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IL-7
Terms modified by IL-7 Selected AbstractsGene expression of colony-stimulating factors and stem cell factor after myocardial infarction in the mouseACTA PHYSIOLOGICA, Issue 3 2002P. R. WOLDBAEK ABSTRACT Recent studies have suggested that cytokines such as macrophage colony-stimulating factor (M-CSF) might be involved in the pathogenesis of ischaemic heart disease. Macrophage colony-stimulating factor, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF), stem cell factor (SCF), interleukin-3 (IL-3) and interleukin-7 (IL-7) are potent cytokines belonging to the same structual class that may affect function, growth and apoptosis both in the heart and other organs. The aims of the present study were to characterize a post-infarction model in the mouse and to examine mRNA expression of M-CSF, GM-CSF, SCF, IL-3 and IL-7 during the development of heart failure. Myocardial infarction (MI) was induced in mice by ligation of the left coronary artery. Average infarct size was 40% and the mice developed myocardial hypertrophy and pulmonary oedema. Ribonuclease (RNAase) protection assays showed abundant cardiac expression of M-CSF and SCF. After MI, we measured down-regulation of cytokine mRNA expression in the heart (M-CSF, SCF), lung (M-CSF), liver (M-CSF) and spleen (M-CSF) compared with sham. Cardiac G-CSF, GM-CSF and IL-7 mRNAs were not detected. In conclusion, abundant cardiac gene expression of M-CSF and SCF was found. In our mouse model of MI, M-CSF and SCF were down-regulated in the heart and several other organs suggesting specific roles for these cytokines during development of ischaemic heart failure. [source] Interleukin-4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010Angela M. Crawley Abstract Signaling via the IL-7 receptor complex (IL-7R,/CD127 and IL-2R,/CD132) is required for T-cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL-2R,-sharing (,C) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL-2, IL-4, IL-7, IL-15) and in humans (IL-2, IL-7), suggesting a common function. IL-4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL-4 in regulating CD127 expression and IL-7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL-4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane-bound CD127 mRNA expression. Pre-treatment of thymocytes or CD8+ T cells with IL-4 inhibited IL-7-mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL-4 is a potential contributor to impaired CD8+ T-cell function in some anti-viral and anti-tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL-7 activity is impaired and IL-4 concentrations are elevated. [source] Splenic stromal cells mediate IL-7 independent adult lymphoid tissue inducer cell survivalEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2010Tie Zheng Hou Abstract Lymphoid tissue inducer cells (LTi) play an important role in the development of lymphoid tissue in embryos. Adult CD4+CD3, LTi-like cells present a similar phenotype and gene expression to their embryonic counterpart and have important roles in CD4+ T-cell memory and lymphoid tissue recovery following viral infection. However, adult LTi-like cells are heterogeneous populations and the factors that regulate their survival and accumulation within secondary lymphoid organs remain unclear, in particular whether the T-zone stroma is involved. Here we report the identification and characterization of a distinct subset of podoplanin+ murine splenic stromal cells that support adult LTi-like cell survival. We have identified and isolated CD45,podoplanin+ stromal cell populations which have a similar but distinct phenotype to T-zone reticular cells in LN. CD45,podoplanin+ fibroblast-like cells mediate LTi-like cell survival in vitro; surprisingly this was not dependent upon IL-7 as revealed through blocking Ab experiments and studies using LTi-like cells unable to respond to , chain cytokines. Our findings show that adult LTi-like cells require extrinsic signals from podoplanin+ splenic stromal cells to survive and suggest that IL-7 is not necessary to mediate their survival in the adult spleen. [source] IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ memory T cells in chronic colitisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2009Takayuki Tomita Abstract We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4+CD45RBhigh T cells into IL-7,/,×RAG-1,/, mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7,/,×RAG-1,/, mice parabiosed with colitic CD4+CD45RBhigh T-cell-transferred RAG-1,/, mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4+ T cells by surgically separating these parabionts. Surprisingly, the separated IL-7,/,×RAG-1,/, mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7,/,×RAG-1,/, partners. CD4+ T cells isolated from the separated RAG-1,/, or IL-7,/,×RAG-1,/, mice were then transferred into new RAG-1,/, or IL-7,/,×RAG-1,/, mice. Regardless of the source of donor cells, RAG-1,/, recipients developed colitis, whereas IL-7,/,×RAG-1,/, recipients did not. Collectively, these results demonstrate that IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ T cells rather than the maintenance of those cells in established colitic mice. They also provide a basis for the timing of IL-7/IL-7R blockade for the treatment of inflammatory bowel diseases. [source] Progressive CD127 down-regulation correlates with increased apoptosis of CD8 T cells during chronic HIV-1 infectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2009Shu-Ye Zhang Abstract Chronic HIV-1 infection can induce a significant decrease in CD127 expression on CD8 T cells, but the underlying mechanisms and immunological consequences are unclear. In this study, we investigated CD127 expression on CD8 T cells from a total of 51 HIV-1-infected subjects and 16 healthy individuals and analyzed the association between CD127 expression and CD8 T-cell apoptosis in these HIV-1-infected subjects. We found that CD127 expression on total CD8 T cells was significantly down-regulated, which was correlated with the increased CD8 T-cell apoptosis and disease progression of chronic HIV-1 infection. The in vitro addition of IL-7 efficiently rescued the spontaneous apoptosis of CD8 T cells from HIV-1-infected individuals. IL-7 stimulation also transiently down-regulated CD127 expression, whereas some of the CD127, CD8 T cells regained CD127 expression soon after IL-7 was retracted from the incubation medium. Thus, IL-7 stimulation reduced apoptosis of both CD127+ and CD127,CD8 T cells to some degree. These data indicate that CD127 loss might impair IL-7 signaling and increase CD8 T-cell apoptosis during HIV-1 infection. This study, therefore, will extend the notion that IL-7 could be a good candidate for immunotherapy in HIV-1-infected patients. [source] Staying alive , naïve CD4+ T cell homeostasisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2007Jared F. Purton Abstract The immune system must maintain a broad repertoire of naïve T cells in order to respond to the diverse range of pathogens that it will encounter over the course of a lifetime. Although it is known that contact with IL-7 is crucial for the survival of naïve T cells, the precise intracellular signals that mediate its effects remain obscure. An article in this issue of the European Journal of Immunology has found that IL-7 requires the coordinated action of multiple pathways to maintain naïve CD4+ T cells. See accompanying article: http://dx.doi.org/10.1002/eji.200737234 [source] The role of Notch and IL-7 signaling in early thymocyte proliferation and differentiationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2005Gina Balciunaite Abstract We have analyzed the roles of Notch and IL-7 signaling in the proliferation and differentiation of mouse progenitor thymocyte subpopulations cultured on Notch delta-like-1 ligand-expressing OP9 stromal cells. Using bulk and limiting dilution cultures, we show that DN1 and DN2 cells require both Notch and IL-7 signaling for efficient proliferation and differentiation into cytoplasmic TCR, and surface TCR,/, and TCR,/, expressing T cells. Selection for cytoplasmic TCR,-positive cells is dependent on preT, expression. Both ,/, and ,/, TCR expressing T cells arising in culture can be efficiently stimulated by anti-CD3 cross-linking, suggesting that they might be functional. The differentiation of adult, but not fetal, DN1 and DN2 thymocytes into CD4 and/or CD8 expressing cells is inhibited by IL-7. Finally, efficient proliferation and differentiation of DN3 cells requires Notch signaling and preTCR expression, but is independent of IL-7. [source] Impaired B-1 and B-2 B,cell development and atypical splenic B,cell structures in IL-7 receptor-deficient miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004Lena Erlandsson Abstract The cytokine IL-7 and its receptor are essential for normal B and T,lymphopoiesis. We have analyzed the role of this receptor in B,cell development throughout ontogeny in IL-7 receptor,,-deficient mice. We demonstrate that the IL-7 receptor becomes progressively more important with age. B,lymphopoiesis takes place, albeit at reduced levels, in fetal liver and bone marrow of young mice, but is arrested in adults. The outcome is a severe reduction, from an early age, in peripheral B,cells including follicular, marginal zone and B-1 B,cells as well as perturbed splenic B,cell structures, which are restored after adoptive transfer of normal spleen cells. We conclude that in the absence of the IL-7 receptor, the residual B,lymphopoiesis occurring early in ontogeny must be facilitated by another component, whereas the IL-7 receptor is the key factor in adults. The impairment of marginal zone and B-1 B,cells in IL-7 receptor- but not IL-7-deficient mice suggests non-redundant functions for the IL-7 receptor ligands, IL-7 and thymic stromal lymphopoietin. [source] Impaired lymphocyte development and function in Clast5/Stra13/DEC1-transgenic miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2004Mika Seimiya Abstract Clast5/Stra13/DEC1 is a member of the helix-loop-helix family of transcriptional repressors. We have previously shown that Clast5 is rapidly down-regulated upon B,cell activation and its overexpression inhibits cell cycle progression in B,lymphoma cells. In the present study, we show that Clast5 expression is developmentally regulated during B,cell differentiation, being expressed at theprogenitor B,cells, down-regulated at the precursor B,cells, elevated in immature and mature resting B,lymphocytes, and down-regulated again in germinal center B,ells. To investigate the function of Clast5 in regulating lymphocyte development, we have generated transgenic mice expressing Clast5 in B- and T-lineage cells (Clast5-Tg). Clast5-Tg mice grew and bred normally but their spleen and thymus cellularity was reduced compared with control littermates. The development of B,cells in the bone marrow and T,cells in the thymus was impaired, with the expansion of progenitor B and T,cells most strongly affected. The frequency of IL-7-responsive cells in the bone marrow of Clast5-Tg mice was reduced by >80% and their proliferative response to IL-7 was also compromised. Mature B,cells from Clast5-Tg mice were hyporesponsive to antigen receptor cross-linking and exhibited mild reduction in the proliferative response to CD40 ligation or lipopolysaccharide stimulation. Moreover, thedevelopment of germinal center B,cells and antibody production against a T-dependent antigen were reduced in Clast5-Tg mice. These results reveal a critical role for Clast5/Stra13/DEC1 in negatively regulating lymphocyte development and function in vivo. [source] IL-7 inhibits dexamethasone-induced apoptosis via Akt/PKB in mature, peripheral T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2003Hadassah Sade Abstract We have investigated the mechanism of IL-7-mediated inhibition of dexamethasone-induced apoptosis in T cells. Broad-spectrum caspase inhibitors block dexamethasone-triggered nuclear fragmentation, but not the loss of mitochondrial transmembrane potential or membrane integrity in CD3+ mature T cells isolated from adult mouse spleens. IL-7 blocked dexamethasone-induced apoptosis and the processing of caspase-3 and caspase-7. IL-7 also blocked dexamethasone-triggered dephosphorylation of the serine-threonine kinase Akt/PKB and its target, the Ser136 residue in Bad. The loss of anti-apoptotic proteins Bcl-xL and inhibitor of apoptosis protein-2 (IAP-2) was also blocked by IL-7. The protective effect was attenuated by pharmacological inhibitors of phosphatidylinositol-3 kinase (PI3K) with one exception: inhibition of PI3K did not abrogate Bcl-xL expression in the presence of IL-7. The anti-apoptotic role of Akt suggested by these experiments was tested by overexpression of constitutively active Akt, which blocked dexamethasone-induced apoptosis and elevated IAP-2 but not Bcl-xL levels in a mature T cell line. Thus, IL-7 regulates IAP-2 expression and inhibits dexamethasone-induced apoptosis by activating Akt via PI3K-dependent signaling, but regulates Bcl-xL expression via a PI3K-independent pathway in mature T cells. [source] Developing and maintaining protective CD8+ memory T cellsIMMUNOLOGICAL REVIEWS, Issue 1 2006Matthew A. Williams Summary:, A critical aim of vaccine-related research is to identify the mechanisms by which memory T cells are formed and maintained over long periods of time. In recent years, we have designed experiments aimed at addressing two key questions: (i) what are the factors that maintain functionally responsive CD8+ memory cells over long periods of time, and (ii) what are the signals during the early stages of infection that drive the differentiation of long-lived CD8+ memory T cells? We have identified a role for CD4+ T cells in the generation of CD8+ T-cell-mediated protection from secondary challenge. While CD4+ T cells appear to play a role in the programme of CD8 memory, we find that they are also required for the long-term maintenance of CD8+ memory T-cell numbers and function. This property is independent of CD40,CD40L interactions, and we propose a role for CD4+ T cells in maintaining the ability of CD8+ memory T cells to respond to interleukin-7 (IL-7) and IL-15. By manipulating both the time course of infection and the timing of antigen presentation to newly recruited CD8+ T cells, we also demonstrate that the programming of effector and memory potential are at least partially distinct processes. [source] Interleukin-7 promotes the survival of human CD4+ effector/memory T cells by up-regulating Bcl-2 proteins and activating the JAK/STAT signalling pathwayIMMUNOLOGY, Issue 3 2010Nizar Chetoui Summary Interleukin-7 (IL-7) is a crucial cytokine involved in T-cell survival and development but its signalling in human T cells, particularly in effector/memory T cells, is poorly documented. In this study, we found that IL-7 protects human CD4+ effector/memory T cells from apoptosis induced upon the absence of stimulation and cytokines. We show that IL-7 up-regulates not only Bcl-2 but also Bcl-xL and Mcl-1 as well. Interleukin-7-induced activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is sufficient for cell survival and up-regulation of Bcl-2 proteins. In contrast to previous studies with naive T cells, we found that IL-7 is a weak activator of the phosphatidylinositol 3 kinase (PI3K)/AKT (also referred as protein kinase B) pathway and IL-7-mediated cell survival occurs independently from the PI3K/AKT pathway as well as from activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Considering the contribution of both IL-7 and CD4+ effector/memory T cells to the pathogenesis of autoimmune diseases such as rheumatoid arthritis and colitis, our study suggests that IL-7 can contribute to these diseases by promoting cell survival. A further understanding of the mechanisms of IL-7 signalling in effector/memory T cells associated with autoimmune inflammatory diseases may lead to potential new therapeutic avenues. [source] Rapid and reliable generation of invariant natural killer T-cell lines in vitroIMMUNOLOGY, Issue 3 2009Asako Chiba Summary Several tools have proved useful in the study of invariant natural killer T (iNKT) cells, including CD1d-deficient mice, J,281-deficient mice, synthetic lipid antigens and antigen-loaded CD1d tetramers. However, the generation and examination of long-term primary murine iNKT cell lines in vitro has been challenging. Here, we show the rapid generation of iNKT cell lines from splenic iNKT cells of V,14 T-cell receptor (TCR) transgenic (Tg) mice. These purified iNKT cells were stimulated by bone marrow-derived dendritic cells (BMDCs) loaded with ,-galactosylceramide (,GalCer) and cultured with interleukin (IL)-2 and IL-7. iNKT cells proliferated dramatically, and the cell number exhibited a 100-fold increase within 2 weeks and a 105 -fold increase in 8 weeks after repeated stimulation with ,GalCer. The iNKT cell lines consisted of iNKT cells expressing V, chains including V,8.1/8.2, V,14, V,10, V,6 and V,7, and responded to stimulation with ,GalCer presented both by BMDCs and by plate-bound CD1d. In addition, the iNKT cell lines produced interferon (IFN)-, when activated by lipopolysaccharide (LPS) or CpG oligodeoxynucleotide (ODN)-stimulated BMDCs. Further, we show that iNKT cell lines produced cytokines in response to microbial antigens. In summary, high-yield iNKT cell lines were generated very rapidly and robustly expanded, and these iNKT cells responded to both TCR and cytokine stimulation in vitro. Given the desire to study primary iNKT cells for many purposes, these iNKT cell lines should provide an important tool for the study of iNKT cell subsets, antigen and TCR specificity, activation, inactivation and effector functions. [source] A tolerogenic peptide down-regulates mature B cells in bone marrow of lupus-afflicted mice by inhibition of interleukin-7, leading to apoptosisIMMUNOLOGY, Issue 2 2009Hava Ben-David Summary Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by T and B cells. It is characterized by a variety of autoantibodies and systemic clinical manifestations. A tolerogenic peptide, designated hCDR1, ameliorated the serological and clinical manifestations of SLE in both spontaneous and induced models of lupus. In the present study, we evaluated the status of mature B cells in the bone marrow (BM) of SLE-afflicted mice, and determined the effect of treatment with the tolerogenic peptide hCDR1 on these cells. We demonstrate herein that mature B cells of the BM of SLE-afflicted (New Zealand Black × New Zealand White)F1 mice were largely expanded, and that treatment with hCDR1 down-regulated this population. Moreover, treatment with hCDR1 inhibited the expression of the pathogenic cytokines [interferon-, and interleukin (IL)-10], whereas it up-regulated the expression of transforming growth factor-, in the BM. Treatment with hCDR1 up-regulated the rates of apoptosis of mature B cells. The latter was associated with inhibited expression of the survival Bcl-xL gene and of IL-7 by BM cells. Furthermore, the addition of recombinant IL-7 abrogated the suppressive effects of hCDR1 on Bcl-xL in the BM cells and resulted in elevated levels of apoptosis. Hence, the down-regulated production of IL-7 contributes to the hCDR1-mediated apoptosis of mature B cells in the BM of SLE-afflicted mice. [source] Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere lengthIMMUNOLOGY, Issue 2 2006Diana L. Wallace Summary Interleukin (IL)-7 and IL-15 are cytokines implicated in homeostatic control of the peripheral CD8 T-cell pool. We compared the effects of IL-7 and IL-15 on survival and proliferation of purified human CD8+ T-cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl-2 up-regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL-15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up-regulation of telomerase and the maintenance of telomere length. These data show that IL-7 and IL-15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset-dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T-cell pool. [source] Interleukin-4 supports interleukin-12-induced proliferation and interferon-, secretion in human activated lymphoblasts and T helper type 1 cellsIMMUNOLOGY, Issue 1 2006Martin A. Kriegel Summary Interleukin-12 (IL-12) and IL-4 are known to differentially promote T helper (Th) cell differentiation. While IL-12 induces interferon-, (IFN-,) production and maturation of Th1 cells, IL-4 is thought to antagonize IL-12 and to favour Th2 development. Here we studied the combined action of various concentrations of common ,-chain (,c -chain) cytokines, including IL-4 and the Th1 cytokine IL-12, in human activated lymphoblasts and Th1 cells. IL-4 and IL-7 potentiated IL-12-induced proliferation at every concentration tested (1,10 ng/ml) without increasing rescue from apoptosis, indicating that proliferation was directly affected by these cytokine combinations. With regards to cytokine secretion, IL-2 together with IL-12 initiated tumour necrosis factor-, synthesis, enhanced IFN-, production, and shedding of soluble IL-2 receptor , as expected. Importantly, combining IL-4 with IL-12 also enhanced IFN-, secretion in lymphoblasts and a Th1 cell line. Investigating signal transduction in lymphoblasts induced by these cytokines, we found that not only IL-2 but also IL-4 enhances signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation by IL-12. Tyrosine phosphorylations of janus kinase 2 (JAK-2), tyrosine kinase 2 (TYK2), extracellular signal-regulated kinase (ERK) and STAT4, STAT5 and STAT6 were not potentiated by combinations of these cytokines, suggesting specificity for increased STAT3 phosphorylation. In conclusion, two otherwise antagonizing cytokines co-operate in activated human lymphoblasts and Th1 cells, possibly via STAT3 as a converging signal. These data demonstrate that IL-4 can directly enhance human Th1 cell function independently of its known actions on antigen-presenting cells. These findings should be of importance for the design of cytokine-targeted therapies of human Th-cell-driven diseases. [source] Reduced numbers of IL-7 receptor (CD127) expressing immune cells and IL-7-signaling defects in peripheral blood from patients with breast cancerINTERNATIONAL JOURNAL OF CANCER, Issue 7 2007Nalini Kumar Vudattu Abstract Interleukin-7-receptor-signaling plays a pivotal role in T-cell development and maintenance of T-cell memory. We studied IL-7R, (CD127) expression in PBMCs obtained from patients with breast cancer and examined IL-7 receptor-mediated downstream effects defined by STAT5 phosphorylation (p-STAT5). Reduced numbers of IL-7R,-positive cells were identified in CD4+ T-cells as well as in a CD8+ T-cell subset defined by CD8,/, homodimer expression in patients with breast cancer. PBMCs obtained from healthy donors (n = 19) and from patients with breast cancer (n = 19) exhibited constitutive p-STAT5 expression in the range of 0,6.4% in CD4+ T-cells and 0,4% in CD8+ T-cells. Stimulation with recombinant human IL-7 for 15 min increased p-STAT5 expression up to 36,97% in CD4+T-cells and to 26,90% in CD8+T-cells obtained from healthy control donors (n = 19). In contrast, PBMCs obtained from 13/19 patients with breast cancer did not respond to IL-7 as defined by STAT5 phosphorylation, despite expression of IL-7R, on T-lymphocytes. T-cells were further characterized for IL- 2 and IFN-, production induced by PMA/Ionomycin. PBMCs from 9/19 patients with breast cancer showed decreased IL-2 and IFN-, production combined with IL-7-signaling defects; PBMCs from 4 patients with breast cancer exhibited deficient IL-7-signaling, yet intact cytokine production. Reduced numbers of IL-7R,-positive cells and nonresponsiveness to IL-7, defined by lack of STAT5 phosphorylation, characterizes the immunological profile in T-cells from patients with breast cancer. © 2007 Wiley-Liss, Inc. [source] Association between genetic polymorphisms in the human interleukin-7 receptor ,-chain and inhalation allergyINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2007Z. Shamim Summary Thymic stromal-derived lymphopoietin (TSLP) and interleukin-7 share a common receptor chain, IL-7R,. IL-7 is involved in T-cell homeostasis, and TSLP induces production of pro-allergic cytokines. The gene encoding the IL-7R, chain is polymorphic, and investigation of inhalation allergic patients compared with controls showed significant association with two alleles at position +1237 and +2087. [source] Increased expression of non-interleukin-2 T cell growth factors and their implications during liver allograft rejection in ratsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2007Wei-Lin Wang Abstract Background and Aim:, Rejection remains a problem in the transplantation field. The aim of this study was to establish acute and chronic rejection models in rats and to investigate the roles of non-interleukin (IL)-2 T cell growth factors such as IL-15, IL-7 and IL-13 during rejection. Methods:, A liver transplant model was established using Dark Agouti and Brown Norway rats. The rats were divided into group A, left without treatment; group B, received cyclosporinee (1 mg/kg/day); and group C, cyclosporinee (4 mg/kg/day). Histopathological, reverse transcriptase-polymerase chain reaction and western blot were performed in liver specimens obtained from different time-points after transplantation in the three groups. Results:, In group A, the livers showed irreversible acute cellular rejection with cell infiltration. In group B, chronic liver rejection was found, with graft infiltration, ductular damage or proliferation, obliterative arteriopathy and liver fibrosis. No apparent histological alterations were observed in group C. IL-15, IL-7 and IL-13 messenger RNA and their protein were all highly expressed in the liver specimens of groups A and B. Upregulated expression was found in IL-15 since the first day after transplantation and in IL-7 and IL-13 since day 6. The extent of IL-15 upregulation was more than that of IL-7 and IL-13. Conclusions:, Liver transplantation in Dark Agouti to Brown Norway rats with low-dose immunosuppression can induce chronic rejection. In the process of acute and chronic allograft rejections, non-IL-2 T cell growth factors such as IL-15, IL-7 and IL-13 play roles. Strategies should pay more attention to regulating these cytokines after liver transplantation. [source] Bovine Anterior Pituitary Progenitor Cell Line Expresses Interleukin (IL)-18 and IL-18 ReceptorJOURNAL OF NEUROENDOCRINOLOGY, Issue 11 2008Y. Nagai In the anterior pituitary gland, inflammatory mediators regulate cell function through an immuno-endocrine pathway. Recent studies have shown that undifferentiated stem cells act as immunomodulators. These studies prompted us to establish a progenitor cell line from the bovine anterior pituitary gland and to detail its function. First, we localised interleukin (IL)-18 by immunohistochemistry to the marginal cell layer of Rathke's pouch that is assumed to embody a stem/progenitor cell compartment of the postnatal pituitary gland. A cloned anterior pituitary-derived cell line from the bovine anterior pituitary gland was established from single cell clone by the limiting dilution method and was designated as bovine anterior pituitary-derived cell line (BAPC)-1. BAPC-1 cells constantly expressed mRNAs for IL-18 and IL-18 receptor, and grew steadily and rapidly in the medium containing epidermal growth factor and basic fibroblast growth factor. The cell line also expressed the mRNAs for the stem/progenitor cell- related factors such as Nanog, Oct-4, Ptch1, Nestin, Notch1, Hes1, Lrp and Fzd4, and the mRNAs for embryonic pituitary-related factors, such as Lhx3, PitX1 and Pit-1. The nuclei of BAPC-1 were immunostained positively for Pit-1, Hes1 and ,-catenin antibodies. Furthermore, BAPC-1 cells expressed mRNAs for cytokine such as IL-1,, IL-6, IL-7, IL-12 and IL-15. Stimulation of BAPC-1 cells with IL-18 increased expression of mRNAs for IL-1,, IL-6, IL-1, and IL-8. At day 6 in culture, BAPC-1 cells also express growth hormone mRNA. These results strongly suggest that BAPC-1 is a stem/progenitor cell line and modulates the immuno-endocrine function of the anterior pituitary cells through its cytokine production. [source] A multiplex immunoassay demonstrates reductions in gingival crevicular fluid cytokines following initial periodontal therapyJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2010D. H. Thunell Thunell DH, Tymkiw KD, Johnson GK, Joly S, Burnell KK, Cavanaugh JE, Brogden KA, Guthmiller JM. A multiplex immunoassay demonstrates reductions in gingival crevicular fluid cytokines following initial periodontal therapy. J Periodont Res 2009; doi: 10.1111/j.1600-0765.2009.01204.x. © 2009 John Wiley & Sons A/S Background and Objective:, Cytokines and chemokines play an important role in the pathogenesis of periodontal diseases. The objective of this study was to quantitatively assess the effect of initial periodontal therapy on gingival crevicular fluid levels of a comprehensive panel of cytokines and chemokines, including several less extensively studied mediators. Material and Methods:, Clinical examinations were performed and gingival crevicular fluid samples obtained from six subjects with generalized severe chronic periodontitis prior to initial periodontal therapy and at re-evaluation (6,8 weeks). Four diseased and two healthy sites were sampled in each subject. Twenty-two gingival crevicular fluid mediators were examined using a multiplex antibody capture and detection platform. Statistical analyses were performed by fitting mixed effects linear models to log-transformed gingival crevicular fluid values. Results:, Gingival crevicular fluid interleukin (IL)-1, and IL-1, were the only cytokines to differ in initially diseased vs. initially healthy sites. Following initial therapy, 13 of the 16 detectable cytokines and chemokines decreased significantly in diseased sites, including IL-1,, IL-1,, IL-2, IL-3, IL-6, IL-7, IL-8, IL-12 (p40), CCL5/regulated on activation, normally T cell expressed and secreted (RANTES), eotaxin, macrophage chemotactic protein-1, macrophage inflammatory protein-1, and interferon-,. At healthy sites, only three of the 16 mediators were significantly altered following therapy. Conclusion:, This is the first study, to our knowledge, to evaluate such an extensive panel of gingival crevicular fluid mediators within the same sample prior to and following initial therapy. The results confirm that periodontal therapy effectively reduces pro-inflammatory cytokines and chemokines, including less well-described mediators that may be important in initiation and progression of periodontitis. The multiplex assay will prove useful for future gingival crevicular fluid studies. [source] Relationship of serum interleukin-7 concentration and the coagulation state in children with nephrotic syndromePEDIATRICS INTERNATIONAL, Issue 4 2005Anna Wasilewska Abstract, Background:,Enhanced platelet reactivity may play a significant role in the hypercoagulable state of nephrotic syndrome (NS). Thrombocytosis with platelet aggregation cause the release of some cytokines, among them interleukin-7 (IL-7). The aim of the study was to evaluate serum IL-7 levels in children with the symptoms of NS and to determine a correlation between its concentration and platelet count, other hemostatic factors, and NS intensity. Methods:,The study was performed in two groups. I , the examined group of 26 children with NS (12 boys, 14 girls) aged 6.8 ± 2.1 years, subjected to two examinations: A , before treatment, B , during treatment with prednisone (60 mg/kg 24 h after albuminuria regression); and II , the control group (C) of 20 healthy children. Serum IL-7 level was assayed by enzyme-linked immunosorbent assay method using a R & D Quantikine set. Results:,In group I, IL-7 level in examination A (33.33 ± 33.24 pg/mL) was higher than in the control subjects (P < 0.01). In examination B, IL-7 concentration was reduced to the level of 10.86 ± 5.22 pg/mL and did not differ from the controls (P > 0.05). A positive correlation was observed between IL-7 and platelet count and serum fibrinogen level. A negative correlation was noted with antithrombin III concentration. No correlation was found with serum levels of albumin and cholesterol or urine protein. Conclusion:,In children with NS, serum IL-7 level increases proportionally to the elevated platelet count and other hemostatic components, but shows no correlation with serum albumin or urine protein. [source] Disengaging the IL-2 Receptor with Daclizumab Enhances IL-7,Mediated Proliferation of CD4+ and CD8+ T CellsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009P. Monti Allograft rejection is mainly driven by the production of IL-2, which expands T cells by linking the IL-2 receptor (IL-2R) composed of three subunits: CD25, CD122 and CD132. Daclizumab, widely used in immunosuppression, is a humanized anti-CD25 antibody that disrupts IL-2 signaling by binding to CD25 and preventing the assembly of the high-affinity IL-2R. Here we show that Daclizumab, while blocking the T-cell response to IL-2, increases CD4+ and CD8+ T-cell proliferative response to the homeostatic cytokine IL-7. The IL-7R shares CD132 with the IL-2R and blocking of CD25 by Daclizumab results in the enhanced formation of the IL-7R that in turn allows IL-7 to bind more efficiently on the cell surface. The consequently increased IL-7R signaling boosts intracellular phosphorylated STAT5 and T-cell proliferation. In addition, treatment with Daclizumab delays the internalization of CD127 upon IL-7 treatment, retaining T-cell sensitivity to IL-7 for a prolonged time. This effect of Daclizumab highlights the redundancy of the cytokine system, which may influence T-cell proliferation in transplanted patients, and provides information to improve future immunosuppressive strategies. [source] Neutralizing IL-7 Promotes Long-Term Allograft Survival Induced by CD40/CD40L Costimulatory BlockadeAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2006Y. Wang Memory T cells are somewhat resistant to immunosuppresion. They therefore pose a threat to inducing long-term allograft survival. IL-7 is essential for memory T-cell generation. Here, we investigated whether neutralizing IL-7 promotes allograft survival. We found that neutralizing IL-7 alone did not significantly prolong allograft survival. However, blocking both IL-7 and CD154 signaling synergistically prolonged allograft survival. In contrast, neutralizing IL-2 failed to further prolong allograft survival induced by CD40/CD154 costimulatory blockade. Allospecific memory CD8+ T-cell generation was severely impaired under the treatment of anti-IL-7 plus anti-CD154 Ab while administering recombinant IL-7 enhanced CD8+ memory generation even under donor-specific transfusion plus anti-CD154 Ab treatment. Neutralizing IL-7, but not IL-2, together with blocking CD154 synergistically suppressed the proliferation of naïve/effector CD8+ T cells infiltrating grafts. Nevertheless, neutralizing IL-7 did not alter regulatory T-cell generation while neutralizing IL-2 suppressed their generation. Hence, targeting IL-7 represents a new strategy to prolong allograft survival by acting on both naïve and memory T cells. Long-term allograft survival may be achieved by neutralizing IL-7 plus CD40/CD154 blockade, since CD40/CD154 costimulatory blockade prevents acute rejection while neutralizing IL-7 suppresses the generation of memory T cells that persist and mediate late or chronic rejection. [source] Increased expression of interleukin-7 in labial salivary glands of patients with primary Sjögren's syndrome correlates with increased inflammationARTHRITIS & RHEUMATISM, Issue 4 2010A. Bikker Objective To study the expression levels and immunostimulatory capacities of interleukin-7 (IL-7) in primary Sjögren's syndrome. Methods Labial salivary gland (LSG) IL-7 expression was determined by immunohistochemistry, using a quantitative scoring system, in 30 patients with sicca syndrome: 15 patients with primary Sjögren's syndrome (SS) and 15 patients with non-SS sicca syndrome. The correlation of IL-7 expression in LSGs with parameters of local and peripheral disease was studied, and serum and salivary IL-7 levels were determined. Additionally, the effects of IL-7 on cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with primary SS were determined in vitro by Luminex multicytokine assay and compared with the effects in control subjects. Results The expression of IL-7 in LSGs was higher in patients with primary SS compared with that in patients with non-SS sicca syndrome. IL-7 was observed primarily in the vicinity of lymphocytic infiltrates. Salivary IL-7 levels in patients with primary SS were higher than those in control subjects. In all 30 patients with sicca syndrome, IL-7 expression in LSGs correlated with parameters of both local and peripheral disease. Furthermore, IL-7 stimulated T cell,attracting and T cell,differentiating cytokines (monokine induced by interferon-, [IFN,], IFN,-inducible 10-kd protein, IL-12, and IL-15), as well as Th1 (IFN,), Th2 (IL-4), Th17 (IL-17A), proinflammatory (tumor necrosis factor , and IL-1,), and regulatory (IL-10 and IL-13) cytokine production by PBMCs. All of these cytokines were previously shown to be associated with primary SS. The IL-7,induced increase in IL-10 production in patients with primary SS was reduced compared with that in control subjects. Conclusion The correlation between LSG IL-7 expression and (local) disease parameters in primary SS as well as the IL-7,mediated induction of inflammatory cytokines indicate that IL-7 might contribute to the immunopathology of primary SS. [source] Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 2 2010Heidi Kokkonen Objective To identify whether cytokines, cytokine-related factors, and chemokines are up-regulated prior to the development of rheumatoid arthritis (RA). Methods A nested case,control study was performed in 86 individuals who had donated blood samples before experiencing any symptoms of disease (pre-patients) and 256 matched control subjects (1:3 ratio). In 69 of the pre-patients, blood samples were also obtained at the time of the diagnosis of RA. The plasma levels of 30 cytokines, related factors, and chemokines were measured using a multiplex system. Results The levels of several of the cytokines, cytokine receptors, and chemokines were significantly increased in individuals before disease onset compared with the levels in control subjects; i.e., those representing signs of general immune activation (interleukin-1, [IL-1,], IL-2, IL-6, IL-1 receptor antagonist, and tumor necrosis factor), activation of Th1 cells (interferon-,, IL-12), Th2 cells (IL-4, eotaxin), Treg cells (IL-10), bone marrow,derived factors (IL-7, granulocyte,macrophage colony-stimulating factor, and granulocyte colony-stimulating factor), as well as chemokines (monocyte chemotactic protein 1 and macrophage inflammatory protein 1,). The levels were particularly increased in anti,cyclic citrullinated peptide antibody, and rheumatoid factor,positive individuals, and the concentration of most of these increased further after disease onset. The concentration of IL-17 in individuals before disease onset was significantly higher than that in patients after disease onset. Individuals in whom RA subsequently developed were discriminated from control subjects mainly by the presence of Th1 cells, Th2 cells, and Treg cell,related cytokines, while chemokines, stromal cell,derived cytokines, and angiogenic-related markers separated patients after the development of RA from individuals before the onset of RA. Conclusion Individuals in whom RA later developed had significantly increased levels of several cytokines, cytokine-related factors, and chemokines representing the adaptive immune system (Th1, Th2, and Treg cell,related factors); after disease onset, the involvement and activation of the immune system was more general and widespread. [source] Elevated expression of interleukin-7 receptor in inflamed joints mediates interleukin-7,induced immune activation in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 9 2009Sarita A. Y. Hartgring Objective To evaluate the expression and functional ability of the high-affinity interleukin-7 receptor (IL-7R,) in patients with rheumatoid arthritis (RA). Methods Expression of IL-7R, and IL-7 was determined in synovial tissue from RA patients and was compared with that in synovial tissue from patients with undifferentiated arthritis (UA) and osteoarthritis (OA). IL-7R, expression on CD4 T cells, CD19 B cells, and CD14 monocyte/macrophages from RA synovial tissue, synovial fluid, and peripheral blood was also assessed. The proliferative capacity of IL-7R,bright and IL-7R,dim/, T cells was measured. In addition, we examined IL-7R blockade with soluble human IL-7R, (hIL-7R,) in the prevention of immune activation of peripheral blood mononuclear cells. Results We found significantly higher IL-7R, expression in RA and UA synovial tissue than in OA synovial tissue, and the level of IL-7R, expression correlated significantly with the levels of CD3 and IL-7 expression. CD4 T cells from RA synovial fluid and synovial tissue strongly expressed IL-7R,. A substantial percentage of B cells and macrophages from RA synovial fluid and synovial tissue also expressed IL-7R,, although less prominently than T cells. We found that peripheral blood IL-7R,bright T cells that did not express FoxP3 were highly proliferative as compared with IL-7R,dim/, T cells that did express high levels of FoxP3. Soluble hIL-7R, inhibited IL-7,induced proliferation and interferon-, production by mononuclear cells from RA patients. Conclusion Our data suggest that enhanced expression of IL-7R, and IL-7 in RA patients contributes significantly to the joint inflammation by activating T cells, B cells, and macrophages. The inhibition of IL-7R,mediated immune activation by soluble hIL-7R, further indicates an important role of IL-7R, in inflammatory responses in RA, suggesting IL-7R, as a therapeutic target for immunotherapy in RA. [source] Interleukin-7 stimulates secretion of S100A4 by activating the JAK/STAT signaling pathway in human articular chondrocytesARTHRITIS & RHEUMATISM, Issue 3 2009Raghunatha R. Yammani Objective S100A4 has been shown to be increased in osteoarthritic (OA) cartilage and to stimulate chondrocytes to produce matrix metalloproteinase 13 (MMP-13) through activation of the receptor for advanced glycation end products (RAGE). The aim of this study was to examine the mechanism of S100A4 secretion by chondrocytes. Methods Human articular chondrocytes isolated from ankle cartilage were stimulated with 10 ng/ml of interleukin-1, (IL-1,), IL-6, IL-7, or IL-8. Cells were pretreated with either a JAK-3 inhibitor, brefeldin A, or cycloheximide. Immunoblotting with phospho-specific antibodies was used to determine the activation of signaling proteins. Secretion of S100A4 was measured in conditioned media by immunoblotting, and MMP-13 was measured by enzyme-linked immunosorbent assay. Results Chondrocyte secretion of S100A4 was observed after treatment with IL-6 or IL-8 but was much greater in cultures treated with equal amounts of IL-7 and was not observed after treatment with IL-1,. IL-7 activated the JAK/STAT pathway, with increased phosphorylation of JAK-3 and STAT-3, leading to increased production of S100A4 and MMP-13. Overexpression of a dominant-negative RAGE construct inhibited the IL-7,mediated production of MMP-13. Pretreatment of chondrocytes with a JAK-3 inhibitor or with cycloheximide blocked the IL-7,mediated secretion of S100A4, but pretreatment with brefeldin A did not. Conclusion IL-7 stimulates chondrocyte secretion of S100A4 via activation of JAK/STAT signaling, and then S100A4 acts in an autocrine manner to stimulate MMP-13 production via RAGE. Since both IL-7 and S100A4 are up-regulated in OA cartilage and can stimulate MMP-13 production by chondrocytes, this signaling pathway could contribute to cartilage destruction during the development of OA. [source] Identification of interleukin-7 as a candidate disease mediator in spondylarthritis,ARTHRITIS & RHEUMATISM, Issue 11 2008Markus Rihl Objective Understanding of the molecular pathophysiology of spondylarthritis (SpA) remains largely elusive. This is related both to the complexity of the disease (axial versus peripheral disease, inflammation versus tissue remodeling) and to the difficulty in obtaining samples from primary disease sites. This study was undertaken to explore a gene expression approach for identifying novel candidate mediators of SpA. Methods Sacroiliac joint fluid aspirates from 3 SpA patients with active sacroiliitis were studied by microarray analysis. The expression of selected candidate molecules in peripheral synovitis was confirmed by reverse transcriptase,polymerase chain reaction and enzyme-linked immunosorbent assay. Results Microarray analysis identified 4 sacroiliitis gene clusters, containing a total of 47 messenger RNA (mRNA) transcripts. Two clusters contained genes expressed in all sacroiliitis samples, corresponding to both known and unsuspected candidate mediators of SpA pathology. These included proinflammatory molecules as well as molecules involved in tissue remodeling, such as transforming growth factor ,2. Of the novel candidate genes selected for confirmation, interleukin-7 (IL-7) mRNA expression was higher in SpA peripheral synovial fluid and synovial tissue samples than in osteoarthritis samples, and similar to expression in rheumatoid arthritis (RA) samples. At the protein level, synovial fluid IL-7 levels were even higher in SpA than in RA, despite lower levels of tumor necrosis factor , and IL-1,. Conclusion In the present study, both known and unsuspected candidate mediators of SpA pathogenesis were identified, including IL-7. The specific overexpression of IL-7 at sites of peripheral synovitis in SpA suggests that further functional investigations of the role of this cytokine in SpA pathogenesis are warranted. [source] Proinflammatory mediator,induced reversal of CD4+,CD25+ regulatory T cell,mediated suppression in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 3 2007Jocea M. R. van Amelsfort Objective We previously demonstrated that CD4+,CD25+ regulatory T (Treg) cells are present in increased numbers in the synovial fluid (SF) of rheumatoid arthritis (RA) patients and display enhanced suppressive activity as compared with their peripheral blood (PB) counterparts. Despite the presence of these immunoregulatory cells in RA, chronic inflammation persists. The purpose of the present study was to investigate whether particular proinflammatory mediators that are associated with RA could abrogate CD4+,CD25+ Treg,mediated suppression. Methods Monocyte phenotype was determined by flow cytometry and cytokine levels by enzyme-linked immunosorbent assay. Magnetically sorted CD4+,CD25, and CD4+,CD25+ T cells derived from the PB and SF obtained from RA patients were stimulated alone or in coculture with anti-CD3 monoclonal antibody (mAb) and autologous antigen-presenting cells, in the absence or presence of anti-CD28 mAb or the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor , (TNF,), or IL-7. Results Monocytes from the SF of RA patients displayed increased expression of HLA class II molecules, CD80, CD86, and CD40 as compared with PB-derived monocytes, indicating their activated status. Mimicking this increased costimulatory potential, addition of anti-CD28 mAb to cocultures of CD4+,CD25, and CD4+,CD25+ T cells resulted in reduced CD4+,CD25+ Treg,mediated suppression in both PB and SF. Furthermore, IL-7 and, to a limited extent, TNF,, both of which are produced by activated monocytes and were detected in SF, abrogated the CD4+,CD25+ Treg,mediated suppression. In contrast, IL-6 did not influence Treg-mediated suppression. Conclusion Our findings suggest that the interaction of CD4+,CD25+ Treg cells with activated monocytes in the joint might lead to diminished suppressive activity of CD4+,CD25+ Treg cells in vivo, thus contributing to the chronic inflammation in RA. [source] | ||||||||||||||||||||||||||||