAP-4-DSC containing proteins, namely SLPI (secretory leucocyte protease inhibitor) and trappin-2/elafin. Although first described as antiproteases able to inhibit in particular host neutrophil proteases [NE (neutrophil elastase), cathepsin-G and proteinase-3] and as such, able to limit maladaptive tissue damage during inflammation, it has become apparent that these molecules have a variety of other functions (direct antimicrobial activity, bacterial opsonization, induction of adaptive immune responses, promotion of tissue repair, etc.). After providing information about the 'classical' antiproteasic role of these molecules, we will discuss the evidence pertaining to their pleiotropic functions in inflammation and immunity.
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Elafina/inmunología , Inmunidad Mucosa , Proteínas de la Leche/química , Proteínas de la Leche/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Animales , Elafina/química , Elafina/genética , Humanos , Inflamación/inmunología , Proteínas de la Leche/genética , Inhibidores de Proteasas/química , Inhibidores de Proteasas/inmunología , Estructura Terciaria de Proteína , Inhibidor Secretorio de Peptidasas Leucocitarias/química , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Distribución TisularRESUMEN
Eosinophils and secretory leukocyte protease inhibitor (SLPI) are both associated with Th2 immune responses and allergic diseases, but whether the fact that they are both implicated in these conditions is pathophysiologically related remains unknown. Here we demonstrate that human eosinophils derived from normal individuals are one of the major sources of SLPI among circulating leukocytes. SLPI was found to be stored in the crystalline core of eosinophil granules, and its dislocation/rearrangement in the crystalline core likely resulted in changes in immunostaining for SLPI in these cells. High levels of SLPI were also detected in blood eosinophils from patients with allergy-associated diseases marked by eosinophilia. These include individuals with eosinophilic granulomatosis with polyangiitis (EGPA) and atopic dermatitis (AD), who were also found to have elevated SLPI levels in their plasma. In addition to the circulating eosinophils, diseased skin of AD patients also contained SLPI-positive eosinophils. Exogenous, recombinant SLPI increased numbers of migratory eosinophils and supported their chemotactic response to CCL11, one of the key chemokines that regulate eosinophil migratory cues. Together, these findings suggest a role for SLPI in controlling Th2 pathophysiologic processes via its impact on and/or from eosinophils.
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Eosinófilos/inmunología , Granulomatosis con Poliangitis/inmunología , Leucocitos/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Adulto , Movimiento Celular/inmunología , Dermatitis Atópica/inmunología , Femenino , Humanos , Recuento de Leucocitos/métodos , Masculino , Persona de Mediana EdadRESUMEN
Elafin and secretory leukocyte protease inhibitor (SLPI) are pleiotropic molecules chiefly synthesized at the mucosal surface that have a fundamental role in the surveillance against microbial infections. Their initial discovery as anti-proteases present in the inflammatory milieu in chronic pathologies such as those of the lung suggested that they may play a role in keeping in check extracellular proteases released during the excessive activation of innate immune cells such as neutrophils. This soon proved to be a simplistic explanation, as other functions were also soon ascribed to these molecules (antimicrobial, modulation of innate and adaptive immunity, regulation of tissue repair). Data emanating from patients with chronic pathologies (in the lung and elsewhere) have shown that SLPI and elafin are often inactivated in inflammatory secretions, either through the action of host or microbial products, justifying attempts at antiprotease supplementation in clinical protocols. Although these have been sparse, proof of principle has been demonstrated, and future challenges will undoubtedly rest with improvements in methods of delivery in the context of tissue inflammation and in careful selection of patients more likely to benefit from SLPI/elafin augmentation.
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Elafina/inmunología , Inmunidad Innata , Inmunidad Mucosa , Neumonía Bacteriana/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Animales , Antiinfecciosos/uso terapéutico , Antiinflamatorios/uso terapéutico , Elafina/genética , Elafina/historia , Terapia Genética , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/genética , Inmunidad Mucosa/efectos de los fármacos , Inmunidad Mucosa/genética , Neumonía Bacteriana/genética , Neumonía Bacteriana/historia , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/terapia , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Inhibidor Secretorio de Peptidasas Leucocitarias/historia , Transducción de SeñalRESUMEN
Sexually transmitted infections (STIs) and vaginal dysbiosis (disturbed resident microbiota presenting with abnormal Nugent score or candidiasis) have been associated with mucosal inflammation and risk of HIV-1 infection, cancer and poor reproductive outcomes. To date, the temporal relationships between aberrant cervical innate immunity and the clinical onset of microbial disturbance have not been studied in a large population of reproductive age women. We examined data from a longitudinal cohort of 934 Ugandan and Zimbabwean women contributing 3,274 HIV-negative visits who had complete laboratory, clinical and demographic data. Among those, 207 women later acquired HIV, and 584 women were intermittently diagnosed with C. trachomatis (CT), N. gonorrhoeae (NG), genital herpes (HSV-2), T. vaginalis (TV), candidiasis, and abnormal intermediate (4-6) or high (7-10) Nugent score, i.e. bacterial vaginosis (BV). Immune biomarker concentrations in cervical swabs were analyzed by generalized linear and mixed effect models adjusting for site, age, hormonal contraceptive use (HC), pregnancy, breastfeeding, genital practices, unprotected sex and overlapping infections. High likelihood ratios (1.5-4.9) denoted the values of cervical immune biomarkers to predict onset of abnormal Nugent score and candidiasis at the next visits. When controlling for covariates, higher levels of ß-defensin-2 were antecedent to BV, CT and HSV-2, lower anti-inflammatory ratio IL-1RA:IL-1ß-to intermediate Nugent scores and candida, lower levels of the serine protease inhibitor SLPI-to candida, lower levels of the adhesion molecule ICAM-1 -to TV, and lower levels of the oxidative stress mitigator and endothelial activation marker VEGF-to NG. Changes in innate immunity following onset of dysbiosis and infections were dependent on HC use when controlling for all other covariates. In conclusion, imminent female genital tract dysbiosis or infection can be predicted by distinct patterns of innate immunity. Future research should characterize biotic and abiotic determinants of this pre-existing innate immunity state.
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Disbiosis/inmunología , Inmunidad Innata/genética , Enfermedades de Transmisión Sexual/inmunología , Vaginosis Bacteriana/inmunología , Adolescente , Adulto , Biomarcadores/metabolismo , Cuello del Útero/inmunología , Cuello del Útero/microbiología , Cuello del Útero/patología , Disbiosis/epidemiología , Disbiosis/microbiología , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Molécula 1 de Adhesión Intercelular/inmunología , Molécula 1 de Adhesión Intercelular/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Estrés Oxidativo/inmunología , Embarazo , Infecciones del Sistema Genital/epidemiología , Infecciones del Sistema Genital/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Enfermedades de Transmisión Sexual/epidemiología , Enfermedades de Transmisión Sexual/microbiología , Uganda/epidemiología , Vagina/inmunología , Vagina/microbiología , Vaginosis Bacteriana/epidemiología , Vaginosis Bacteriana/microbiología , Factor A de Crecimiento Endotelial Vascular/inmunología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Zimbabwe/epidemiologíaRESUMEN
BACKGROUND: Secretory leucocyte protease inhibitor (SLPI), which is present in many physiological fluids including saliva, sputum and nasal discharge, is the most effective inhibitor of chymase. Previously, we demonstrated that chymase is able to cleave SLPI and that the cleaved portion, cSLPI, is a biomarker of chymase activity. OBJECTIVE: We investigated the potential of cSLPI as a biomarker of chymase activity in subjects with allergic rhinitis (AR) and asthmatic airway disease. METHODS: Baseline sputum samples were collected from atopic asthmatics and healthy controls (HC). Nasal lavages (NAL) were performed in subjects with AR both at baseline and following a nasal challenge with allergen or placebo. Levels of cSLPI and chymase were determined by Western analysis, and tryptase and alpha-2 macroglobulin were measured by immunoassay. RESULTS: As compared with HC, asthmatics showed a significant increase in baseline cSLPI/total SLPI ratios and an increase in chymase levels. There was a high correlation of cSLPI/SLPI ratios to chymase levels in normal individuals and untreated asthmatics. In the NAL of patients with AR, as compared with placebo, allergen challenge increased inflammatory biomarkers, including cSLPI/SLPI ratios, chymase levels, tryptase levels and alpha2-macroglobulin levels. Correlations were observed between cSLPI/SLPI ratios and chymase levels and cSLPI/SLPI ratios and alpha2-macroglobulin levels; no correlation was seen between cSLPI/SLPI ratios and tryptase levels. CONCLUSION: Our data indicate that cSLPI reflects chymase activity in AR and asthma. Hence, cSLPI may serve as a biomarker for disease activity and for monitoring the efficacy of novel anti-inflammatory treatments in chymase-mediated diseases.
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Quimasas/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Líquido del Lavado Nasal/química , Líquido del Lavado Nasal/inmunología , Hipersensibilidad Respiratoria/enzimología , Hipersensibilidad Respiratoria/inmunología , Estudios Retrospectivos , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunología , Esputo/enzimología , Esputo/inmunología , Esputo/metabolismo , Triptasas/metabolismo , alfa-Macroglobulinas/metabolismoRESUMEN
Alarm anti-proteases are secreted locally in response to inflammation and have been shown to be elevated in cancers. Secretory leukocyte protease inhibitor (SLPI), an alarm anti-protease, is amplified in ovarian carcinoma and is induced and binds to and protects progranulin (prgn) in inflammation. We reported prgn is a survival protein in ovarian cancer and now hypothesize that SLPI/prgn would promote proliferation and survival. Neutralizing anti-SLPI antibody treatment of HEY-A8 and OVCAR3 ovarian cancer cells decreased cell number (P < 0.001), induced apoptosis and reduced prgn quantity. This was confirmed using SLPI small interfering RNA. Prgn and SLPI were co-immunoprecipitated and co-localized by confocal microscopy. Prgn is a substrate of the serine protease elastase and SLPI is an inhibitor of elastase. Elastase reduced prgn expression, inhibited proliferation in a dose-dependent manner (P = 0.01) and was pro-apoptotic. SLPI protected prgn from elastase-mediated degradation and restored its survival and proliferative function (P = 0.04). SLPI also reversed elastase's pro-apoptotic effects (P = 0.03), yielding recovery of S-phase fraction (P = 0.001) and increased cyclin D1. Treatment with a general serine protease inhibitor increased prgn, but did not reverse elastase-mediated prgn loss or apoptosis. These data demonstrate that inappropriate over-expression of the alarm anti-protease, SLPI, creates a pro-survival milieu for ovarian cancer.
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Proliferación Celular , Supervivencia Celular/fisiología , Neoplasias Ováricas/patología , Inhibidor Secretorio de Peptidasas Leucocitarias/fisiología , Línea Celular Tumoral , Medios de Cultivo Condicionados , Femenino , Silenciador del Gen , Humanos , Inmunoprecipitación , Microscopía Confocal , Microscopía Fluorescente , Pruebas de Neutralización , Interferencia de ARN , ARN Interferente Pequeño , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Inhibidor Secretorio de Peptidasas Leucocitarias/inmunologíaRESUMEN
The great advantage of being a sexually transmitted disease is the ability to survive and specialize solely on a host species that is present in low numbers and widely distributed so that contact between infected and uninfected organisms by chance is rare. Pathogens of a sparse, but widely distributed host species, must either: i) have an alternative host; ii) be able to survive in a dormant state; or iii) be non-destructive to their host. For the pathogens of a diploid there is a particularly effective strategy, that of being sexually transmitted. Then the hosts' themselves transfer the pathogen.