Praziquantel and liposomized glucan-treatment modulated liver fibrogenesis and mastocytosis in mice infected withMesocestoides vogae(M. corti, Cestoda) tetrathyridia

Parasitology ◽  
2005 ◽  
Vol 132 (4) ◽  
pp. 581-594 ◽  
Author(s):  
G. HRČKOVA ◽  
S. VELEBNÝ ◽  
Z. DAXNEROVÁ ◽  
P. SOLÁR
Keyword(s):  
Cell Proliferation ◽  
Mast Cell ◽  
Inverse Correlation ◽  
Liver Parenchyma ◽  
Dependent Manner ◽  
Proliferative Capacity ◽  
Intensity Of Infection ◽  
Direct Role ◽  
Cell Counts ◽  
The Impact

β–glucans are immunomodulators able to activate innate immunity and to potentiate acquired immune reactions. We investigated the impact of co-administration of liposomized β-glucan on the larvicidal effect of the anthelmintic praziquantel (PZQ) in the livers and peritoneal cavities in mice infected withMesocestoides vogae(M. corti). Also, within 2 weeks following therapy (up to day 29 p.i.) we examined collagen synthesis in the livers of mice by means of biochemical determination of hydroxyprolin concentration, total mast cell counts and cell proliferative capacity using immunohistochemical and radiometrical methods. After co-administration of liposomized glucan (LG) and PZQ efficacy (%) was significantly higher than after treatment with either compond alone, particularly in the peritoneal cavity compared to the liver. In comparison with the control, more intense collagenesis was found in the B-liver parts (high intensity of infection) and lowering of collagen content in the A-parts (very weak infection). This effect was strongest after LG treatment and co-administration of PZQ abolished the pro-fibrotic effect of LG. In all groups, mast cell counts were higher in the B-liver parts than in the A-parts and the dynamics of mastocytosis was profoundly modulated following therapy. Whereas the effect of PZQ was only moderate, early and very strong onset was seen after LG treatment. Administration of PZQ supressed LG induced-elevation of mast cells counts in both liver parts. Using DNA S-phase markers (BrdU and3H-thymidine) the proliferative capacity was shown to be associated with several kinds of liver cells. Therapy significantly stimulated [3H]-thymidine incorporation (cell proliferation) only in the A-parts over that in control, the most after LG administration. In summary (i) the anthelmintic effect of PZQ could be enhanced after simultaneous administration of the immunomodulator β-glucan entrapped in a liposomal carrier, (ii) intense mastocytosis seen after treatment with LG seems to have a direct role in the glucan′s pro-fibrotic activity and can be abolished after co-administration of PZQ in a time-dependent manner, (iii) the pattern of cell proliferation indicates that in the case of PZQ treatment, the reparative processes of liver parenchyma are enhanced in an inverse correlation with the intensity of infection.

PI3-Kinase Inhibition Decreases the Proliferation of ALL Cells, Potentiates mTOR Inhibition, and Abrogates Growth Factor-Mediated Reversal of mTOR Inhibition.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1383-1383
Author(s):  
Jonathan Fish ◽  
Jessica Hulitt ◽  
Marlo Bruno ◽  
Stephan A. Grupp ◽  
Valerie I. Brown
Keyword(s):  
Signal Transduction ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Cell Lines ◽  
Low Dose ◽  
Great Promise ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Mtor Inhibition ◽  
The Impact

Abstract Biologically targeted cancer agents, including signal transduction inhibitors, have shown great promise in treating hematologic malignancies. However, used as single agents, these drugs may not be curative secondary to innate or acquired cellular resistance. Thus, acute lymphoblastic leukemia (ALL) and other cancer cells may become resistant to rapamycin, an mTOR inhibitor (MTI), following extended exposure to the drug. A strategy to overcome such resistance is to combine targeted agents, and thereby inhibit multiple targets simultaneously. Previously, we have shown activity of MTI in models of both human and murine ALL. In mouse models, treatment of ALL with MTI prolongs survival but may not cure disease. IL-7, a lymphoid growth factor important in the regulation of progenitor B cell development and proliferation, can reverse the inhibitory effects of MTI on human and murine pre-B ALL cells. We wished to further explore the mechanisms by which IL-7-mediated signaling protects ALL cells from the inhibitory effects of MTI, through the investigation of modulators of growth factor signaling in ALL. Thus, we have evaluated the impact of LY294002, an inhibitor of phosphatidyl inositol-3 kinase (PI3K). PI3K is a critical signaling molecule in cell survival and proliferation, with one of its central roles being signal transduction from growth factor receptors to the activation of AKT (an upstream regulator of mTOR). PI3K/AKT pathway over-activation has been implicated in many different cancers. Treatment of ALL cell lines with the PI3K inhibitor LY294002 markedly decreased cell proliferation in a dose-dependent manner. More importantly, the inhibitory effects of LY294002 were additive or synergistic with the inhibitory effects of MTI, and prevented the ability of IL-7 to reverse the inhibitory effects of rapamycin. Treatment of pre-B ALL cell lines with 2.5 μM LY294002 resulted in decreased proliferation to 20–45% of baseline as compared to untreated cells, whereas treatment with a higher dose (5 μM) reduced cell proliferation to 10–20%. Combinations of LY294002 and rapamycin, even at low doses, inhibited cell proliferation to a greater degree than each drug individually. Co-treatment with 2.5 μM LY294002 and low dose rapamycin (1 ng/ml) resulted in profound inhibition of proliferation to <=5%, compared to 20–30% with rapamycin alone. Furthermore, co-treatment with low-dose LY294002 and low-dose rapamycin resulted in greater inhibition than even higher doses of each of these agents individually. While the addition of IL-7 (1 U/ml) to rapamycin-treated cells resulted in the reversal of rapamycin-mediated cell inhibition, the further addition of 2.5 μM LY294002 significantly antagonized this growth factor rescue of MTI-treated ALL cells. The blockade by LY294002 of the IL-7 effect was most apparent in ALL cell lines that were IL-7 dependent, with cell proliferation reduced to <20%. However, the effects were still significant in IL-7 independent cell lines, with proliferation reduced to 20–60%. Similar results were seen using human ALL cell lines. These data suggest that the PI3K signaling pathway serves as a potential rescue pathway from mTOR inhibition, mediating the ability of growth factors to rescue cells from rapamycin;PI3K itself is a therapeutic target for ALL; andcombination therapy with MTI and PI3K inhibitors may be more active than either agent alone.

scholarly journals Interleukin-17F Has Anti-Tumor Effects in Oral Tongue Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 650 ◽  
Author(s):  
Rabeia Almahmoudi ◽  
Abdelhakim Salem ◽  
Sakhr Murshid ◽  
Mauricio Rocha Dourado ◽  
Ehsanul Hoque Apu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tongue Cancer ◽  
Tube Formation ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
Oral Tongue ◽  
Tumor Spheroids ◽  
Regulatory Pathways ◽  
The Impact ◽  
Interleukin 17F

We recently showed that extracellular interleukin-17F (IL-17F) correlates with better disease-specific survival in oral tongue squamous cell carcinoma (OTSCC) patients. However, the underlying mechanisms of such effect remain obscure. Here, we used qRT-PCR to assess the expression of IL-17F and its receptors (IL-17RA and IL-17RC) in two OTSCC cell lines (HSC-3 and SCC-25) and in normal human oral keratinocytes (HOKs). IL-17F effects on cancer cell proliferation, migration, and invasion were studied using a live-imaging IncuCyte system, and a Caspase-3/7 reagent was used for testing apoptosis. 3D tumor spheroids were utilized to assess the impact of IL-17F on invasion with or without cancer-associated fibroblasts (CAFs). Tube-formation assays were used to examine the effects of IL-17F on angiogenesis using human umbilical vein endothelial cells (HUVEC). OTSCC cells express low levels of IL-17F, IL-17RA, and IL-17RC mRNA compared with HOKs. IL-17F inhibited cell proliferation and random migration of highly invasive HSC-3 cells. CAFs promoted OTSCC invasion in tumor spheroids, whereas IL-17F eliminated such effect. IL-17F suppressed HUVEC tube formation in a dose-dependent manner. Collectively, we suggest that IL-17F counteracts the pro-tumorigenic activity in OTSCC. Due to its downregulation in tumor cells and inhibitory activity in in vitro cancer models, targeting IL-17F or its regulatory pathways could lead to promising immunotherapeutic strategies against OTSCC.

scholarly journals Consequences of early postnatal lipopolysaccharide exposure on developing lungs in mice

2019 ◽  
Vol 316 (1) ◽  
pp. L229-L244 ◽  
Author(s):  
Amrit Kumar Shrestha ◽  
Matthew L. Bettini ◽  
Renuka T. Menon ◽  
Vashisht Y. N. Gopal ◽  
Shixia Huang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Development ◽  
Dependent Manner ◽  
T Regulatory Cell ◽  
Lung Macrophage ◽  
Flow Cytometric ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Apoptosis ◽  
Proliferation And Differentiation ◽  
The Impact

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infants that is characterized by interrupted lung development. Postnatal sepsis causes BPD, yet the contributory mechanisms are unclear. To address this gap, studies have used lipopolysaccharide (LPS) during the alveolar phase of lung development. However, the lungs of infants who develop BPD are still in the saccular phase of development, and the effects of LPS during this phase are poorly characterized. We hypothesized that chronic LPS exposure during the saccular phase disrupts lung development by mechanisms that promote inflammation and prevent optimal lung development and repair. Wild-type C57BL6J mice were intraperitoneally administered 3, 6, or 10 mg/kg of LPS or a vehicle once daily on postnatal days (PNDs) 3–5. The lungs were collected for proteomic and genomic analyses and flow cytometric detection on PND6. The impact of LPS on lung development, cell proliferation, and apoptosis was determined on PND7. Finally, we determined differences in the LPS effects between the saccular and alveolar lungs. LPS decreased the survival and growth rate and lung development in a dose-dependent manner. These effects were associated with a decreased expression of proteins regulating cell proliferation and differentiation and increased expression of those mediating inflammation. While the lung macrophage population of LPS-treated mice increased, the T-regulatory cell population decreased. Furthermore, LPS-induced inflammatory and apoptotic response and interruption of cell proliferation and alveolarization was greater in alveolar than in saccular lungs. Collectively, the data support our hypothesis and reveal several potential therapeutic targets for sepsis-mediated BPD in infants.

scholarly journals Impact of Nano-Crystalline Diamond Enhanced Hydrophilicity on Cell Proliferation on Machined and SLA Titanium Surfaces: An In-Vivo Study in Rodents

Nanomaterials ◽  
2018 ◽  
Vol 8 (7) ◽  
pp. 524 ◽  
Author(s):  
Robert Stigler ◽  
Kathrin Becker ◽  
Michela Bruschi ◽  
Doris Steinmüller-Nethl ◽  
Robert Gassner
Keyword(s):  
Cell Proliferation ◽  
Inflammatory Responses ◽  
Region Of Interest ◽  
Tissue Integration ◽  
Hydrophilic Surfaces ◽  
Cell Counts ◽  
Nano Crystalline ◽  
Healing Phase ◽  
The Impact

By coating surfaces with nano-crystalline diamond (NCD) particles, hydrophilicity can be altered via sidechain modifications without affecting surface texture. The present study aimed to assess the impact of NCD hydrophilicity on machined and rough SLA titanium discs on soft tissue integration, using a rodent model simulating submerged healing. Four different titanium discs (machined titanium = M Titanium, NCD-coated hydrophilic machined titanium = M-O-NCD, sand blasted acid etched (SLA Titanium) titanium, and hydrophilic NCD-coated SLA titanium = SLA O-NCD) were inserted in subdermal pockets of 12 Wistar rats. After one and four weeks of healing, the animals were sacrificed. Biopsies were embedded in methyl methacrylate (MMA), and processed for histology. The number of cells located within a region of interest (ROI) of 10 µm around the discs were counted and compared statistically. Signs of inflammation were evaluated descriptively employing immunohistochemistry. At one week, M-O-NCD coated titanium discs showed significantly higher amounts of cells compared to M Titanium, SLA Titanium, and SLA-O-NCD (p < 0.001). At four weeks, significant higher cell counts were noted at SLA-O-NCD surfaces (p < 0.01). Immunohistochemistry revealed decreased inflammatory responses at hydrophilic surfaces. Within the limits of an animal study, M-O-NCD surfaces seem to stimulate cell proliferation in the initial healing phase, whereas SLA-O-NCD surfaces appeared advantageous afterwards.

scholarly journals HMGA1B/2 transcriptionally activated-POU1F1 facilitates gastric carcinoma metastasis via CXCL12/CXCR4 axis-mediated macrophage polarization

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Cheng Tang ◽  
Xiong Lei ◽  
Lingqiang Xiong ◽  
Zhigao Hu ◽  
Bo Tang
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Poor Prognosis ◽  
Macrophage Polarization ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
The Impact ◽  
Cxcr4 Axis

AbstractTumor-associated macrophages (TAMs) in the tumor microenvironment contribute to poor prognosis in gastric cancer (GC). However, the underlying mechanism by which TAMs promote GC progression and metastasis remains elusive. Expression of POU1F1 was detected in 60 matched GC-normal tissue pairs using qRT-PCR and immunohistochemistry (IHC) analysis. The correlation between POU1F1 and the clinical-pathological factors of GC patients were further assessed. Cell proliferation was monitored by CCK-8, colony formation, and 5-Ethynyl-2’-deoxyuridine (EdU) incorporation assays. Cell migration and invasion were assessed by transwell assays. The impact on angiogenesis was evaluated by tube formation assay. Xenograft model was generated to investigate the role of POU1F1 on tumor growth and lung metastasis in vivo. GST pull-down and Co-immunoprecipitation (Co-IP) were used to study the interaction between HMGA1B/2 and POU1F1. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were performed to investigate the transcriptional regulation of POU1F1. Flow cytometry was performed to detect the surface expression of macrophage markers. Upregulated POU1F1 observed both in GC tissues and cell lines was positively correlated with poor prognosis. Knockdown of POU1F1 inhibited cell proliferation, migration, invasion, and angiogenesis in vitro, and suppressed tumor growth in vivo. HMGA1B/2 transcriptionally activated-POU1F1. POU1F1 promoted GC progression via regulating macrophage proliferation, migration, polarization, and angiogenesis in a CXCL12/CXCR4-dependent manner. POU1F1 also promoted GC metastasis in lung by modulating macrophage polarization through CXCL12/CXCR4 axis in vivo. HMGA1B/2-upregulated POU1F1 promoted GC metastasis via regulating macrophage polarization in a CXCL12/CXCR4-dependent manner.

scholarly journals Impact of Different Layer Housing Systems on Eggshell Cuticle Quality and Salmonella Adherence in Table Eggs

Foods ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2559
Author(s):  
Garima Kulshreshtha ◽  
Cristina Benavides-Reyes ◽  
Alejandro B. Rodriguez-Navarro ◽  
Ty Diep ◽  
Maxwell T. Hincke
Keyword(s):  
Salmonella Enteritidis ◽  
Bacterial Load ◽  
Inverse Correlation ◽  
Production Chain ◽  
Free Range ◽  
Housing Systems ◽  
Cell Counts ◽  
Food Borne ◽  
Key Factor ◽  
The Impact

The bacterial load on the eggshell surface is a key factor in predicting the bacterial penetration and contamination of the egg interior. The eggshell cuticle is the first line of defense against vertical penetration by microbial food-borne pathogens such as Salmonella Enteritidis. Egg producers are increasingly introducing alternative caging systems into their production chain as animal welfare concerns become of greater relevance to today’s consumer. Stress that is introduced by hen aggression and modified nesting behavior in furnished cages can alter the physiology of egg formation and affect the cuticle deposition/quality. The goal of this study was to determine the impact of caging systems (conventional, enriched, free-run, and free-range), on eggshell cuticle parameters and the eggshell bacterial load. The cuticle plug thickness and pore length were higher in the free-range eggs as compared to conventional eggs. The eggshells from alternative caging (enriched and free-range) had a higher total cuticle as compared to conventional cages. A reduction in bacterial cell counts was observed on eggshells that were obtained from free-range eggs as compared to the enriched systems. An inverse correlation between the contact angle and Salmonella adherence was observed. These results indicate that the housing systems of layer hens can modify the cuticle quality and thereby impact bacterial adherence and food safety.

Lenalidomide Inhibits Proliferation Of Chronic Lymphocytic Leukemia Cells Via a Cereblon/p21WAF1/Cip1-Dependent Mechanism

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4139-4139
Author(s):  
Jessie-Farah Fecteau ◽  
Laura G Corral ◽  
Diahnn Futalan ◽  
Svetlana Gaidarova ◽  
Ila Bharati ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Direct Effects ◽  
P53 Expression ◽  
The Impact

Abstract Lenalidomide has demonstrated clinical activity in patients with chronic lymphocytic leukemia (CLL). However, its mechanism of action is not fully elucidated. Lenalidomide is not directly cytotoxic to CLL cells in vitro, but can alter the capacity of CLL cells to interact with cells in its microenvironment. This has led to the speculation that its primary activity is indirect, although direct effects on CLL cells have been observed. In this study, we examined the direct effects of lenalidomide on CLL cells. We performed transcriptome analysis on primary CLL cell samples exposed to lenalidomide in vitro for 6 and 24hrs and found a significant upregulation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21), which was also confirmed at the protein level. Since p21 can inhibit the progression of cells from G1 to S phase of the cell cycle, this suggests that lenalidomide may render CLL cells less responsive to proliferation stimuli from the microenvironment. To test this hypothesis, we induced CLL cells to proliferate in vitro using accessory cells made to express CD154 and media containing human interleukin (IL)-4 and IL-10. We monitored for proliferation of CLL cells cultured with and without lenalidomide using carboxyfluorescein succinimidyl ester (CFSE). In repeated experiments, we observed that lenalidomide consistently and significantly inhibited the proliferation of CLL cells in a dose-dependent manner, at concentrations that are achieved in treated patients. Evaluation of the DNA content of CLL cells using propidium iodide and flow cytometry also revealed that lenalidomide significantly decreased the fraction of CLL cells in S and in G2/M phases of the cell cycle and concomitantly increased the percentage of CLL cells in G0/G1 phases. This block in cell proliferation also was accompanied by the upregulation of p21, and the extent of which correlated with the degree to which leukemia-cell proliferation was inhibited. In additional studies, we used small interfering RNA (siRNA) to silence p21 in CLL cells and measured the effect of silencing on cell proliferation in the presence of lenalidomide. We observed that the ability of lenalidomide to inhibit CLL cell proliferation was significantly reduced in CLL cells silenced for p21 compared to CLL cells transfected with control siRNA, supporting a role for p21 expression in mediating the proliferation block induced by lenalidomide. We did not however observe the induction of p53 expression following lenalidomide exposure, suggesting that lenalidomide may upregulate p21 via a p53-independent mechanism. Cereblon (CRBN) is the only known molecular target of lenalidomide. To functionally interrogate the potential role of CRBN in lenalidomide activity on CLL cells, we used siRNA to silence CRBN in primary CLL cells and monitored the impact of silencing on the ability of lenalidomide to upregulate p21 and to inhibit proliferation. We observed lower levels of p21 expression in CRBN-silenced cells exposed to lenalidomide compared to cells transfected with non-specific siRNA, suggesting that CRBN may play a role in p21 upregulation. Furthermore, we observed that CRBN silencing significantly abrogated the anti-proliferative effect of lenalidomide. These results indicate the involvement of CRBN in the anti-proliferative activity of lenalidomide, which is mediated, at least in part, by p21. This study demonstrates that lenalidomide inhibits the proliferation of CLL cells in a CRBN/p21-dependent manner. This direct effect of lenalidomide on CLL cells may account in part for the highly infrequent observation of disease progression in patients receiving long-term maintenance therapy with this agent (Blood, 2013, PMID:23801633). Disclosures: Fecteau: Celgene: Research Funding. Corral:Celgene: Employment. Gaidarova:Celgene: Employment. Cathers:Celgene: Employment. Lopez-Girona:Celgene: Employment. Messmer:Celgene: Research Funding. Kipps:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals Developmentally distinct in vivo effects of FSH on proliferation and apoptosis during testis maturation

2005 ◽  
Vol 186 (3) ◽  
pp. 429-446 ◽  
Author(s):  
Sarah J Meachem ◽  
Saleela M Ruwanpura ◽  
Jessica Ziolkowski ◽  
Jacquelyn M Ague ◽  
Michael K Skinner ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Germ Cell ◽  
Sertoli Cell ◽  
Germ Cells ◽  
Cathepsin L ◽  
Passive Immunisation ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
The Impact

The critical influence of follicle stimulating hormone (FSH) on male fertility relates both to its impact on Sertoli cell proliferation in perinatal life and to its influence on the synthesis of Sertoli cell-derived products essential for germ cell survival and function in the developing adult testis. The nature and timing of this shift of germ cells to their reliance on specific Sertoli cell-derived products are not defined. Based on existing data, it is apparent that the dominant function of FSH shifts between 9 and 18 day postpartum (dpp) during the first wave of spermatogenesis from driving Sertoli cell proliferation to support germ cells. To enable comprehensive analysis of the impact of acute in vivo FSH suppression on Sertoli and germ cell development, FSH was selectively suppressed in Sprague–Dawley rats by passive immunisation for 2 days and/or 4 days prior to testis collection at 3, 9 and 18 dpp. The 3 dpp samples displayed no measurable changes, while 4 days of FSH suppression decreased Sertoli cell proliferation and numbers in 9 dpp, but not 18 dpp, animals. In contrast, germ cell numbers were unaffected at 9 dpp but decreased at 18 dpp following FSH suppression, with a corresponding increase in germ cell apoptosis measured at 18 dpp. Sixty transcripts were measured as changed at 18 dpp in response to 4 days of FSH suppression, as assessed using Affymetrix microarrays. Some of these are known as Sertoli cell-derived FSH-responsive genes (e.g. StAR, cathepsin L, insulin-like growth factor binding protein-3), while others encode proteins involved in cell cycle and survival regulation (e.g. cyclin D1, scavenger receptor class B 1). These data demonstrate that FSH differentially affects Sertoli and germ cells in an age-dependent manner in vivo, promoting Sertoli cell mitosis at day 9, and supporting germ cell viability at day 18. This model has enabled identification of candidate genes that contribute to the FSH-mediated pathway by which Sertoli cells support germ cells.

scholarly journals Induction by a Lactic Acid Bacterium of a Population of CD4+ T Cells with Low Proliferative Capacity That Produce Transforming Growth Factor β and Interleukin-10

2001 ◽  
Vol 8 (4) ◽  
pp. 695-701 ◽  
Author(s):  
Thierry von der Weid ◽  
Christine Bulliard ◽  
Eduardo J. Schiffrin
Keyword(s):  
T Cells ◽  
Lactic Acid ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Proliferative Capacity ◽  
Murine Splenocytes ◽  
The Impact ◽  
Dose Dependent

ABSTRACT We investigated whether certain strains of lactic acid bacteria (LAB) could antagonize specific T-helper functions in vitro and thus have the potential to prevent inflammatory intestinal immunopathologies. All strains tested induced various levels of both interleukin-12 (IL-12) and IL-10 in murine splenocytes. In particular,Lactobacillus paracasei (strain NCC2461) induced the highest levels of these cytokines. Since IL-12 and IL-10 have the potential to induce and suppress Th1 functions, respectively, we addressed the impact of this bacterium on the outcome of CD4+ T-cell differentiation. For this purpose, bacteria were added to mixed lymphocyte cultures where CD4+ T-cells from naive BALB/c mice were stimulated weekly in the presence of irradiated allogeneic splenocytes. In these cultures, L. paracasei NCC2461 strongly inhibited the proliferative activity of CD4+ T cells in a dose-dependent fashion. This was accompanied by a marked decrease of both Th1 and Th2 effector cytokines, including gamma interferon, IL-4, and IL-5. In contrast, IL-10 was maintained and transforming growth factor β (TGF-β) was markedly induced in a dose-dependent manner. The bacteria were not cytotoxic, because cell viability was not affected after two rounds of stimulation. Thus, unidentified bacterial components from L. paracasei NCC2461 induced the development of a population of CD4+ T cells with low proliferative capacity that produced TGF-β and IL-10, reminiscent of previously described subsets of regulatory cells implicated in oral tolerance and gut homeostasis.

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