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Various Cytokines (various + cytokine)
Selected AbstractsCardiovascular risk factors and collateral artery formationEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2009D. De Groot Abstract Arterial lumen narrowing and vascular occlusion is the actual cause of morbidity and mortality in atherosclerotic disease. Collateral artery formation (arteriogenesis) refers to an active remodelling of non-functional vascular anastomoses to functional collateral arteries, capable to bypass the site of obstruction and preserve the tissue that is jeopardized by ischaemia. Hemodynamic forces such as shear stress and wall stress play a pivotal role in collateral artery formation, accompanied by the expression of various cytokines and invasion of circulating leucocytes. Arteriogenesis hence represents an important compensatory mechanism for atherosclerotic vessel occlusion. As arteriogenesis mostly occurs when lumen narrowing by atherosclerotic plaques takes place, presence of cardiovascular risk factors (e.g. hypertension, hypercholesterolaemia and diabetes) is highly likely. Risk factors for atherosclerotic disease affect collateral artery growth directly and indirectly by altering hemodynamic forces or influencing cellular function and proliferation. Adequate collateralization varies significantly among atherosclerotic patients, some profit from the presence of extensive collateral networks, whereas others do not. Cardiovascular risk factors could increase the risk of adverse cardiovascular events in certain patients because of the reduced protection through an alternative vascular network. Likewise, drugs primarily thought to control cardiovascular risk factors might contribute or counteract collateral artery growth. This review summarizes current knowledge on the influence of cardiovascular risk factors and the effects of cardiovascular medication on the development of collateral vessels in experimental and clinical studies. [source] Plasma-soluble Fas (APO-1, CD95) and soluble Fas ligand in immune thrombocytopenic purpuraEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2000Chie Yoshimura Abstract: We investigated the levels of various cytokines and soluble factors in ITP patients, in order to determine the influence of these factors on the pathogenesis of ITP. We found increases in IL-2, IL-6, IFN-,, and M-CSF levels in ITP patients compared with those in healthy individuals. On lymphocyte phenotype analysis, we found no clear difference in total T cell population (CD2+ CD19, cells) or cytotoxic T cell frequency (CD8+ CD11b, cells) between these two groups. The frequency of helper/inducer T cells (CD4+ CD8, cells) was decreased in ITP patients. There was a significant increase in activated T cells (CD3+ HLA-DR+ cells) in ITP patients. Furthermore, frequencies of NK cells of potent activity (CD16+ CD56+ cells) were significantly elevated in ITP patients. Seventeen of the 54 ITP patients (31.5%) had elevated levels of sFas, and 11 of the 54 patients (20.4%) of sFasL. In addition, a significant increase of sFasL was observed in sFas-positive ITP patients, and in these patients the sFasL level was correlated with that of sFas (r=0.687, p<0.01). We found significant increases in IL-2 and sIL-2R levels in sFas-positive ITP patients. For other factors examined, however, there were no differences in level between sFas-positive and-negative ITP patients. Percentages of activated T cells (CD3+ and HLA-DR+ cells) and NK cells (CD16+ and CD56+ cells) were significantly higher in sFas-positive ITP patients than in sFas-negative ITP patients. These findings suggests that the pathogenesis of ITP includes alteration of the Fas/FasL pathway. [source] A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patientsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2003M. T. Khayyal Abstract The aqueous extract of propolis has been formulated as a nutritional food product and administered, as an adjuvant to therapy, to patients with mild to moderate asthma daily for 2 months in the framework of a comparative clinical study in parallel with a placebo preparation. The diagnosis of asthma was made according to the criteria of patient classification of the National Institutes of Health and Global Initiative for Asthma Management. At inclusion, the pulmonary forced expiratory volume in the first second (FEV1) as a percentage of the forced vital capacity (FVC) was more than 80% in mild persistent cases, and between 60 and 80% in moderate persistent cases, showing an increase in the degree of reversibility of >,15% in FEV1. All patients were on oral theophylline as controller therapy, none was receiving oral or inhaled corticosteroids, none had other comorbidities necessitating medical treatment, and all were from a middle-class community and had suffered from asthma for the last 2,5 years. Twenty-four patients received the placebo, with one drop-out during the study, while 22 received the propolis extract, with no drop-outs. The age range of the patients was 19,52 years; 36 were male and 10 female. The number of nocturnal attacks was recorded on a weekly basis, while pulmonary function tests were performed on all patients at the beginning of the trial, 1 month later and at the termination of the trial. Immunological parameters, including various cytokines and eicosanoids known to play a role in asthma, were measured in all patients at the beginning of the trial and 2 months later. Analysis of the results at the end of the clinical study revealed that patients receiving propolis showed a marked reduction in the incidence and severity of nocturnal attacks and improvement of ventilatory functions. The number of nocturnal attacks dropped from an average of 2.5 attacks per week to only 1. The improvement in pulmonary functions was manifested as a nearly 19% increase in FVC, a 29.5% increase in FEV1, a 30% increase in peak expiratory flow rate (PEFR), and a 41% increase in the forced expiratory flow rate between 25 and 75% of the vital capacity (FEF25-75). The clinical improvement was associated with decreases by 52, 65, 44 and 30%, respectively, of initial values for the pro-inflammatory cytokines tumor necrosis factor (TNF)-,, ICAM-1, interleukin (IL)-6 and IL-8, and a 3-fold increase in the ,protective' cytokine IL-10. The levels of prostaglandins E2 and F2, and leukotriene D4 were decreased significantly to 36, 39, and 28%, respectively, of initial values. Patients on the placebo preparation showed no significant improvement in ventilatory functions or in the levels of mediators. The findings suggest that the aqueous propolis extract tested is potentially effective as an adjuvant to therapy in asthmatic patients. The benefits may be related to the presence in the extract of caffeic acid derivatives and other active constituents. [source] Intravesical instillation therapy with bacillus Calmette-Guérin for superficial bladder cancer: Study of the mechanism of bacillus Calmette-Guérin immunotherapyINTERNATIONAL JOURNAL OF UROLOGY, Issue 2 2007Yasuyo Shintani Aim: In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured. Methods: After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte,macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-,, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1,, IL-8, interferon (IFN)-,, and IL-12. Results: After the BCG therapy, various cytokines, such as GM-CSF, TNF-,, G-CSF, IL-1,, IL-8, IFN-,, and IL-12 were secreted, comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-, 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-, or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-, level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively. Conclusions: We suggested that the urinary levels of TNF-, might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence. [source] Modulation of expression of LDH isoenzymes in endothelial cells by laminin: Implications for angiogenesisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008V.B. Sameer Kumar Abstract Endothelial cell (EC) matrix interaction is critical in angiogenesis. Although matrix components can regulate the process of angiogenesis by acting as a reservoir of various cytokines, it is not clear if extracellular matrix (ECM) can modulate the production and activity of angiogenic cytokines. Investigations were therefore carried out to study the influence of the basement membrane (BM) protein, laminin (Ln) on the activity of vascular endothelial growth factor (VEGF), the major angiogenic cytokine, using isolated human umbilical vein ECs (HUVECs) in culture. Analysis of the biochemical markers of angiogenesis confirmed proangiogenic effect of Ln. The levels of VEGF protein and mRNA were not different in cells maintained on Ln, collagen I or polylysine substrata. Chorioallantoic membrane assay using VEGF isolated from cell extracts however revealed that Ln increased its angiogenic potency. Immunoblotting and HPLC analysis showed considerable reduction in poly adenosyl ribosylation of VEGF associated with a significant decrease in the levels of NAD+, in cells maintained on Ln substrata. Further, a shift in the isoenzymic pattern of LDH towards the B rich forms and an upregulation of LDH B gene were observed in cells maintained on Ln. Ln modulates expression of LDH gene through ,6,4 integrin mediated downstream signaling involving p38 mitogen activated protein kinases (MAPK) pathway. It thus appears that Ln can affect aerobic metabolism of ECs by modulating the expression of LDH isoenzymes resulting in a decrease in the level of NAD+ that can cause a reduction in the poly adenosyl ribosylation of VEGF altering its angiogenic potency. J. Cell. Biochem. 103: 1808,1825, 2008. © 2007 Wiley-Liss, Inc. [source] Development of granulocytes in haematopoietic tissues of Rhizoprionodon lalandiiJOURNAL OF FISH BIOLOGY, Issue 4 2002F. J. Pacheco Granulocytes of the epigonal and Leydig organs of Rhizoprionodon lalandii were identified and classified into three different cell types, type I and type II eosinophils and neutrophils. The development of these cells in the haematopoietic tissues was dynamic, demonstrated by nuclear immunopositivity for the proliferating cell nuclear antigen (PCNA) proteins and was regulated by various cytokines, including the transforming growth factor , -l (TGF/,1). The expression pattern of these cells was heterogeneous among individual cells and TGF/,1 -immunostaining was found principally in the cytoplasm of immature granulocytes. The presence of TGF/,1 in cells about to divide was demonstrated suggesting that modulation of differentiation and proliferation occurs in the haematopoietic tissues of this species of elasmobranch. [source] Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 3JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2003F Terenghi Intravenous immunoglobulins (IVIg) are successfully used as immunomodulatory therapy in patients with multifocal motor neuropathy (MMN) but their mechanism of action remains unknown. An anti-idiotypic block of pathogenic autoantibodies has been often postulated even if other possible mechanisms, including a modulation of the release of various cytokines, have been proposed. To evaluate the expression of cytokines in patients with MMN and their possible modulation by IVIg, we determined circulating levels of TNF,, INF,, IL2, IL4, IL10, and IL12 by ELISA in serum samples of 17 patients with MMN and compared them with 12 patients with amyotrophic lateral sclerosis (ALS), 12 with multiple sclerosis (MS), 6 with chronic inflammatory demyelinating polyneuropathy (CIDP), 5 with myasthenia gravis (MG) and 12 healthy controls (NS). Comparable levels of INF,, IL2, IL4, IL10 and IL12 were detected in patients' sera and controls. Even if TNF, levels did not differ significantly among patients' groups, they were higher than in any healthy control (mean ± SD 1.2 ± 0.5 pg/ml, range 0.7,2.4 pg/ml), in 12 (70%) MMN patients (mean ± SD 3.6 ± 1.9 pg/ml; range 0.2,7.5 pg/ml), all ALS, 3 MS (25%), 2 CIDP (40%) and 2 MG (40%). We then measured the concentration of TNF, before and after IVIg therapy in 9 MMN and 2 ALS patients. In all but one MMN patients, circulating levels of TNF, slightly increased after treatment with IVIg (mean values 4.3 vs. 7.2 pg/ml) and decreased 3 weeks after therapy while in both ALS patients they decreased or remained unchanged. No detectable level of TNF, was found in IVIg preparation. This study shows that, similarly to what previously reported in other autoimmune neuropathy as GBS and CIDP, TNF, serum levels are slightly increased in MMN but, at odds with what reported in these disease, their concentration tend to increase parallel to clinical improvement after IVIg therapy. Further studies are necessary to clarify the pathogenetic implication of this finding and in particular whether a possible deviation from a presumably Th2 to a Th1 immune response may help explaining the effect of IVIg in MMN. [source] In situ estrogen production and its regulation in human breast carcinoma: From endocrinology to intracrinologyPATHOLOGY INTERNATIONAL, Issue 11 2009Hironobu Sasano The great majority of breast carcinomas arising in postmenopausal women are estrogen dependent or positive for estrogen receptor (ER) in carcinoma cells despite markedly low plasma or circulating estrogen concentrations. In these patients, biologically active estrogens are locally produced from circulating inactive steroids including adrenal androgens in an intracrine mechanism in the breast cancer tissues and confer estrogenic activities on carcinoma cells. A series of enzymes are involved in this intra-tumoral or in situ production of estrogens in breast carcinoma tissues but aromatase, a member of the cytochrome P450 family, is a key enzyme of estrogen production through conversion from circulating adrenal androgens in estrogen-dependent postmenopausal breast cancer. It then becomes important to identify the sites of this estrogen production. There has been, however, controversy regarding intra-tumoral localization of aromatase in breast carcinoma, especially whether intra-tumoral production of estrogens through aromatase occurs in carcinoma or stromal cells. The enzyme was demonstrated to be expressed in both carcinoma and stromal cells in breast carcinoma tissues on immunohistochemistry with a well-characterized mAb 677 and combined laser capture microdissection/qualitative reverse transcriptase,polymerase chain reaction. Intra-tumoral aromatase in both of these cell types was subsequently demonstrated to be induced by carcinoma,stromal interactions associated with carcinoma invasion in breast tissue. The signals through various nuclear receptors, especially estrogen-related receptor-, in carcinoma cells and liver receptor homologue-1 in adipocytes adjacent to carcinoma invasion, in conjunction with various cytokines and/or growth factors, play pivotal roles in this induction of intra-tumoral aromatase. This increased aromatase subsequently results in increased in situ estrogen concentrations of breast cancer. Aromatase inhibitors are currently established as the gold standard for the treatment for ER-positive breast carcinoma but resistance to the therapy still remains to be solved by other modes of suppression of intra-tumoral estrogen production. [source] Effects of Cytokines on VEGF Expression and Secretion by Human First Trimester Trophoblast Cell LineAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 2 2002SUN JU CHOI PROBLEM:,The mechanism through which vascular endothelial growth factor (VEGF) regulation occurs at the feto-maternal interface is poorly understood. The aim of this study was to investigate the effects of various cytokines on VEGF expression and secretion by trophoblast cells. METHOD OF STUDY:,We investigated the effects of cytokines on VEGF expression in human first trimester trophoblast cell line by analyzing VEGF messenger RNA (mRNA) by reverse transcription-polymerase chain reaction and VEGF protein secretion by enzyme linked immunosorbent assay. RESULTS:,The trophoblast cells expressed VEGF mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165. When cultured in the presence of interferon (IFN)-,, interleukin (IL)-1,, tumor necrosis factor (TNF)-,, IL-2, or IL-10, VEGF mRNA expression was found to be significantly increased by IL-1,, IFN-, and TNF-, but to be unaffected by IL-2 and IL-10. Moreover, VEGF secretion was most significantly increased by IFN-, treatment. CONCLUSION:,These results suggest that IL-1,, IFN-,, and TNF-, may regulate the production of VEGF in early gestational trophoblasts. [source] Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissuesARTHRITIS & RHEUMATISM, Issue 7 2010Mohammed F. Shamji Objective Prior reports document macrophage and lymphocyte infiltration with proinflammatory cytokine expression in pathologic intervertebral disc (IVD) tissues. Nevertheless, the role of the Th17 lymphocyte lineage in mediating disc disease remains uninvestigated. We undertook this study to evaluate the immunophenotype of pathologic IVD specimens, including interleukin-17 (IL-17) expression, from surgically obtained IVD tissue and from nondegenerated autopsy control tissue. Methods Surgical IVD tissues were procured from patients with degenerative disc disease (n = 25) or herniated IVDs (n = 12); nondegenerated autopsy control tissue was also obtained (n = 8) from the anulus fibrosus and nucleus pulposus regions. Immunohistochemistry was performed for cell surface antigens (CD68 for macrophages, CD4 for lymphocytes) and various cytokines, with differences in cellularity and target immunoreactivity scores analyzed between surgical tissue groups and between autopsy control tissue regions. Results Immunoreactivity for IL-4, IL-6, IL-12, and interferon-, (IFN,) was modest in surgical IVD tissue, although expression was higher in herniated IVD samples and virtually nonexistent in control samples. The Th17 lymphocyte product IL-17 was present in >70% of surgical tissue fields, and among control samples was detected rarely in anulus fibrosus regions and modestly in nucleus pulposus regions. Macrophages were prevalent in surgical tissues, particularly herniated IVD samples, and lymphocytes were expectedly scarce. Control tissue revealed lesser infiltration by macrophages and a near absence of lymphocytes. Conclusion Greater IFN, positivity, macrophage presence, and cellularity in herniated IVDs suggests a pattern of Th1 lymphocyte activation in this pathology. Remarkable pathologic IVD tissue expression of IL-17 is a novel finding that contrasts markedly with low levels of IL-17 in autopsy control tissue. These findings suggest involvement of Th17 lymphocytes in the pathomechanism of disc degeneration. [source] Inhibition of NF-,B signaling by fasudil as a potential therapeutic strategy for rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 1 2010Hiroshi Okamoto Objective Rheumatoid arthritis (RA) is the most common systemic autoimmune disease and is characterized mainly by symmetric polyarticular joint disorders. The pathologic processes are mediated by a number of cytokines, chemokines, cell adhesion molecules, and matrix metalloproteinases. The expression of most of these molecules is controlled at the transcriptional level. In addition, activation of NF-,B is involved in RA pathogenesis. This study was performed to explore the role of a novel serine/threonine kinase inhibitor, fasudil, in the control of the NF-,B activation pathway and to investigate the therapeutic effects of fasudil on arthritis development in a rat model of RA. Methods Fibroblast-like synoviocytes (FLS) from RA patients and human endothelial cells (ECs) were established and maintained. To study the role of fasudil on cytokine expression, various cytokines expressed in the RA FLS and human ECs were measured by enzyme-linked immunosorbent assay following stimulation of the cells with interleukin-1, (IL-1,) in the presence of various concentrations of fasudil. The role of fasudil on NF-,B activation was studied using a reporter gene assay, Western blotting of I,B,, immunofluorescence analysis of the p65 subunit of NF-,B, and electrophoretic mobility shift assay. The in vivo effects of fasudil on arthritis were studied in a rat adjuvant-induced arthritis (AIA) model. Results Fasudil inhibited cytokine expression in RA FLS and human ECs and also inhibited the activation of ECs, in a dose-dependent manner. Fasudil inhibited IL-1,,induced activation of NF-,B independent of the inhibition of I,B, degradation and nuclear translocation of NF-,B, and inhibited IL-1,,induced DNA binding of NF-,B. Finally, in vivo, fasudil ameliorated arthritis in rats with AIA, without any adverse effects. Conclusion Serine/threonine kinase inhibitor fasudil inhibits the development of arthritis in a rat model of RA, and also inhibits the NF-,B signaling required for binding of NF-,B to specific DNA sequences through, for example, the phosphorylation of p65, suggesting that a specific target of fasudil might be a novel NF-,B kinase. Thus, fasudil serves as a novel strategy for the treatment of RA. [source] HLA,B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis-like diseaseARTHRITIS & RHEUMATISM, Issue 1 2007Matthew J. Turner Objective HLA,B27 is implicated in the pathogenesis of spondylarthritis (SpA), yet the molecular mechanisms are incompletely defined. HLA,B27 misfolding has been associated with endoplasmic reticulum stress and activation of the unfolded protein response (UPR) in macrophages from HLA,B27/human ,2 -microglobulin,transgenic (B27-transgenic) rats. This study was performed to assess the mechanisms that drive activation of the HLA,B27,induced UPR and to determine whether splenocytes respond in a similar manner. Methods Splenocytes were isolated and bone marrow macrophages were derived from B27-transgenic and wild-type rats. Cells were treated for up to 24 hours with cytokines that induce class I major histocompatibility complex expression. HLA,B27 expression and misfolding were assessed by real-time reverse transcription,polymerase chain reaction, flow cytometry, and immunoblotting. Activation of the UPR was measured by quantifying UPR target gene expression and X-box binding protein 1 messenger RNA (mRNA) splicing. Results HLA,B27 mRNA up-regulation was accompanied by a dramatic increase in the accumulation of misfolded heavy chains and preceded robust activation of the UPR in macrophages. When macrophages were treated with various cytokines, the magnitude of the UPR correlated strongly with the degree of HLA,B27 up-regulation. In contrast, B27-transgenic splenocytes exhibited only low-level differences in the expression of UPR target genes after exposure to interferon-, or concanavalin A, which resulted in minimal HLA,B27 up-regulation. Conclusion These results suggest that HLA,B27,associated activation of the UPR in macrophages is attributable to the accumulation of misfolded heavy chains, and that certain cell types may be more susceptible to the effects of HLA,B27 misfolding. Strategies that eliminate HLA,B27 up-regulation and/or the accumulation of misfolded heavy chains may be useful in evaluating the role of these events in the pathogenesis of SpA. [source] Inhibitory effect of pioglitazone on expression of adhesion molecules on neutrophils and endothelial cellsBIOFACTORS, Issue 1 2004Eiko Imamoto Abstract The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in various inflammatory and immune diseases. It has been suggested that peroxisome proliferator-activated receptor-, (PPAR-,, a member of the nuclear receptor superfamily of transcription factors) might be involved in the control of inflammation and in modulating the expression of various cytokines. The aim of this investigation was to evaluate the anti-inflammatory properties of PPAR-, activators, as well as the inhibitory effect of PPAR-, on the expression of adhesion molecules on leukocytes and vascular endothelial cells. Pioglitazone, a synthetic PPAR-, activator, suppressed the increase of CD11b/CD18 expression on FMLP-activated leukocytes, as detected by immunofluorescence flow cytometry. However, the FMLP-induced elevation of cytosolic Ca+2 in leukocytes was not suppressed by pioglitazone. Pioglitazone inhibited the expression of VCAM-1 protein and mRNA on activated human umbilical vein endothelial cells (HUVEC) after IL-1, stimulation, as detected by ELISA and real-time PCR. However, it showed little effect on the expression of ICAM-1 and E-selectin. The present study revealed that pioglitazone can influence monocyte-EC binding by inhibiting VCAM-1 expression on activated EC and neutrophil-EC binding by inhibiting upregulation of CD11b/CD18 on activated neutrophils. Accordingly, pioglitazone may be useful for treating inflammatory diseases. [source] Expression of eotaxin, interleukin 13 and tumour necrosisfactor-, in dermatitis herpetiformisBRITISH JOURNAL OF DERMATOLOGY, Issue 5 2000P. Amerio Background,The dermal and perivascular infiltrate in dermatitis herpetiformis (DH), which is mainly composed of CD4+ lymphocytes, neutrophils and eosinophils, is believed to play an important part in the pathogenesis of the disease. Previous studies suggest that cytokines such as interleukin (IL) -8, granulocyte-macrophage colony-stimulating factor, IL-4 and IL-5 could be involved in the pathogenesis of DH. These cytokines appear to drive tissue infiltration and maturation of eosinophils. Part of the effect of T-helper (Th) 2-type cytokines (IL-4, IL-5) on eosinophils could be mediated by eotaxin, which is a highly specific chemotactic protein induced by various cytokines [IL-4, IL-13, tumour necrosis factor (TNF) -, and interferon-,]. Objectives,To evaluate the expression of eotaxin and its inducers, IL-13 and TNF-,, in DH. Methods,We examined lesions collected from 10 DH patients with active disease. Sections from each specimen were incubated with anti-IL-13, anti-TNF-, and anti-eotaxin antibodies. Chloroacetyl esterase reaction was performed to show mast cell infiltration. Results,Eotaxin was mainly expressed at the tips of the dermal papillae, within the microabscesses. Positivity was also found in the lymphomonocytic infiltrate in the dermis. IL-13 was expressed in the dermal infiltrate and TNF-, was found in the inflammatory infiltrate and in dermal vascular cells. Conclusions,These findings confirm the importance of the lymphomonocytic infiltrate and of Th2 cytokines in the pathogenesis of this disease, suggesting that tissue infiltration in DH is mediated by cell-specific chemokines such as eotaxin and not only by non-specific chemokines such as IL-8. [source] NF-,B activation in development and progression of cancerCANCER SCIENCE, Issue 3 2007Jun-ichiro Inoue Nuclear factor-,, (NF-,B) binds specifically to NF-,B-binding sites (,B sites, 5,-GGGRNNYYCC-3,; R, purine; Y, pyrimidine; N, any nucleotide) present in enhancer regions of various genes. Binding of various cytokines, growth factors and pathogen-associated molecular patterns to specific receptors activates NF-,B and expression of genes that play critical roles in inflammation, innate and acquired immunity, bone remodeling and generation of skin appendices. Activation of NF-,B is also involved in cancer development and progression. NF-,B is activated in cells that become malignant tumors and in cells that are recruited to and constitute the tumor microenvironment. In the latter scenario, the TLR-TRAF6-NF-kB pathways seem to play major roles, and NF-,B activation results in production of cytokines, which in turn induce NF-,B activation in premalignant cells, leading to expression of genes involved abnormal growth and malignancy. Furthermore, NF-,B activation is involved in bone metastasis. Osteoclasts, whose generation requires the RANK-TRAF6-NF-,B pathways, release various growth factors stored in bone, which results in creation of microenvironment suitable for proliferation and colonization of cancer cells. Therefore, NF-,B and molecules involved its activation, such as TRAF6, are attractive targets for therapeutic strategies against cancer. (Cancer Sci 2007; 98: 268,274) [source] Complement factor H and factor B expression in RPE cellsACTA OPHTHALMOLOGICA, Issue 2008Purpose Age-related macular degeneration (AMD) is the leading cause of untreatable blindness in the developed world. The pathogenesis of AMD is not fully understood. Recent evidence suggests that local inflammation in particular complement activation plays an important role. We aim to understand how complement activation is regulated at retina/choroidal interface. Methods The expression and distribution of complement factor H (CFH) and factor B (CFB) in mouse ocular tissues were examined by immunohistochemistry. Regulation of CFH and CFB gene expression by various cytokines or photoreceptor outer segments (POS) was investigated in vitro in cultured RPE cells. Changes in CFH or CFB gene expression after treatment were evaluated by RT-PCR. Results In normal mouse eyes, CFH was detected in corneal epithelial cells, ciliary body, RPE cells, Bruch's membrane and choroidal vessels. There is no significant change in either the expression level or the distribution pattern of CFH in ocular tissues of different ages of mice. CFB was exclusively detected in RPE cells in normal mice. The expression of CFB in RPE cells increases with age. In vitro in RPE cultures, the expression of CFH was negatively regulated by cytokine TNF-alpha and IL-6, whereas the expression of CFB was positively regulated by TNF-alpha and IFN-gamma. Short-term incubation of RPE cells with POS did not alter the expression of CFH or CFB, whereas long-term incubation of RPE cells with POS significantly down-regulated CFH expression but up-regulated CFB expression. Conclusion Complement regulatory factors CFH and CFB are produced locally in the retina/choroidal interface by RPE cells. The production of CFH and CFB in RPE cells is regulated differently by various cytokines and oxidized POS. [source] Regulation of bovine corneal endothelial cell cycle by transforming growth factor-,ACTA OPHTHALMOLOGICA, Issue 5 2003Yutaka Motegi Abstract. Purpose:,The transforming growth factor-, (TGF-,) family includes three multifunctional proteins, TGF-,1, TGF-,2 and TGF-,3, expressed in ocular tissue, which are involved in regulating cell differentiation, cell proliferation and other cell functions. TGF-, is present in aqueous humour and regulates corneal endothelial cells. This study explores the mechanism by which TGF-, regulates the cell cycle in cultured corneal endothelial cells. Methods:,The expression of specific receptors for the TGF-, family was investigated at the protein level by affinity cross-linking with radio-iodinated TGF-,1 and immunoprecipitation with specific antibodies to TGF-, receptors. Regulation of entry into the S-phase of the cell cycle was determined by 5-bromo-2, deoxyuridine (BrdU) incorporation into the cells. The signal transduction pathways were investigated using various blocking agents for protein kinase transducers involved in intracytoplasmic signal transduction. Results:,Cultured bovine corneal endothelial cells were confirmed to express TGF-, type 1 and type 2 receptors and endoglin. In the confluent state, TGF-,1 and TGF-,2 stimulated the cells to progress to the S-phase of the cell cycle through platelet-derived growth factor-B (PDGF-B) chain production and protein kinase C. Conclusions:,TGF-, accelerated cell cycle progression from the G0/G1 phase to the S-phase in cultured corneal endothelial cells, under our experimental conditions, through pathways involving protein kinase C. These pathways are related to the cross-talk between TGF-, and other cytokines. The conditions employed in the present experiments may be useful for investigating the complex cross-talk between various cytokines and growth factors. [source] Role of interleukin-17F in chronic inflammatory and allergic lung diseaseCLINICAL & EXPERIMENTAL ALLERGY, Issue 9 2006N. Hizawa Summary IL-17 family members belong to a distinct category of cytokines that coordinate local tissue inflammation by inducing the release of pro-inflammatory and neutrophil-mobilizing cytokines. The importance of the IL-17 family in inflammatory and autoimmune disease is becoming increasingly apparent. IL-17F is a recently discovered member of the IL-17 family that has a number of biological activities through induction of various cytokines, chemokines, and mediators. IL-17A, the founding member of the IL-17 family, and IL-17F are produced by several inflammatory cells, including activated T cells, in response to infectious and antigenic stimuli. Overexpression of IL-17A or IL-17F in the lungs results in induction of CXC chemokines and neutrophil recruitment. In a case,control study of 1125 unrelated Japanese subjects, a His161 to Arg161 (H161R) substitution in the third exon of the IL17F gene was shown to be associated with asthma and chronic obstructive pulmonary disease (COPD). Functionally, this variant failed to induce cytokines and chemokines, and interestingly, was able to antagonize the activity of wild-type IL-17F. These results provide an experimental basis for the observed genetic association with chronic inflammatory lung diseases, and also suggest the potential therapeutic utility of this antagonistic variant of IL-17F. Given that asthma and COPD are complex diseases involving a number of genetic and environmental factors, the genetic impact of IL-17F H161R with regard to the development of chronic airway inflammation likely varies among individuals with different genetic backgrounds and environmental exposures. [source] | |||||||||||||