Citations of BMS810FF
Characterization of Human Cellular Immune Responses to Novel Mycobacterium tuberculosis Antigens Encoded by Genomic Regions Absent in Mycobacterium bovis BCG
Al-Attiyah,R.; Mustafa,A.S.
Infection and Immunity 2008;76:4190-4198.
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Abstract
Comparative genomics has identified several regions of differences (RDs) between the infectious Mycobacterium tuberculosis and the vaccine strains of Mycobacterium bovis BCG. We aimed to evaluate the cellular immune responses induced by antigens encoded by genes predicted in 11 RDs. Synthetic peptides covering the sequences of RD1, RD4 to RD7, RD9 to RD13, and RD15 were tested for antigen-induced proliferation and secretion of Th1 cytokine, gamma interferon (IFN-{gamma}), by peripheral blood mononuclear cells (PBMC) obtained from culture-proven pulmonary tuberculosis (TB) patients and M. bovis BCG-vaccinated healthy subjects. Among the peptide pools, RD1 induced the best responses in both donor groups and in both assays. In addition, testing of TB patients' PBMC for secretion of proinflammatory cytokines (tumor necrosis factor alpha [TNF-{alpha}], interleukin 6 [IL-6], IL-8, and IL-1{beta}), Th1 cytokines (IFN-{gamma}, IL-2, and TNF-{beta}), and Th2 cytokines (IL-4, IL-5, and IL-10) showed differential effects of RD peptides in the secretion of IFN-{gamma} and IL-10, with high IFN-{gamma}/IL-10 ratios (32 to 5.0) in response to RD1, RD5, RD7, RD9, and RD10 and low IFN-{gamma}/IL-10 ratios (<1.0) in response to RD12, RD13, and RD15. Peptide-mixing experiments with PBMC from healthy subjects showed that secretion of large quantities of IL-10 in response to RD12 and RD13 correlated with inhibition of Th1 responses induced by RD1 peptides. In conclusion, our results suggest that M. tuberculosis RDs can be divided into two major groups--one group that activates PBMC to preferentially secrete IFN-{gamma} and another group that activates preferential secretion of IL-10--and that these two groups of RDs may have roles in protection against and pathogenesis of TB, respectively
2535
Virulence factors of Staphylococcus aureus induce Erk-MAP kinase activation and c-Fos expression in S9 and 16HBE14o- human airway epithelial cells
Below,Sabine; Konkel,Anne; Zeeck,Cathrin; Muller,Christian; Kohler,Christian; Engelmann,Susanne; Hildebrandt,Jan Peter
Lung Cellular and Molecular Physiology 2009;296:L470-L479.
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Abstract
Part of the innate defense of bronchial epithelia against bacterial colonization is regulated secretion of salt, water, and mucus as well as defensins and cytokines involving MAP kinase activation and alterations in early gene expression. We tested two different types of immortalized human airway epithelial cells (S9, 16HBE14o-) for activation of Erk-type MAP kinases and for expression of c-Fos on treatment with Staphylococcus aureus culture supernatants from the stationary growth phase [optical density (OD)540nm = 10] or with recombinant S. aureus hemolysins A and B (Hla, Hlb). OD10 supernatants activated Erk-type MAP kinases and c-Fos expression in a concentration-dependent manner. Hla induced Erk-type kinase phosphorylation in S9 but not in 16HBE14o- cells. Hlb induced Erk activation in either cell type. Basal and stimulated levels of Erk-type MAP kinase phosphorylation were sensitive to the Mek1 inhibitor PD-98059, indicating that the bacterial products activated the entire signaling cascade that coregulates IL-8 induction and secretion. While c-Fos expression was enhanced by OD10 supernatants, Hla, and Hlb in S9 cells, 16HBE14o- cells responded to OD10 supernatant and Hlb but not to Hla. In S9 cells, PD-98059 suppressed c-Fos upregulation by OD10 supernatant, Hla, or Hlb, indicating that c-Fos expression requires activation of Erk-type MAP kinases. In 16HBE14o- cells, however, c-Fos expression by OD10 supernatant was sensitive to PD-98059, while that induced by Hlb was not. This indicates that ingredients of OD10 supernatants other than Hla or Hlb are activating Erk-type MAP kinases in 16HBE14o- cells and that other intracellular signaling systems apart from Erk-type MAP kinases contribute to Hlb-mediated regulation of c-Fos. Thus interaction of bacterial factors with airway epithelial cells may be highly cell type specific
2310
Interleukin (IL)-1beta, IL-6 and IL-8 in nasal secretions: a common role for innate immunity in viral bronchial infection in infants?
Bermejo-Martin,J.F.; Bernardo,D.; Dominguez-Gil,M.; Alonso,A.; Garcia-Arevalo,M.C.; Pino,M.; de Lejarazu,R.O.; Eiros,J.M.; Ardura,J.; Leon,A.J.; Garrote,J.A.; Resino,S.; Blanco-Quiros,A.; Munoz-Fernandez,M.A.; Arranz,E.
Br J Biomed.Sci. 2006;63:173-175.
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Abstract
There is growing evidence to support a role for the immune response in lower respiratory tract infection (LRTI) due to viruses in children.1,2 Respiratory syncytial virus (RSV) is the most frequent aetiological agent of LRTI, but other respiratory viruses (human metapneumovirus [hMPV], parainfluenza virus types 1, 2 and 3, influenza virus B, adenovirus types 1, 2 and 5, and mycoplasmas) can produce symptoms indistinguishable from those elicited by RSV. Currently, however, there is controversy over the ability of the different viral agents to induce pro-inflammatory cytokines. Differences in the locally secreted cytokine profile in nasal washes between RSV and metapneumovirus infections have been described, as have similarities between RSV and influenza.3 Additionally, immune function in neonates differs from that in adults.4
1324
Phenotypic and Functional Analysis of CD4+CD25-Foxp3+ T Cells in Patients with Systemic Lupus Erythematosus
Bonelli,Michael; Savitskaya,Anastasia; STEINER,CARL WALTER; Rath,Eva; Smolen,Josef S.; Scheinecker,Clemens
The Journal of Immunology 2009;182:1689-1695.
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Abstract
CD4+CD25+Foxp3+ regulatory T cells (Treg) that specialize in the suppression of immune responses might be critically involved in the pathogenesis of autoimmune diseases. Recent studies have described increased proportions of CD4+Foxp3+ T cells that lacked expression of CD25 in systemic lupus erythematosus (SLE) patients but the suppressive capacity of these cells has not been analyzed so far. We therefore performed combined phenotypic and functional analyses of CD4+CD25-Foxp3+ T cells in patients with autoimmune diseases and healthy controls (HC). Phenotypic analysis revealed increased proportions of CD4+CD25-Foxp3+ T cells in SLE patients as compared with patients with systemic sclerosis, rheumatoid arthritis, (RA), or HC. In addition, increased proportions of CD4+CD25-Foxp3+ T cells correlated with the clinical disease activity and the daily cortisone dose. According to phenotypic analysis, CD4+CD25-Foxp3+ T cells resembled regulatory T cells rather than activated T cells. For functional analysis, a surrogate surface marker combination to substitute for intracellular Foxp3 was defined: CD4+CD25-CD127- T cells from SLE patients were isolated by FACS sorting and analyzed for their suppressive capacity in vitro. CD4+CD25-CD127- T cells, that contained up to 53% Foxp3+ T cells, were found to suppress T cell proliferation but not IFN-{gamma} production in vitro. In summary, CD4+CD25-Foxp3+ T cells phenotypically and to a certain extent also functionally resemble conventional Treg. Despite increased proportions, however, their selective functional defects might contribute to the failure of Treg to control autoimmune dysregulation in SLE patients
2359
Variation in numbers of CD4+CD25highFOXP3+ T cells with normal immuno-regulatory properties in long-term graft outcome
Braudeau,C.; Racape,M.; Giral,M.; Louis,S.; Moreau,A.; Berthelot,L.; Heslan,M.; shton-Chess,J.; Soulillou,J.P.; Brouard,S.
Transpl.Int 2007;20:845-855.
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Abstract
Chronic rejection (CR) is a major cause of long-term graft loss that would be avoided by the induction of tolerance. We previously showed that renal transplant patients with CR have lower numbers of peripheral CD4(+)CD25(high) T cells than operationally tolerant patients, patients with stable graft function and healthy volunteers (HV). We explored here the profile of CD4(+)CD25(high) blood T cells in these patients focusing on their expression of the regulatory T cells (Treg) gene Forkhead Box P3 (FOXP3) and their suppressive function. We show that CR is associated with a decreased number of CD4(+)CD25(high)FOXP3(+)T cells with normal regulatory profile, whereas graft acceptance is associated with CD4(+)CD25(high)FOXP3(+)T cell numbers similar to HVs. These data suggest that Treg numbers, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of renal transplants
1327
Expansion of Vdelta1 T lymphocytes producing IL-4 in low-grade non-Hodgkin lymphomas expressing UL-16-binding proteins
Catellani S,Poggi A,Bruzzone A,Dadati P,Ravetti JL,Gobbi M,Zocchi MR.
Blood 2007;109:2078-2085.
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Abstract
Data on 23 patients with low-grade non-Hodgkin lymphomas (NHLs), 4 mantle (MT), 4 marginal zone (MZ), and 15 follicular (FL), were analyzed and compared with 10 high-risk (HR) B-cell chronic lymphocytic leukemias (B-CLLs) with lymph node involvement and 4 diffuse large-cell lymphomas (DLCLs). A significant increase in circulating V1 T lymphocytes producing interleukin-4 (IL-4) was found in patients with FL, MT, and MZ NHL, at variance with DLCL and HR B-CLL. IL-4 was also detectable in the sera and lymph nodes of the same patients. In 19 of the 23 patients with NHL with increased circulating V1 T lymphocytes, B cells expressing the UL-16-binding proteins (ULBPs) ULBP2 or ULBP3 or both were found in peripheral blood, bone marrow, or lymph nodes. Of note, in HR B-CLL or in DLCL, where leukemic cells were negative for ULBPs, no V1 T-cell increase was found. Moreover, V1 T lymphocytes from patients with FL NHL proliferate in response to ULBP2+ and ULBP3+ lymphoma cells. Finally, patients with high expression of ULBPs, increased circulating V1 T lymphocytes, and high levels of serum IL-4 showed stable disease in a 1-year follow-up in contrast to patients with low circulating V1 T cells and undetectable IL-4 or ULBPs.
1307
Immuno-regulatory effects of CKBM on the activities of mitogen-activated protein kinases and the release of cytokines in THP-1 monocytic cells.
Chan Siu Lung,Anthony; Yip Chun-Hung,Eric; Yung Ying,Lisa; Pang,Haihong; Luk Chui-Wah,Sharon; Pang Fun,Shiu; Wong Hou,Yung
Biol.Pharm.Bull. 2005;28:1645-1650.
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Abstract
CKBM is an herbal formula composed of five Chinese medicinal herbs (Panax ginseng, Schisandra chinensis, Fructus crataegi, Ziziphus jujube and Glycine Max) supplemented with processed Saccharomyces cerevisiae. Previous studies have demonstrated that CKBM is capable of triggering the release of IL-6 and TNFalpha from human peripheral blood mononuclear cells, and its anti-tumorigenic activity has been demonstrated in nude mice with gastric cancer. In this report, we utilized the THP-1 monocytic cell line as a cellular model to investigate how CKBM regulates the intracellular signaling of monocytes and the subsequent release of the produced cytokines. In terms of mitogen-activated protein kinase (MAPK) cascades, CKBM (20%) had no significant effect on ERK, but was linked to an inhibitory effect on JNK and a stimulatory effect on p38 MAPK. The differential responsiveness of JNK and p38 was dependent on the duration of treatment, as well as on the dosage of CKBM. Treatment of CKBM alone induced the release of IL-10 and IFNgamma, but not IL-1beta, IL-4, IL-6 and TNFbeta, while increase of intracellular Ca2+ concentration by A23187 triggered the release of IL-10 only. Interestingly, A23187 synergized with the activities of CKBM-treated THP-1 cells in terms of IL-1beta and IFNgamma production, while the IL-10 production showed no synergistic relationship between CKBM and A23187. This A23187-induced synergism was associated with a dose-dependent character towards CKBM administration. In view of the intracellular Ca2+ elevation during monocyte activation, our results suggest that CKBM can serve as a promoting agent for modulating the functions of monocytes.
468
Soluble HLA Class I Molecules Exert Differentiated Influence on Renal Graft Condition
Chudyk,A.; Masiuk,M.; Myslak,M.; Domanski,L.; Sienko,J.; Sulikowski,T.; Machalinski,B.; Giedrys-Kalemba,S.
Transplantation Proceedings 2006;38:90-93.
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Abstract
The function of soluble HLA (sHLA) antigens in the process of immunoregulation and especially in graft tolerance versus rejection has not yet been established. It has been suggested that donor-derived sHLA may exert an immunotolerant influence on the graft. We sought to determine the role of sHLA class I in kidney graft survival by evaluating the influence of these molecules on allotypic lymphocytotoxic antibodies and the concentration of gamma interferon (INF-?). Analysis of sHLA was performed indirectly utilizing their ability to inhibit lymphocytotoxic reaction dependent on complement activation. To demonstrate the inhibitory properties of sHLA, we modified the NIH microcytotoxic test. Furthermore, we determined the concentration of INF-? in all sera samples for comparison with the intensity of the cytotoxic test. The comparison of the intensity of cytotoxic test inhibition with the concentration of INF-? revealed that high concentrations of this cytokine were associated with stronger inhibition of the cytotoxic test, thus with higher concentrations of sHLA class I molecules in recipient sera. We observed that high concentrations of sHLA class I molecules in recipient sera significantly inhibited cytotoxic reactions, which could contribute to a protective influence of sHLA on renal grafts. On the other hand, the observed increase of INF-? concentration might be caused by sHLA themselves, which would produce a detrimental influence on a transplanted organ. Therefore we concluded that the role of sHLA class I molecules in renal graft condition remains ambiguous.
925
Tolerance Induction in Experimental Autoimmune Encephalomyelitis Using Non-myeloablative Hematopoietic Gene Therapy With Autoantigen
Eixarch,Herena; Espejo,Carmen; Gomez,Alba; Mansilla,Maria Jose; Castillo,Mireia; Mildner,Alexander; Vidal,Francisco; Gimeno,Ramon; Prinz,Marco; Montalban,Xavier; Barquinero,Jordi
Mol Ther 2009;17:897-905.
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Abstract
Experimental autoimmune encephalomyelitis (EAE) constitutes a paradigm of antigen (Ag)-specific T cell driven autoimmune diseases. In this study, we transferred bone marrow cells (BMCs) expressing an autoantigen (autoAg), the peptide 40-55 of the myelin oligodendrocytic glycoprotein (MOG40-55), to induce preventive and therapeutic immune tolerance in a murine EAE model. Transfer of BMC expressing MOG40-55 (IiMOG-BMC) into partially myeloablated mice resulted in molecular chimerism and in robust protection from the experimental disease. In addition, in mice with established EAE, transfer of transduced BMC with or without partial myeloablation reduced the clinical and histopathological severity of the disease. In these experiments, improvement was observed even in the absence of engraftment of the transduced hematopoietic cells, probably rejected due to the previous immunization with the autoAg. Splenocytes from mice transplanted with IiMOG-BMC produced significantly higher amounts of interleukin (IL)-5 and IL-10 upon autoAg challenge than those of control animals, suggesting the participation of regulatory cells. Altogether, these results suggest that different tolerogenic mechanisms may be mediating the preventive and the therapeutic effects. In conclusion, this study demonstrates that a cell therapy using BMC expressing an autoAg can induce Ag-specific tolerance and ameliorate established EAE even in a nonmyeloablative setting.
2284
Cytokine concentrations in basal cell carcinomas of different histological types and localization
Elamin,R.D.Zeèeviæ,D.Vojvodiæ,L.Medenica,and M.D.Pavloviæ
Acta Dermatoven APA 2008;17:55-59.
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Abstract
Background: Basal cell carcinoma (BCC) is the most common malignant skin tumor. Cytokines as majormediators of the immune system have been shown to play an important role in biology of the neoplasmwith the general predomination of Th2 cytokines, whereas IFN-ã and other Th1 cytokines are prevalent inspontaneously regressing tumors.Objective: We were interested in comparing cytokine levels in BCC and cutaneous squamous cell tumorswith BCC of different localization and histological subtypes.Material and methods: Explants from freshly excised BCC from 18 patients, and cutaneous squamouscell tumors (solar keratoses and Bowen's disease) from 9 patients were cultivated for 24 h. Cytokine (IL-2, IFN-ã, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNFá, IL-1â) concentrations in culture supernatants weredetermined by a sandwich immunoassay.Results: Tissue explants of BCC contained significantly higher concentrations of IL-1â, IL-4, IL-5, andIL-6 compared to those of squamous cell tumors. Higher levels of TNF-á (p = 0.042), IL-4 (p = 0.028), andIL-5 (p = 0.012) were found in tumors localized to the head and neck compared to those on the trunk orextremities. Interleukin-6 concentrations were higher in aggressive BCC variants (infiltrative andmicronodular), but the difference was not statistically significant (p = 0.068).Conclusions: Confirming the earlier findings that BCC is a tumor with a Th2 cytokine microenvironment,this study further shows that BCC situated on the head and neck produce even more of certain Th2cytokines (IL-4 and IL-5) and TNF-á, a crucial immunosuppressive cytokine released upon UVB irradiation.
1310
Heat shock protein 70 (HSP70) induces cytotoxicity of T-helper cells
Figueiredo,Constanca; Wittmann,Miriam; Wang,Dong; Dressel,Ralf; Seltsam,Axel; Blasczyk,Rainer; Eiz-Vesper,Britta
Blood 2009;113:3008-3016.
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Abstract
Heat shock protein 70 (HSP70) has gained plenty of attention because of its adjuvant capability to induce CD8+ cytotoxic T lymphocyte and CD4+ T-helper cell responses. We investigated the behavior of T-cell subsets stimulated with endotoxin-free HSP70 with respect to proliferation, cytokine expression, cytotoxicity against allogeneic B-lymphoblastoid cell line and K562 cells, as well as target-independent cytotoxicity. CD4+ cells exhibited a strong increase in proliferation after stimulation with HSP70 (29%). In the presence of targets, a 35-fold up-regulation of granzyme B was observed after stimulation of CD4+ T cells with HSP70 in combination with interleukin-7 (IL-7)/IL-12/IL-15. The target cell-independent secretion of granzyme B by CD4+ cells was greatly augmented after stimulation with HSP70 plus IL-2 or IL-7/IL-12/IL-15. In this study, we showed that HSP70 is capable of inducing a cytotoxic response of T-helper cells in the absence of lipopolysaccharide. The granzyme B secretion and cytolytic activity of T-helper cells are induced in a target-independent way, whereas the cytotoxic activity of CD3+ and CD8+ T cells can be further enhanced in the presence of target cells. Our data provide novel insights into the role of extracellular HSP70 on T-cell immune response concerning the induction of target-independent T-helper cell cytotoxicity
2309
Simultaneous detection of multiple cytokines and chemokines from nonhuman primates using luminex technology
Giavedoni,L.D.
Journal of Immunological Methods 2005;301:89-101.
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Abstract
Cytokines and chemokines are soluble mediators of the immune system that play a crucial role in intercellular signaling, and in the recruitment of cells to inflammation sites. Identification of these molecules in nonhuman primates (NHP) is crucial for the understanding of complex physiological and pathological mechanisms that occur in these species, and to demonstrate whether these mechanisms function similarly in humans. The Luminex100 system is a bench-top flow cytometer that allows the user to perform up to 100 tests simultaneously in a single tube. Recently, a significant number of commercial vendors have developed kits for the simultaneous detection of multiple cytokines and chemokines of human origin with the Luminex system. These kits were tested for their capacity to recognize chemokines and cytokines of nonhuman primate origin. ELISA and ELISPOT assays were also adapted to the Luminex format, and novel assays based on new combinations of antibodies were developed. PBMC were isolated from blood from chimpanzees, rhesus macaques, baboons, cynomolgus macaques, pig-tailed macaques, and African green monkeys; these cells were stimulated in vitro and culture supernatants were used for the determination of cytokines and chemokines. Crossreactivity tables were prepared based on the ability of the reagents to detect cytokines and chemokines in NHP samples with similar intensity to the ones observed in human samples. By mixing commercially available reagents and newly developed ones, a combination has been created that allows for the detection of 20 NHP chemokines and cytokines in a single sample, including G-CSF, GM-CSF, IFN-?, IL-1ß, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 (p40), IL-17, IL-18, MCP-1, MIP-1a, MIP-1ß, RANTES, TNF-a, and TNF-ß. These reagents may become a very useful resource for scientists working with these NHP species, which are relevant pre-clinical models for human diseases and transplantation because they approximate humans in physiology and genetics more closely than any other animal.
952
Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis
Kauss,Tina; Moynet,Daniel; Rambert,J; Al-Kharrat,Abir; Brajot,Stephane; Thiolat,Denis; Ennemany,Rachid; Fawaz,Fawaz;
Arthritis Research & Therapy 2008;10:R19› Link
Abstract
Dietary flavonols may play an important role in the adjunct therapy of chronic inflammation. The availability of therapeutic formulations of pentahydroxyflavone glycoside, rutoside (RU), led us to investigate the ability of this molecule to modulate the release of various proinflammatory mediators from human activated macrophages in vitro and to ameliorate arthritic markers in a rat model. Methods RU was added simultaneously to human macrophages during their activation. Cells were then analyzed for inflammation-related gene expression using a specific array, and cell supernatants were collected to measure inflammatory mediators. RU was also injected into adjuvant-induced arthritic rats, and disease progression and body weight were evaluated until 50 days after injection. Sera and peritoneal macrophages were also collected to quantify the RU effect on various inflammatory markers. Results RU inhibited inflammation-related gene expression in activated human macrophages and the release of nitric oxide, tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6 from these cells. In a rat model, RU inhibited clinical signs of chronic arthritis, correlating with decreased levels of inflammatory cytokines detected in rat sera and macrophage supernatants. Conclusion Thus, RU may have clinical value in reducing inflammatory manifestations in human arthritis and other inflammatory diseases
2661
Probiotic intervention has strain-specific anti-inflammatory effects in healthy adults
Kekkonen,R.A.; Lummela,N.; Karjalainen,H.; Latvala,S.; Tynkkynen,S.; Jarvenpaa,S.; Kautiainen,H.; Julkunen,I.; Vapaatalo,H.; Korpela,R.
World J Gastroenterol. 2008;14:2029-2036.
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Abstract
AIM: To evaluate the effects of three potentially anti-inflammatory probiotic bacteria from three different genera on immune variables in healthy adults in a clinical setting based on previous in vitro characterization of cytokine responses. METHODS: A total of 62 volunteers participated in this randomized, double-blind and placebo-controlled parallel group intervention study. The volunteers were randomized to receive a milk-based drink containing either Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis ssp. lactis Bb12 (Bb12), or Propionibacterium freudenreichii ssp. shermanii JS (PJS) or a placebo drink for 3 wk. Venous blood and saliva samples were taken at baseline and on d 1, 7 and 21. Fecal samples were collected at baseline and at the end of intervention. RESULTS: The serum hsCRP expressed as the median AUC(0-21) (minus baseline) was 0.018 mg/L in the placebo group, -0.240 mg/L in the LGG group, 0.090 mg/L in the Bb12 group and -0.085 mg/L in the PJS group (P = 0.014). In vitro production of TNF-alpha from in vitro cultured peripheral blood mononuclear cells (PBMC) was significantly lower in subjects receiving LGG vs placebo. IL-2 production from PBMC in the Bb12 group was significantly lower compared with the other groups. CONCLUSION: In conclusion, probiotic bacteria have strain-specific anti-inflammatory effects in healthy adults
1317
Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells
Makela,Sanna M.; Strengell,Mari; Pietila,Taija E.; Osterlund,Pamela; Julkunen,Ilkka
Journal of Leukocyte Biology 2009;85:664-672.
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Abstract
TLRs are innate immune receptors that recognize pathogen-associated structures. Binding of ligands to different TLRs can induce the production of proinflammatory cytokines in a synergistic manner. We have analyzed the molecular mechanisms of synergy in TLR ligand-stimulated human monocyte-derived macrophages and dendritic cells (moDCs). Stimulation of moDCs with the TLR8 ligand together with the TLR3 or TLR4 ligand led to synergistic IL-6, IL-10, IL-12, and TNF-{alpha} mRNA expression and cytokine production. DNA-binding assays showed that TLR3 and TLR8 stimulation induced binding of multiple IFN regulatory factor (IRF) and STAT transcription factors to the IL-12p35 gene promoter IFN-stimulated response element in moDCs and macrophages but with different binding profiles and kinetics. We also demonstrate that NF-{kappa}B, MAPKs and PI-3K pathways have an important role in TLR-induced cytokine gene expression, as pharmacological inhibitors of these signaling pathways inhibited TLR3, TLR4, and TLR8 ligand-induced cytokine mRNA expression and protein production. Especially, synergistic IL-12p70 production was abolished completely in NF-{kappa}B, MAPK p38, and PI-3K inhibitor-treated moDCs. Our data suggest that TLR-dependent, synergistic cytokine gene expression results from enhanced activation and cooperation among NF-{kappa}B, IRF, MAPK, PI-3K, and STAT signaling pathways
2308
Chemotherapy induces inflammatory response in breast cancer patients
Michlmayr A.,S.Baumann,M.Zellner,C.Burghuber,P.Schuch,C.Wenzel,R.Bartsch,U.Pluschnig,I.Rech-Weichselbraun,G.Steger,R.Jakesz,M.Gnant and T.Bachleitner-Hofmann,M.Bergmann,R.Oehler
Keystonesymposia, Inflammation, Microenvironment and Cancer 2008;Abstract
Chemotherapeutic treatment of breast cancer patients supposedly mediates its effect via direct elimination of tumor cells. However, there is growing evidence that activation of immune cells in the tumor micro environment is essential for tumor regression. We investigated whether chemotherapy is associated with an inflammatory response which is detectable also in the peripheral blood. Blood was taken from 24 breast cancer patients before and 4 days after receiving the first course of neoadjuvant chemotherapy (epirubicin/docetaxel). This combination therapy leads to substantial tumor regression in about 50% of patients. To assess the inflammatory response we performed an analysis of 17 different inflammatory mediators using a beads based multiplex immunoassay. Systemic IL-6 and IL-10 levels increased in response to chemotherapy while sPECAM and sICAM-3 levels decreased. These results were verified by ELISA (p<0.01). To get a broader view of the effect of chemotherapy a proteomic analysis was performed using 2D-DIGE. Thirty-one out of 642 protein spots showed a more than 1.4 fold (p < 0.05) change within 4 days of chemotherapy including complement factors C1, C3 and C4, alpha2HSglycoprotein, and alpha1-anti chymotrypsin. These proteins are induced in the course of acute phase response during inflammation. These data show that chemotherapy induces inflammation in breast cancer patients. However, it cannot be concluded whether this occurs due to a direct effect of treatment on cancer cells or to a side effect on other tissues. The degree of protein induction varied between patients. Future studies are planned to clarify whether such variations are associated with the clinical response rate to therapy.
1288
The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin on human peripheral blood eosinophils
Munitz,Ariel; Bachelet,Ido; Eliashar,Ron; Moretta,Alessandro; Moretta,Lorenzo; Levi-Schaffer,Francesca
Blood 2006;107:1996-2003.
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Abstract
Allergic, inflammatory, and immune responses carried out by eosinophils are regulated by the cross talk between activatory and inhibitory signals. While much data has been obtained on activatory signals, inhibitory receptors on these cells have received scant attention. Therefore, we screened the surface of human peripheral blood eosinophils for inhibitory receptors using monoclonal antibodies (mAbs) previously generated to recognize receptors on human natural killer cells. Eosinophils from all of the donors examined expressed the inhibitory receptors IRp60, LIR3/ILT5, Fc{gamma}RIIB, and p75/AIRM but not LIR1/ILT2, p58.1, p58.2, p70, or NKG2A/CD94 (n = 15). Interestingly, 25% of the donors expressed p140. IRp60 cross-linking inhibited eotaxin-dependent transmigration of eosinophils in a calcium-independent fashion. In addition, cross-linking of IRp60 on the eosinophils in the presence of IL-5/GM-CSF inhibited the antiapoptotic effect of these cytokines and blocked the release of TNF-{alpha}, IL-1[beta], IFN-{gamma}, IL-4, and 3T3 fibroblast proliferation. Cross-linking of IRp60 inhibited IL-5-mediated JAK2 phosphorylation as well as eotaxin- and IL-5/GM-CSF-mediated ERK1/2 and p38 phosphorylation. Furthermore, upon cross-linking, IRp60 underwent tyrosine phosphorylation and recruited SHP-1 but not SHP-2. These findings demonstrate a novel pathway for suppressing the activity of human eosinophils, thus indicating IRp60 as a future potential target for the treatment of allergic and eosinophil-associated diseases
30
Cellular Immune Responses Associated with Occult Hepatitis C Virus Infection of the Liver
Quiroga,Juan A.; Llorente,Silvia; Castillo,Inmaculada; Rodriguez-Inigo,Elena; Pardo,Margarita; Carreno,Vicente
Journal of Virology 2006;80:10972-10979.
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Abstract
Occult hepatitis C virus (HCV) infection is a type of recently identified chronic infection that is evidenced only by detection of HCV RNA in liver; patients consistently test negative for antibodies to HCV and HCV RNA in serum. Using ex vivo and in vitro measures of T-cell responses, we have identified functional virus-specific memory CD4+ and CD8+ T cells in the peripheral blood of patients with occult HCV infection. The features of the virus-specific T cells were consistent with immune surveillance functions, supporting previous exposure to HCV. In addition, the magnitudes of CD4+ and CD8+ T-cell responses were in parallel and correlated inversely with the extent of liver HCV infection. The detection of HCV-specific T cells in individuals in whom HCV RNA can persist in the liver despite the absence of viremia and antibodies indicates that HCV replication is prolonged in the face of virus-specific CD4+ and CD8+ T-cell responses. These findings demonstrate that HCV-specific cellular immune responses are markers not only of previous exposure to and recovery from HCV but also of ongoing occult HCV infection
749
Molecular Blocking of CD23 Supports Its Role in the Pathogenesis of Arthritis
Rambert,Jerome; Mamani-Matsuda,Maria; Moynet,Daniel; Dubus,Pierre; Desplat,Vanessa; Kauss,Tina; Dehais,Jo; Schaeverbeke,Thierry; Ezzedine,Khaled; Malvy,Denis; Vincendeau,Philippe;
PLoS ONE 2009;4:› Link
Abstract
Background CD23 is a differentiation/activation antigen expressed by a variety of hematopoietic and epithelial cells. It can also be detected in soluble forms in biological fluids. Initially known as the low-affinity receptor for immunoglobulin E (FcÁRII), CD23 displays various other physiologic ligands such as CD21, CD11b/c, CD47-vitronectin, and mannose-containing proteins. CD23 mediates numerous immune responses by enhancing IgE-specific antigen presentation, regulating IgE synthesis, influencing cell differentiation and growth of both B- and T-cells. CD23-crosslinking promotes the secretion of pro-inflammatory mediators from human monocytes/macrophages, eosinophils and epithelial cells. Increased CD23 expression is found in patients during allergic reactions and rheumatoid arthritis while its physiopathologic role in these diseases remains to be clarified. Methodology/Principal Findings We previously generated heptapeptidic countrestructures of human CD23. Based on in vitro studies on healthy and arthritic patients' cells, we showed that CD23-specific peptide addition to human macrophages greatly diminished the transcription of genes encoding inflammatory cytokines. This was also confirmed by significant reduction of mediator levels in cell supernatants. We also show that CD23 peptide decreased IgE-mediated activation of both human and rat CD23 + macrophages. In vivo studies in rat model of arthritis showed that CD23-blocking peptide ameliorates clinical scores and prevent bone destruction in a dose dependent manner. Ex-vivo analysis of rat macrophages further confirmed the inhibitory effect of peptides on their activation. Taken together our results support the role of CD23 activation and subsequent inflammatory response in arthritis. Conclusion CD23-blocking peptide (p30A) prevents the activation of monocytes/macrophages without cell toxicity. Thus, targeting CD23 by antagonistic peptide decreases inflammatory markers and may have clinical value in the treatment of human arthritis and allergic reactions involving CD23
2689
The B subunit of Escherichia coli heat-labile enterotoxin inhibits Th1 but not Th17 cell responses in established autoimmune uveoretinitis
Raveney,B.J.; Richards,C.M.; Aknin,M.L.; Copland,D.A.; Burton,B.R.; Kerr,E.C.; Nicholson,L.B.; Williams,N.A.; Dick,A.D.
Invest Ophthalmol.Vis.Sci. 2008;49:4008-4017.
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Abstract
Purpose: To investigate the efficacy of B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Background: Murine experimental autoimmune uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal-antigen-specific Th1 and Th17 CD4(+) T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T cell activity. Methods: EAU was induced in B10.RIII mice by immunisation with peptide of hIRBP161-180. Disease severity was measured by clinical and histological assessment and functional responses of macrophages (Mphi) and T cells were assessed both in vivo and in in vitro co-cultures. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EAU induction. Results: Pre-immunisation treatment with EtxB protected mice from EAU, limiting both the number and the activation status of retinal infiltrating immune cells. Treatment following EAU induction did not alter disease course, despite suppression of IFN-gamma. Although EtxB treatment of in vitro co-cultures of T cells and Mphi increased IL-10 production, EtxB treatment in vivo increased the proportion and numbers of IL-17-producing CD4(+) cells infiltrating the eye. Conclusion: EtxB pre-immunisation protects mice from EAU induction by inhibiting Th1 responses, but the resulting reduction in IFN-gamma responses by EtxB does not effect infiltration or structural damage in established EAU, where Th17 responses predominate. These data highlight the critical importance of the dynamics of T cell phenotype and infiltration during EAU when considering immunomodulatory therapy
1318
Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis
Saadoun,D.; Rosenzwajg,M.; Landau,D.; Piette,J.C.; Klatzmann,D.; Cacoub,P.
Blood 2008;111:5334-5341.
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Abstract
Rituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as mixed cryoglobulinemia (MC). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of peripheral blood B- and T-cell subsets, the clonal VH1-69 cells, as well as the cytokine profile following rituximab therapy. The study involved 21 patients with hepatitis C-related MC who received rituximab, of whom 14 achieved a complete response. Compared with healthy and hepatitis C virus (HCV) controls, pretreatment abnormalities in MC patients included a decreased percentage of naive B cells (P < .05) and CD4(+)CD25(+)FoxP3(+) regulatory T cells (P = .02) with an increase in memory B cells (P = .03) and plasmablasts (P < .05). These abnormalities were reverted at 12 months after rituximab. Clonal VH1-69(+) B cells dramatically decreased following treatment (32% +/- 6% versus 8% +/- 2%, P = .01). Complete responders of rituximab exhibited an expansion of regulatory T cells (P < .01) accompanied with a decrease in CD8(+) T-cell activation (P < .01) and decreased production of interleukin 12 (IL-12; P = .02) and interferon-gamma (IFN-gamma; P = .01). Our findings indicate that in patients with MC, response to B-cell depletion induced by rituximab effectively normalizes many of the disturbances in peripheral B- and T-lymphocyte homeostasis
1314
Intratumoural injection of the toll-like receptor-2/6 agonist 'macrophage-activating lipopeptide-2' in patients with pancreatic carcinoma: a phase I/II trial.
Schmidt J,Welsch T,Jäger D,Mühlradt PF,Büchler MW,Märten A.
British Journal of Cancer 2007;97:598-604.
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Abstract
This phase I/II trial examined safety and efficacy of the toll-like receptor 2/6 agonist MALP-2 in combination with gemcitabine in patients with incompletely resectable pancreas carcinomas. MALP-2 is a toll-like receptor 2/6 agonist, acts as an immunological adjuvant, and has been described recently to prolong survival in a mouse model of an orthotopic, syngeneic pancreas tumour. Male and female patients with incompletely resectable pancreas carcinomas were eligible while those with R0 or R1 resections or with peritoneal carcinosis were excluded. Ten patients were injected intratumourally during surgery with 20-30 g MALP-2 followed by postoperative chemotherapy. Samples were taken from peripheral blood and wound secretion, and assayed for cell content, cytokine and CRP levels, and NK activity. An MALP-2 dose of 20 g was well tolerated. Clear signs of local MALP-2 effects were presented by the influx of lymphocytes and monocytes in wound secretions, and abolishment of inhibition of NK activity. The actual mean survival is 17.1±4.2 months; the median survival being 9.3 months. Two patients are still alive after 31 months. Up to 20 g MALP-2 was well tolerated, and no systemic side effects were noted. The mean survival of 17.1 months is remarkably high.
1309
An analytical workflow for investigating cytokine profiles
Siebert,J.C.; Inokuma,M.; Waid,D.M.; Pennock,N.D.; Vaitaitis,G.M.; Disis,M.L.; Dunne,J.F.; Wagner,D.H.,Jr.; Maecker,H.T.
Cytometry A 2008;73:289-298.
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Abstract
Understanding cytokine profiles of disease states has provided researchers with great insight into immunologic signaling associated with disease onset and progression, affording opportunities for advancement in diagnostics and therapeutic intervention. Multiparameter flow cytometric assays support identification of specific cytokine secreting subpopulations. Bead-based assays provide simultaneous measurement for the production of ever-growing numbers of cytokines. These technologies demand appropriate analytical techniques to extract relevant information efficiently. We illustrate the power of an analytical workflow to reveal significant alterations in T-cell cytokine expression patterns in type 1 diabetes (T1D) and breast cancer. This workflow consists of population-level analysis, followed by donor-level analysis, data transformation such as stratification or normalization, and a return to population-level analysis. In the T1D study, T-cell cytokine production was measured with a cytokine bead array. In the breast cancer study, intracellular cytokine staining measured T cell responses to stimulation with a variety of antigens. Summary statistics from each study were loaded into a relational database, together with associated experimental metadata and clinical parameters. Visual and statistical results were generated with custom Java software. In the T1D study, donor-level analysis led to the stratification of donors based on unstimulated cytokine expression. The resulting cohorts showed statistically significant differences in poststimulation production of IL-10, IL-1 beta, IL-8, and TNF beta. In the breast cancer study, the differing magnitude of cytokine responses required data normalization to support statistical comparisons. Once normalized, data showed a statistically significant decrease in the expression of IFN gamma on CD4+ and CD8+ T cells when stimulated with tumor-associated antigens (TAAs) when compared with an infectious disease antigen stimulus, and a statistically significant increase in expression of IL-2 on CD8+ T cells. In conclusion, the analytical workflow described herein yielded statistically supported and biologically relevant findings that were otherwise unapparent
2730
Lactoferrin, a major defense protein of innate immunity, is a novel maturation factor for human dendritic cells
Spadaro,M.; Caorsi,C.; Ceruti,P.; Varadhachary,A.; Forni,G.; Pericle,F.; Giovarelli,M.
FASEB Journal 2008;22:2747-2757.
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Abstract
Lactoferrin (LF) is an important protein component of the innate immune system that is broadly distributed within the body fluids. LF is endowed with multiple biological activities. Talactoferrin (TLF), a recombinant human LF, is in clinical development as an anticancer agent and is entering Phase III clinical trials. Here, we show that TLF induces the maturation of human dendritic cells (DCs) derived from monocytes. TLF, at physiologically relevant concentrations (100 microg/ml) up-regulates the expression of human leukocyte antigen (HLA) class II, CD83, CD80, and CD86 costimulatory molecule and CXCR4 and CCR7 chemokine receptors, acting primarily through the p38 MAPK signaling pathway. DCs matured by TLF displayed an enhanced release of IL-8 and CXCL10, as well as a significantly reduced production of IL-6, IL-10, and CCL20. They also display a reduced ability to take up antigen and increased capacity to trigger proliferation and release IFN-gamma in the presence of allogeneic human T cells. TLF-matured DCs are able to prime naive T cells to respond to KLH antigen and display a significantly increased capacity to present Flu-MA(58-66) peptide to HLA-A2-matched T cells. These data suggest that a key immunomodulatory function that may be mediated by TLF is to link the innate with adaptive immunity through DC maturation
1321
Impaired CD4 and CD8 Effector Function and Decreased Memory T Cell Populations in ICOS-Deficient Patients
Takahashi,Naomi; Matsumoto,Kenji; Saito,Hirohisa; Nanki,Toshihiro; Miyasaka,Nobuyuki; Kobata,Tetsuji; Azuma,Miyuki; Lee,Sang Kyou; Mizutani,Shuki; Morio,Tomohiro
The Journal of Immunology 2009;182:5515-5527.
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Abstract
Interaction of ICOS with its ligand is essential for germinal center formation, T cell immune responses, and development of autoimmune diseases. Human ICOS deficiency has been identified worldwide in nine patients with identical ICOS mutations. In vitro studies of the patients to date have shown only mild T cell defect. In this study, we report an in-depth analysis of T cell function in two siblings with novel ICOS deficiency. The brother displayed mild skin infections and impaired Ig class switching, whereas the sister had more severe symptoms, including immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T cells in both patients showed a decreased percentage of CD4 central and effector memory T cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or PMA/ionophore stimulation. The defective polarization into effector cells was associated with impaired induction of T-bet, GATA3, MAF, and retinoic acid-related orphan nuclear hormone receptor (RORC). Reduced CTLA-4+CD45RO+FoxP3+ regulatory T cells and diminished induction of inhibitory cell surface molecules, including CTLA-4, were also observed in the patients. T cell defect was not restricted to CD4 T cells because reduced memory T cells and impaired IFN-{gamma} production were also noted in CD8 T cells. Further analysis of the patients demonstrated increased induction of receptor activator of NF-{kappa}B ligand (RANKL), lack of IFN-{gamma} response, and loss of Itch expression upon activation in the female patient, who had autoimmunity. Our study suggests that extensive T cell dysfunction, decreased memory T cell compartment, and imbalance between effector and regulatory cells in ICOS-deficient patients may underlie their immunodeficiency and/or autoimmunity
2339
Efficient In Vitro Expansion of Human Immunodeficiency Virus (HIV)-Specific T-Cell Responses by gag mRNA-Electroporated Dendritic Cells from Treated and Untreated HIV Type 1-Infected Individuals
Van Gulck,Ellen R.; Vanham,Guido; Heyndrickx,Leo; Coppens,Sandra; Vereecken,Katleen; Atkinson,Derek; Florence,Eric; Kint,Ilse; Berneman,Zwi Nisan; Tendeloo,Viggo Van
Journal of Virology 2008;82:3561-3573.
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Abstract
Developing an immunotherapy to keep human immunodeficiency virus type 1 (HIV-1) replication suppressed while discontinuing highly active antiretroviral therapy (HAART) is an important challenge. In the present work, we evaluated in vitro whether dendritic cells (DC) electroporated with gag mRNA can induce HIV-specific responses in T cells from chronically infected subjects. Monocyte-derived DC, from therapy-naive and HAART-treated HIV-1-seropositive subjects, that were electroporated with consensus codon-optimized HxB2 gag mRNA efficiently expanded T cells, secreting gamma interferon (IFN-{gamma}) and interleukin 2 (IL-2), as well as other cytokines and perforin, upon restimulation with a pool of overlapping Gag peptides. The functional expansion levels after 1 week of stimulation were comparable in T cells from HAART-treated and treatment-naive patients and involved both CD4+ and CD8+ T cells, with evidence of bifunctionality in T cells. Epitope mapping of p24 showed that stimulated T cells had a broadened response toward previously nondescribed epitopes. DC, from HAART-treated subjects, that were electroporated with autologous proviral gag mRNA equally efficiently expanded HIV-specific T cells. Regulatory T cells did not prevent the induction of effector T cells in this system, whereas the blocking of PD-L1 slightly increased the induction of T-cell responses. This paper shows that DC, loaded with consensus or autologous gag mRNA, expand HIV-specific T-cell responses in vitro
2543
Streptococcus pyogenes activates human plasmacytoid and myeloid dendritic cells
Veckman,V.; Julkunen,I.
J Leukoc.Biol 2008;83:296-304.
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Abstract
Human peripheral blood contains two major dendritic cell (DC) populations, namely CD11c(-)CD123+ plasmacytoid DCs (PDCs) and CD11c+CD123(-) myeloid DCs (MDCs). Although the activation of these DC types by various TLR ligands has been relatively well-characterized, less is known about the ability of whole live bacteria to induce PDC and MDC activation. In the present report, we have compared the activation of human PDCs and MDCs in response to major human bacterial pathogen Streptococcus pyogenes (group A streptococci) and influenza A virus. S. pyogenes stimulation resulted in the maturation of both DC types, as evidenced by enhanced expression of costimulatory molecules and production of proinflammatory cytokines and chemokines. Furthermore, S. pyogenes-stimulated PDCs and MDCs activated naive CD4+ T cells and enhanced their Th1 cytokine production. Influenza A virus infection induced rapid PDC activation, whereas MDCs were extremely sensitive to influenza A virus-induced cell death. The most significant differences between DC types were seen in the production of IL-10 and IL-12, which were only produced by S. pyogenes-stimulated MDCs. Although S. pyogenes was able to induce PDC activation, only influenza A virus infection resulted in detectable IFN-alpha production. Our results show that depending on the infecting microbe, the functions of PDCs and MDCs may be partially overlapping, suggesting a considerable flexibility of the human DC system
1316
Human cathelicidin CAP18/LL-37 changes mast cell function toward innate immunity
Yoshioka,M.; Fukuishi,N.; Kubo,Y.; Yamanobe,H.; Ohsaki,K.; Kawasoe,Y.; Murata,M.; Ishizumi,A.; Nishii,Y.; Matsui,N.; Akagi,M.
Biol Pharm.Bull. 2008;31:212-216.
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Abstract
The antimicrobial peptide LL-37 is generated from skin keratinocytes during infection of Gram-negative bacteria and exerts a microbicidal effect. LL-37 also causes functional changes in mast cells. Mast cells in the skin are involved in the innate immune system response against microbial infections via Toll-like receptors (TLRs), such as TLR4, which that is known to recognize lipopolysaccharide (LPS), a bacterial component. Thus, in the present study, we examined the effects of LL-37 on the expression of TLRs and the generation of cytokines on mast cells, and considered functional changes in the host defense system against bacteria. We observed that LL-37 increased the level of TLR4 mRNA and TLR4 protein, and that LL-37 induced the release of IL-4, IL-5 and IL-1beta from mast cells. Cross-interaction between LL-37-triggered TLR4 augmentation and LL-37-inducible cytokine generation was also examined. Although the up-regulation of LL-37-inducible Th2 cytokines was cancelled by LPS, the augmentation of pro-inflammatory cytokine production was still observed. These findings indicate that LL-37 co-existing with the bacterial component switches mast cell function and directs human mast cells toward innate immunity. In conclusion, LL-37 may be a candidate modifier of the host defense against bacterial entry by serving as an alarm for sentinels such as mast cells
1313
Systemic inflammation is associated with pulmonary hypertension in patients undergoing haemodialysis
Yu,Tung Min; Chen,Yi Hsing; Hsu,Jeng Yuan; Sun,Chung Shu; Chuang,Ya Wen; Chen,Cheng Hsu; Wu,Ming Ju; Cheng,Chi Hung; Shu,Kuo Hsiung
Nephrology Dialysis Transplantation 2009;24:1946-1951.
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Abstract
Background. Pulmonary hypertension (PH) is an overlooked cardiovascular morbidity in patients undergoing haemodialysis. Inflammation has been demonstrated to play a significant role with certain types of PH in non-uraemic patients, but studies analysing the mechanisms in dialyzed patients with PH are rare. Hence, we investigated systemic and local inflammation biomarkers associated with PH in uraemia patients to elucidate the potential mechanism. Methods. A cross-sectional study was conducted in which 97 haemodialysis patients were initially evaluated in our hospital. Twelve inflammatory cytokines were measured using a cytometric beads assay in patients with and without PH. FENO (fractional exhaled nitric oxide) was checked by a chemiluminescence analyser in patients with and without PH as well as by normal controls. Results. Thirty-nine eligible patients were enrolled. Compared to patients without PH (group A), patients with PH (group B) had significantly higher serum levels of hs-CRP, IL-1{beta}, TNF-{alpha} and IL-6. FENO was also measured. Though the pre-dialysis FENO levels were elevated in both groups; group B patients had significantly higher pre-dialysis FENO levels than group A patients (39.9 {+/-} 16.7 versus 31.8 {+/-} 10.3, P = 0.045). The post-dialysis FENO levels returned to normal in group A while the remaining were significantly higher in group B (30.3 {+/-} 10.3 versus 20.1 {+/-} 10.9, P = 0.003). Conclusions. Our study revealed that dialyzed patients with PH had a significantly higher level of airway FENO as well as serum levels of acute phase reactive protein and cytokines, including IL-1{beta}, TNF-{alpha} and IL-6. A chronic inflammation might play an important role in the pathogenesis of PH in patients undergoing haemodialysis
2406
