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Cytokine Expression (cytokine + expression)
Kinds of Cytokine Expression Selected AbstractsInhibition of Proinflammatory Cytokine Expression by NF-,B (p65) Antisense Oligonucleotide in Helicobacter pylori -Infected MiceHELICOBACTER, Issue 6 2005Sang Gyun Kim ABSTRACT Background.,Helicobacter pylori induces the expression of proinflammatory cytokines in vitro by activating nuclear factor-,B, a transcriptional regulator. However, it has not been clarified whether H. pylori -induced proinflammatory cytokines are also mediated through nuclear factor-,B in vivo. The aim of this study was to evaluate the role of nuclear factor-,B on the expressions of proinflammatory cytokines in H. pylori -infected mice. Materials and Methods., We evaluated nuclear factor-,B (p65) activation in the H. pylori -infected gastric mucosa of mice by immunofluorescent staining using antip65 polyclonal antibody, and the expressions of proinflammatory cytokines with inhibition of nuclear factor-,B pathway by using phosphorothioate antisense and sense oligonucleotide against the nuclear factor-,B (p65). Results., In the H. pylori -infected gastric mucosa of mice, immunofluorescent staining using antip65 polyclonal antibody showed nuclear factor-,B (p65) activation, which was particularly localized to epithelial cells. Tumor necrosis factor-, and interleukin-1, concentrations in gastric mucosa by enzyme-linked immunosorbent assay (ELISA) were elevated in the infected group versus the uninfected group. Pretreatment with nuclear factor-,B (p65) antisense oligonucleotide inhibited the activation of nuclear factor-,B and the expressions of tumor necrosis factor-, and interleukin-1, in H. pylori -infected gastric mucosa. Sense oligonucleotide did not influence on the expression of proinflammatory cytokines. Conclusions.,H. pylori infection was found to activate the expressions of proinflammatory cytokines via nuclear factor-,B in vivo, and this may play an important role in the initiation of H. pylori- induced gastric inflammation. [source] ORIGINAL ARTICLE: Correlation Between Natural Cytotoxicity Receptors and Intracellular Cytokine Expression of Peripheral Blood NK Cells in Women with Recurrent Pregnancy Losses and Implantation FailuresAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2009Atsushi Fukui Problem, Natural cytotoxicity receptors (NCRs) are unique markers, which regulate NK cell cytotoxicity and cytokine production. We investigated whether women with recurrent pregnancy losses (RPLs) and implantation failures have aberrant correlation between NCRs and intracellular cytokine expression of NK cells. Method of study, Peripheral blood NK cells (CD56dim and CD56bright) were analyzed for NCRs (NKp46, NKp44 and NKp30) and cytokine expression (TNF-,, IFN-,, IL-4, IL-10) using flow cytometry in RPL (n = 22), implantation failures (n = 23) or controls (n = 15). Results, In type 1 cytokine studies, CD56bright/NKp30+ cells in controls (r = 0.696, P < 0.05) were positively correlated with CD56bright/IFN-,+/TNF-,+ cells. CD56bright/NKp46+ cells in implantation failures (r = ,0.76, P < 0.01) were negatively correlated with CD56bright/IFN-,+/TNF-,, cells. RPL did not have any correlation. In type 2 cytokine studies, CD56+/NKp46+ cells (r = 0.758, P < 0.01) and CD56+/NKp30+ cells (r = 0.637, P < 0.05) were positively correlated with CD56bright/IL-4+/IL-10+ cells in controls. CD56+/NKp30+ cells in implantation failures (r = ,0.778, P < 0.05) were negatively correlated with CD56bright/IL-10+/IL-4+ cells. There were no correlations in RPL. Conclusion, Recurrent pregnancy losses and implantation failures have lack of, or negative correlation between NCRs and intracellular cytokines expression. This observation suggests that excessive pro-inflammatory cytokine expression in NK cells in RPL and implantation failures may be exerted through the NCRs or interruption of signal transduction processes. [source] ORIGINAL ARTICLE: The Role of Cytokine Expression in Different Subgroups of Subfertile MenAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2009Srividya Seshadri Problem, The aim of this study was to evaluate the levels of seminal plasma cytokines interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10), interleukin 11 (IL-11), interleukin 12 (IL-12), tumour necrosis factor alpha (TNF-,) and interferon gamma (IFN-,) in male subfertility. Method of study, A total of 73 male partners of an infertile couple attending a regional andrology unit were recruited into this prospective study and subdivided into the various groups based on semen analysis. Concentrations of cytokines such as IL-6, IL-8, IL-10, IL-11, IL-12, TNF-, and IFN-, in the seminal plasma were determined using enzyme linked immunosorbent assay (ELISA). Results, Significant higher concentrations (P < 0.05) of IL-6 in the mild and severe oligospermic group, IL-8 and IL-10 in the asthenospermic group and IL-6, IL-10, TNF-, and IFN-, in the obstructed azoospermic group were determined. IL-10 concentrations correlated significantly with other cytokines in the obstructed azoospermic group and the asthenospermic group. Conclusion, Our study confirms that cytokines rarely act in isolation, but rather in a network of other cytokines and may affect sperm function directly or indirectly. The presence of increased levels of cytokines in the obstructed azoospermic group suggests that the cytokines may not originate from the testis. [source] Alterations in Syncytiotrophoblast Cytokine Expression Following Treatment with LipopolysaccharideAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2006Yuehong Ma Problem, The placental syncytium is a differentiated cell type on the surface of the villus that has the potential to release cytokines directly to maternal blood. Responsiveness of this cell type to inflammatory compounds remains largely unelucidated. Method of study, Response to a pro-inflammatory (lipopolysaccharide, LPS) and an anti-inflammatory (dexamethasone, DEX) compound was studied in primary cultures of syncytiotrophoblasts (SCTs). Cells were incubated with and without LPS and DEX. Cytokine levels in conditioned media were determined by enzyme-linked immunosorbent assay and proteome arrays. Results, LPS treatment induced a fourfold increase in interleukin-8 (IL-8) levels in SCTs. LPS enhanced the expression of both pro- and anti-inflammatory cytokines in SCTs. DEX treatment reduced IL-8 levels in control and LPS-treated cultures by 70,90%. Conclusion, Cytokine expression in SCTs was enhanced by LPS treatment and this effect was suppressed by glucocorticoid treatment. This suggests that inflammatory compounds may alter cytokine expression in the syncytium throughout gestation. [source] Tumour Necrosis Factor Receptor 1 and Hepatocyte Regeneration in Acetaminophen Toxicity: A Kinetic Study of Proliferating Cell Nuclear Antigen and Cytokine ExpressionBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 1 2005Laura P. James To examine the effects of tumour necrosis factor receptor 1 on hepatocyte regeneration, immunohistochemical staining with proliferating cell nuclear antigen was performed. Immunohistochemical staining for proliferating cell nuclear antigen was significantly reduced at multiple time points in the knock-out mice and did not normalize until 96 hr. To evaluate the effect of tumour necrosis factor receptor 1 depletion on cytokines known to be involved in regeneration, levels of macrophage inhibitory protein 2, interferon-,-inducible protein-10 and monocyte chemoattractant protein 1 were compared in the two groups of mice. Significant elevation of all cytokines was observed in both groups of mice; however, higher levels were present in the knock-out mice. Depletion of tumour necrosis factor receptor 1 has long-lasting effects on hepatocyte regeneration in acetaminophen toxicity but multiple other factors appear to orchestrate eventual recovery in these mice. [source] Role of NK1.1+ and AsGm-1+ cells in oral immunoregulation of experimental colitisINFLAMMATORY BOWEL DISEASES, Issue 2 2003Shivti Trop Abstract NK1.1 and AsGm-1 expressing cells play a role in immunomodulation. Our purpose was to determine the role of NK1.1+ and AsGm-1+ expressing cells in the inflammatory/tolerance paradigm in experimental colitis. Oral tolerance towards colitis-extracted proteins had previously been shown to alleviate experimental colitis. Colitis was induced in C57/B6 mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Oral tolerance was induced via five oral doses of proteins extracted from TNBS-colitis colonic wall. Clinical, macroscopic, and microscopic scores were used for colitis assessment. To evaluate the putative role of AsGm-1 in tolerance induction, depletion of AsGm-1 expressing cells was performed. To evaluate the mechanism of tolerance induction, liver-associated NKT lymphocytes were harvested 14 days following tolerance induction, and cultured with concanavalin A (con A) and colitis-extracted proteins. T cell subsets were measured by flow cytometry. Cytokine expression was measured by intracellular staining and enzyme-linked immunosorbent assay (ELISA). Orally tolerized mice exhibited significant alleviation of the clinical, macroscopic, and microscopic parameters of colitis, with increased CD4+IL4+/CD4+IFN,+ lymphocyte ratio, increased IL-4, and decreased IFN, and IL-12 serum levels. In contrast, orally fed mice that were AsGm-1 depleted showed evidence of severe colitis. These mice exhibited significant decreased CD4+IL4+/CD4+IFN,+ ratios, and an increase in IFN, and IL-12, with decreased IL-4 levels. NKT cells harvested from tolerized mice secreted high levels of antiinflammatory cytokines. In contrast, in nontolerized mice, NKT cells mainly secreted proinflammatory cytokines. In a tolerized environment, both NK1.1 and AsGm-1 expressing cells are essential for disease alleviation. In contrast, in a nontolerized environment, AsGm-1 expressing cells support an antiinflammatory immune paradigm, while NKT lymphocytes support a proinflammatory shift. [source] ORIGINAL ARTICLE: The Role of TSP-1 on Decidual Macrophages Involved in the Susceptibility to Unexplained Recurrent Spontaneous AbortionAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 3 2009Yan Jin Problem, To investigate the role of TSP-1 on decidual macrophages (DM,) in unexplained recurrent spontaneous abortion (RSA). Method of study, A total of 20 women undergoing artificial abortion in the first trimester and 10 patients with RSA were selected. (i) The expression of TSP-1 mRNA in deciduas was detected by real-time polymerase chain reaction; (ii) Flow cytometry was used to detect the percentage of positive TSP-1, CD36, CD47 markers on macrophages. (iii) Cytokine expression was measured by enzyme-linked immunosorbent spot-forming (ELISPOT) cell assay. Results, (i) The expression of TSP-1 mRNA on DM, in RSA was significantly decreased (P < 0.05). (ii) The increased expression of CD36 (P < 0.01) and the decreased expression of TSP1 (P < 0.01) were found on DM, of RSA. No different CD47 expression level on DM, was observed between two groups. (iii)The expression of IL-10 in DM, of RSA patients was decreased significantly compared with that of controls (P < 0.05). When adding TSP1 into culture medium, there was no change in IFN-, expression, but increased IL-10 (P < 0.05) expression in DM, of RSA patients was observed. The expression of IL-10 was decreased significantly in DM, from controls when adding anti-TSP-1 antibody to culture medium (P < 0.05). Conclusion, TSP-1 on DM, could influence IL-10 expression as Th2 cytokines. The abnormal expression of TSP-1 could make some women undergo pregnancy loss. [source] Alterations in Syncytiotrophoblast Cytokine Expression Following Treatment with LipopolysaccharideAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2006Yuehong Ma Problem, The placental syncytium is a differentiated cell type on the surface of the villus that has the potential to release cytokines directly to maternal blood. Responsiveness of this cell type to inflammatory compounds remains largely unelucidated. Method of study, Response to a pro-inflammatory (lipopolysaccharide, LPS) and an anti-inflammatory (dexamethasone, DEX) compound was studied in primary cultures of syncytiotrophoblasts (SCTs). Cells were incubated with and without LPS and DEX. Cytokine levels in conditioned media were determined by enzyme-linked immunosorbent assay and proteome arrays. Results, LPS treatment induced a fourfold increase in interleukin-8 (IL-8) levels in SCTs. LPS enhanced the expression of both pro- and anti-inflammatory cytokines in SCTs. DEX treatment reduced IL-8 levels in control and LPS-treated cultures by 70,90%. Conclusion, Cytokine expression in SCTs was enhanced by LPS treatment and this effect was suppressed by glucocorticoid treatment. This suggests that inflammatory compounds may alter cytokine expression in the syncytium throughout gestation. [source] Role of osteopontin in synovial Th17 differentiation in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 10 2010Guangjie Chen Objective Osteopontin (OPN) that is aberrantly produced in rheumatoid synovium is thought to play an important role in rheumatoid arthritis (RA). This study was undertaken to investigate the role of OPN in the differentiation and accumulation of Th17 cells in rheumatoid synovium. Methods Peripheral blood mononuclear cells and purified CD4+ T cells derived from patients with RA or healthy controls were used to test the effect of OPN in vitro. Cytokine expression was determined by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Intracellular staining and flow cytometry were used to detect the percentages of Th17 cells and OPN receptors. Signaling and molecular events were analyzed by immunoblotting and chromatin immunoprecipitation. Results The levels of OPN correlated significantly with interleukin-17 (IL-17) production and the frequency of Th17 cells in the synovial fluid (SF) of RA patients. Endogenous OPN produced in RA SF was responsible for markedly increased production of IL-17 in T cells, which was blocked by OPN antibody. The effect of OPN in Th17 differentiation was mediated through a mechanism independent of the IL-6/STAT-3 pathway or other cytokines and specifically involved the OPN receptors CD44 and CD29 and the transcription factor retinoic acid,related orphan receptor (ROR). Furthermore, OPN was found to induce H3 acetylation of the IL17A gene promoter, mainly through the CD44 binding domain in CD4+ T cells, allowing the interaction of the IL17A gene locus with ROR. Conclusion This study reveals new evidence of the critical role of OPN in Th17 differentiation in rheumatoid synovitis. [source] HLA,B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic ratsARTHRITIS & RHEUMATISM, Issue 9 2009Monica L. DeLay Objective To determine whether HLA,B27 misfolding and the unfolded protein response (UPR) result in cytokine dysregulation and whether this is associated with Th1 and/or Th17 activation in HLA,B27/human ,2 -microglobulin (Hu,2m),transgenic rats, an animal model of spondylarthritis. Methods Cytokine expression in lipopolysaccharide (LPS),stimulated macrophages was analyzed in the presence and absence of a UPR induced by chemical agents or by HLA,B27 up-regulation. Cytokine expression in colon tissue and in cells purified from the lamina propria was determined by real-time reverse transcription,polymerase chain reaction analysis, and differences in Th1 and Th17 CD4+ T cell populations were quantified after intracellular cytokine staining. Results Interleukin-23 (IL-23) was found to be synergistically up-regulated by LPS in macrophages undergoing a UPR induced by pharmacologic agents or by HLA,B27 misfolding. IL-23 was also increased in the colon tissue from B27/Hu,2m-transgenic rats concurrently with the development of intestinal inflammation, and IL-17, a downstream target of IL-23, exhibited robust up-regulation in a similar temporal pattern. IL-23 and IL-17 transcripts were localized to CD11+ antigen-presenting cells and CD4+ T cells, respectively, from the colonic lamina propria. Colitis was associated with a 6-fold expansion of CD4+ IL-17,expressing T cells. Conclusion The IL-23/IL-17 axis is strongly activated in the colon of B27/Hu,2m-transgenic rats with spondylarthritis-like disease. HLA,B27 misfolding and UPR activation in macrophages can result in enhanced induction of the pro-Th17 cytokine IL-23. These results suggest a possible link between HLA,B27 misfolding and immune dysregulation in this animal model, with implications for human disease. [source] GATA-3 protects against severe joint inflammation and bone erosion and reduces differentiation of Th17 cells during experimental arthritisARTHRITIS & RHEUMATISM, Issue 3 2009Jan Piet van Hamburg Objective Rheumatoid arthritis is associated with the infiltration of T helper cells into the joints. It is unclear whether interferon-, (IFN,),producing Th1 cells or the novel T helper subset, interleukin-17 (IL-17),producing Th17 cells, are the pathogenic mediators of joint inflammation in chronic nonautoimmune arthritis. Therefore, this study was aimed at examining whether the Th2-specific transcription factor GATA-3 can regulate arthritis, in an experimental murine model, by modulating Th1 and/or Th17 cell polarization. Methods Arthritis was induced with methylated bovine serum albumin (mBSA) in both wild-type and CD2 T cell,specific GATA-3 (CD2,GATA-3),transgenic mice. At days 1 and 7 after the induction of arthritis, knee joints were scored macroscopically for arthritis severity and for histologic changes. Single-cell suspensions were generated from the spleens, lymph nodes, and inflamed knee joints. Cytokine expression by CD4+ T cells was determined using flow cytometry, and IL-17 expression in the inflamed knee joints was determined by enzyme-linked immunosorbent assay. Analyses of gene expression were performed for Th17-associated factors. Results Wild-type mice developed severe joint inflammation, including massive inflammatory cell infiltration and bone erosion that increased significantly over time, reaching maximal arthritis scores at day 7. In contrast, only mild joint inflammation was observed in CD2,GATA-3,transgenic mice. This mild effect was further accompanied by systemic and local reductions in the numbers of IL-17+IFN,, and IL-17+IFN,+, but not IL-17,IFN,+, CD4+ T cells, and by induction of Th2 cytokine expression. Moreover, GATA-3 overexpression resulted in reduced gene expression of the Th17-associated transcription factor retinoic acid,related orphan receptor ,t. Conclusion These results indicate that enforced GATA-3 expression protects against severe joint inflammation and bone erosion in mice, accompanied by reduced differentiation of Th17 cells, but not Th1 cells, during mBSA-induced arthritis. [source] Promotion of the local differentiation of murine Th17 cells by synovial macrophages during acute inflammatory arthritisARTHRITIS & RHEUMATISM, Issue 12 2008Paul J. Egan Objective To examine the generation of proinflammatory Th17 cells at the site of tissue inflammation and in draining lymph nodes using an interleukin-17 (IL-17),dependent model of acute inflammatory arthritis. Methods Arthritis was elicited in mice by intraarticular injection of methylated bovine serum albumin (mBSA) into the knee and subcutaneous injection of IL-1,. Anti,IL-17 or control antibodies were administered during arthritis induction. Cytokine expression was evaluated by intracellular cytokine staining of synovial lymphocytes, by polymerase chain reaction analysis of RNA extracted from lymph node cells, and by enzyme-linked immunosorbent assay of cell culture supernatants. Th17 differentiation of naive CD4+ T cells was assessed in cocultures with macrophages from arthritic mice. Results Anti,IL-17 antibody administered during acute arthritis markedly reduced disease, indicating that the model is IL-17 dependent. IL-17 messenger RNA (mRNA), but not protein, was detected in draining lymph node CD4+ T cells and preceded joint inflammation. In addition, mRNA for Th17 cell,stimulatory cytokines (transforming growth factor ,, IL-6) and Th17 cell,inhibitory cytokines (interferon-,, IL-4) was detected in lymph nodes following injection of mBSA and IL-1,. Th17 cells were clearly identified in the inflamed synovium at the peak of disease. Synovial macrophages supported Th17 cell generation from naive CD4+ T cell precursors stimulated via CD3 in vitro and produced high levels of IL-6. In contrast, peritoneal macrophages failed to induce Th17 cell differentiation and produced less IL-6. Conclusion These results suggest that Th17 cell differentiation is initiated in draining lymph nodes but that IL-17,producing cells are restricted to the inflamed synovium, being generated in response to local cytokines produced by inflammatory macrophages. [source] Down-regulation of the nonspecific and antigen-specific T cell cytokine response in ankylosing spondylitis during treatment with infliximabARTHRITIS & RHEUMATISM, Issue 3 2003Jianxiang Zou Objective Treatment of active ankylosing spondylitis (AS) with the monoclonal tumor necrosis factor , (TNF,) antibody infliximab is highly clinically effective. This study was undertaken to investigate the precise mechanism of action of anti-TNF, treatment in AS. Methods Cytokine expression of CD4+ and CD8+ T cells was investigated before and 6 and 12 weeks after the start of treatment in 10 patients treated with infliximab, and before and after 6 weeks of treatment and 6 weeks after placebo was switched to infliximab in 10 patients treated initially with placebo. Peripheral blood mononuclear cells (PBMCs) were stimulated for 6 hours either nonspecifically with phorbol myristate acetate (PMA)/ionomycin or antigen specifically with a pool of 46 overlapping 18-mer peptides derived from the G1 domain of aggrecan. Cells were stained for T cell surface markers CD4 and CD8 and for the intracellular cytokines interferon-, (IFN,), TNF,, interleukin-4 (IL-4), and IL-10. Positive cells were quantified by flow cytometry. For monocyte-derived cytokines, PBMCs were stimulated with lipopolysaccharide (LPS) for 18 hours and TNF, and IL-10 in the supernatant were measured by enzyme-linked immunosorbent assay. Results Compared with baseline, infliximab treatment induced a significant decrease at 12 weeks in the number of CD4+ and CD8+ T cells that were positive for IFN, and TNF, upon PMA/ionomycin stimulation (P = 0.005). A significant reduction had already begun to occur at 6 weeks. No change in the percent IFN, or TNF, positivity among CD4+ and CD8+ subpopulations was observed after 6 weeks in patients treated with placebo. However, when these patients began infliximab treatment after 6 weeks of receiving placebo, there was a similar significant decrease in IFN, and TNF, production by CD4+ and CD8+ T cells (P < 0.05). Furthermore, infliximab treatment induced a significant reduction in the number of IFN,+ and TNF,+ CD8+ T cells (P = 0.005 at week 6 and week 12) after antigen-specific in vitro stimulation with G1-derived peptides. Between-group analysis showed that the change in the expression of IFN, and TNF, in both CD4+ and CD8+ T cells was significantly different between the infliximab and placebo groups (P = 0.001 for all variables). There was no change in the number of IL-10+ or IL-4+ T cells during treatment. No significant change in the production of TNF, and IL-10 upon in vitro stimulation of PBMCs with LPS was detectable during infliximab treatment. Conclusion Infliximab down-regulates both IFN, and TNF, secreted by T cells but does not induce a change in cytokines produced by monocytes during 3 months of treatment. This is likely to be a relevant mechanism for the clinical efficacy of this therapy. [source] Dominant expression of interleukin 10 but not interferon , in CD4,CD8,,,T cells of autoimmune lymphoproliferative syndromeBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2002Shouichi Ohga Summary. Cytokine expression in CD4,CD8, double-negative (DN) T cells of autoimmune lymphoproliferative syndrome (ALPS) was analysed. Two patients with DN ,,T-cell expansion showed higher serum interleukin 10 (IL-10) levels than one patient without it. Intracellular flow-cytometric analysis indicated the IL-10-expressing CD3+CD4,CD8, cells in patients with lymphoproliferation. Quantitative real-time polymerase chain reaction revealed ,100 times higher IL-10, but not interferon-, or transforming growth factor-, in DN than in single-positive T cells. IL-10 was exclusively expressed in DN ,, but not ,,, cells. Circulating DN ,,T cells may constitutively express IL-10 and contribute to the ALPS phenotype. [source] Brain cytokines and diseaseACTA NEUROPSYCHIATRICA, Issue 6 2002Carlos R Plata-Salaman Cytokines (e.g. various interleukins and subfamily members, tumor necrosis factors, interferons, chemokines and growth factors) act in the brain as immunoregulators and neuromodulators. Over a decade ago, the integrative article ,Immunoregulators in the Nervous System' (Neurosci Biobehav Rev 1991; 15: 185,215) provided a comprehensive framework of pivotal issues on cytokines and the nervous system that recently have been extensively studied. Cytokine profiles in the brain, including cytokine generation and action, have been studied in multiple models associated with neuropathophysiological conditions. These include: (1) acute conditions and disorders such as stroke (cerebral ischemia or infarction and intracranial hemorrhage), traumatic brain injury, spinal cord injury and acute neuropathies; (2) chronic neurodegenerative disorders and chronic conditions, including Alzheimer's disease, Parkinson's disease, neuropathic pain, epilepsy and chronic neuropathies; (3) brain infections, including bacterial meningitis and encephalitis; (4) brain tumors; (5) neuroimmunological disorders per se, such as multiple sclerosis; (5) psychiatric disorders, including schizophrenia and depression; (6) neurological and neuropsychiatric manifestations associated with non- central nervous system (CNS) disorders such as peripheral cancer, liver, kidney and metabolic compromise, and peripheral infectious and inflammatory conditions; and (7) cytokine immunotherapy, which can be accompanied by neuropsychiatric manifestations when administered either via peripheral or brain routes. Cytokine profiles have also been studied in multiple animal models challenged with inflammatory, infectious, chemical, malignant and stressor insults. Essentially data show that cytokines play a pivotal role in multiple neuropathophysiological processes associated with different types of disorders and insults. Cytokine expression and action in the brain shows a different profile across conditions, but some similarities exist. Under a defined temporal sequence, cytokine involvement in neuroprotection or the induction of a deleterious pathophysiological cascade and in resolution/healing is proposed depending on the type of cytokine. In the brain, functional interactions among cytokines, balance between pro-inflammatory and anti-inflammatory cytokines and functional interactions with neurotransmitters and neuropeptides play a pivotal role in the overall cytokine profile, pattern of neuropathophysiological cascades, and quality and magnitude of neuropsychiatric manifestations. In this brief review various selected cytokine-related issues with relevance to the brain are discussed. [source] NF,B, cytokines, TLR 3 and 7 expression in human end-stage HCV and alcoholic liver diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2010Peter Stärkel Eur J Clin Invest 2010; 40 (7): 575,584 Abstract Background/aims, Conflicting observations exist concerning the role of nuclear factor kappa B (NF,B) in alcoholic liver disease (ALD) in animal models. To date no studies have examined this aspect in human liver tissue. We here assessed cytokines and toll-like receptors (TLRs) expressions in conjunction with NF,B activation in non-active end-stage human ALD compared with normal livers and hepatitis C virus (HCV) related end-stage disease. Methods, mRNA and protein expression were examined by quantitative PCR and Western blotting, DNA-binding by electrophoretic mobility shift assays and NF,B sub-cellular localization by immunofluorescent staining of livers. Results, NF,B mRNA and protein expression as well as strong DNA-binding were preserved in ALD but significantly down-regulated in HCV compared with normal livers. P50 immunofluorescence was found in hepatocytes and bile ducts in ALD and normal livers, whereas a shift was observed in p65 staining from non-parenchymal cells in normal livers to hepatocytes in ALD. NF,B responsive genes mRNA levels IkB, and interleukin 6 were significantly higher in ALD compared with HCV. Tumour necrosis factor alpha (TNF,), TLRs 3 and 7 mRNA were up-regulated in ALD and HCV compared with normal liver with TNF, and TLR7 being the highest in HCV. Strong induction of interferon beta was found in HCV but not in ALD or normal liver tissue. Conclusions, Persistent NF,B activation together with high pro-inflammatory cytokine expression and upregulation of TLR3 and TLR7 is associated with end-stage ALD in humans and could contribute to disease progression even in absence of alcohol intake. [source] 22-ene-25-oxa-vitamin D: a new vitamin D analogue with profound immunosuppressive capacitiesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2005C. Daniel Abstract Background, The biologic role of 1,25-dihydroxyvitamin D3, such as anti-inflammatory functions, reduction of cytokine production by T cells and immunoglobulin production by B cells, is well established. However, its clinical use as an immunosuppressive agent is limited because of the hypercalcemic toxicity occurring after systemic application. The purpose of this study was to investigate the immunmodulatory effects of 22-ene-25-oxa-vitamin D (ZK156979), a novel low calcemic vitamin D analogue. Materials and methods, Human peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated using the Ficoll Hypaque technique, cultured for 24 h and treated with different concentrations of ZK156979 ranging from 10,5 to 10,10 mol L,1 compared with 1,25-dihydroxyvitamin D3[10,5,10,10 mol L,1] following phytohaemagglutinin (PHA) stimulation. Interferon gamma (IFN,), tumour necrosis factor alpha (TNF,), interleukin 1 beta (IL-1,), interleukin 10 (IL-10) and interleukin 4 (IL-4) secretion in supernatants were measured by ELISA. Results, ZK156979 inhibited the PHA-induced Th1-response (IFN, and TNF, levels) and the macrophage-product IL-1, in a concentration-dependent manner (10,10,10,5 mol L,1) with the efficiency on cytokine expression compared with 1,25-dihydroxyvitamin D3 being slightly reduced. In contrast, ZK156979 and 1,25-dihydroxyvitamin D3 both affected the Th2 response, leading to significantly increased IL-10- and IL-4 secretion. Conclusions, ZK156979 is a member of novel vitamin D analogues revealing prominent immunomodulatory and suppressive characteristics with distinctive inhibition of Th1-cytokines whereas the Th2 compartment is augmented, thus providing a considerable therapeutic potential in T-cell -mediated diseases. [source] Impairment of dendritic cell function by excretory-secretory products: A potential mechanism for nematode-induced immunosuppressionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2007Mariela Segura Abstract To determine whether helminth-derived products modulate dendritic cell (DC) function, we investigated the effects of excretory-secretory products (ES) and adult worm homogenate (AWH) derived from the gastrointestinal nematode Heligmosomoides polygyrus (Hp) on murine bone marrow-derived DC (BMDC). Compared to the TLR9 ligand CpG, Hp-derived products alone failed to induce DC activation. ES, but not AWH, inhibited BMDC cytokine and chemokine production and co-stimulatory molecule expression (CD40, CD86 and MHC class,II) induced by TLR ligation. TLR ligand-independent, PMA-induced DC activation was unaffected by ES. Recipients of ES-treated BMDC pulsed with OVA had suppressed Ab responses in vivo, irrespective of the Th1 or Th2 isotype affiliation, compared to recipients of control OVA-pulsed BMDC. Importantly, suppression occurred even in the presence of the potent type,1 adjuvant CpG. In contrast to untreated OVA-pulsed BMDC, ES-treated BMDC pulsed with OVA had reduced co-stimulatory molecule and cytokine expression. CD4+CD25+Foxp3, T cells, which secreted high IL-10 levels, were generated in co-cultures of OT-II OVA-specific TCR-transgenic CD4+ T cells and ES-treated BMDC. These IL-10-secreting T cells suppressed effector CD4+ T cell proliferation and IFN-, production, the latter effect mediated by an IL-10-dependent mechanism. Together, these results demonstrate that nematode ES impaired DC function and suppressed both Th1 and Th2 adaptive immune responses possibly by inducing regulatory T cells. [source] Nuclear repositioning marks the selective exclusion of lineage-inappropriate transcription factor loci during T helper cell differentiationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004Susannah Abstract To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a ,-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-, during T helper cell differentiation. Instead, IFN-, was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves. [source] The human basophil , a novel target of the neuropeptide alpha-melanocyte-stimulating hormoneEXPERIMENTAL DERMATOLOGY, Issue 8 2006M. Böhm There is increasing evidence that the basophil does not only play an important role in acute allergic reactions but also in the pathogenesis of chronic allergic disorders. Here we show that human basophils express melanocortin receptors (MC-Rs) and respond to alpha-melanocyte-stimulating hormone (alpha-MSH) with regulation of proallergic cytokine expression and modulation of basophil activation markers. Using primers against all known MC-R subtypes we demonstrate that the human basophil cell line KU812 expresses MC-1R. Expression of MC-1R on the surface of KU812 cells was confirmed by FACS analysis using an anti-MC-1R antibody. The MC-1R expressed by KU812 cells was functionally active as alpha-MSH induced intracellular cAMP in a dose-dependent manner. Moreover, alpha-MSH abrogated the effect of calcium ionophore A23187 on IL-4 mRNA expression in these cells. The relevance of the above findings was corroborated by showing that MC-1R surface expression is also detectable in basophils of leukocyte suspensions derived from whole human blood. Most interestingly, alpha-MSH was capable of suppressing the inductive effect of fMLP on surface expression of the basophil activation marker CD63 in leukocyte suspensions of atopic individuals. Likewise, alpha-MSH significantly blocked grass pollen-induced up-regulation of CD63 in leukocyte suspensions of patients with grass pollen allergy. Our findings highlight a novel functional dimension of alpha-MSH. In addition, MSH peptides may become a novel future therapeutic avenue in treating human allergic diseases. [source] Transcriptional upregulation of inflammatory cytokines in human intestinal epithelial cells following Vibrio cholerae infectionFEBS JOURNAL, Issue 17 2007Arunava Bandyopadhaya Coordinated expression and upregulation of interleukin-1,, interleukin-1,, tumor necrosis factor-,, interleukin-6, granulocyte,macrophage colony-stimulating factor, interleukin-8, monocyte chemotactic protein-1 (MCP-1) and epithelial cell derived neutrophil activator-78, with chemoattractant and proinflammatory properties of various cytokine families, were obtained in the intestinal epithelial cell line Int407 upon Vibrio cholerae infection. These proinflammatory cytokines also showed increased expression in T84 cells, except for interleukin-6, whereas a striking dissimilarity in cytokine expression was observed in Caco-2 cells. Gene expression studies of MCP-1, granulocyte,macrophage colony-stimulating factor, interleukin-1,, interleukin-6 and the anti-inflammatory cytokine transforming growth factor-, in Int407 cells with V. cholerae culture supernatant, cholera toxin, lipopolysaccharide and ctxA mutant demonstrated that, apart from cholera toxin and lipopolysaccharide, V. cholerae culture supernatant harbors strong inducer(s) of interleukin-6 and MCP-1 and moderate inducer(s) of interleukin-1, and granulocyte,macrophage colony-stimulating factor. Cholera toxin- or lipopolysaccharide-induced cytokine expression is facilitated by activation of nuclear factor-,B (p65 and p50) and cAMP response element-binding protein in Int407 cells. Studies with ctxA mutants of V. cholerae revealed that the mutant activates the p65 subunit of nuclear factor-,B and cAMP response element-binding protein, and as such the activation is mediated by cholera toxin-independent factors as well. We conclude that V. cholerae elicits a proinflammatory response in Int407 cells that is mediated by activation of nuclear factor-,B and cAMP response element-binding protein by cholera toxin, lipopolysaccharide and/or other secreted products of V. cholerae. [source] Activation of the complement system in human nonalcoholic fatty liver disease,HEPATOLOGY, Issue 6 2009Sander S. Rensen Activation of the innate immune system plays a major role in nonalcoholic fatty liver disease (NAFLD). The complement system is an important component of innate immunity that recognizes danger signals such as tissue injury. We aimed to determine whether activation of the complement system occurs in NAFLD, to identify initiating pathways, and to assess the relation between complement activation, NAFLD severity, apoptosis, and inflammatory parameters. Liver biopsies of 43 obese subjects with various degrees of NAFLD and of 10 healthy controls were analyzed for deposition of complement factors C1q, mannose-binding lectin (MBL), C4d, activated C3, and membrane attack complex (MAC)-associated C9. Furthermore, hepatic neutrophil infiltration, apoptosis, and pro-inflammatory cytokine expression were quantified. Whereas complement activation was undetectable in the liver of healthy subjects, 74% of the NAFLD patients showed hepatic deposition of activated C3 and C4d. C1q as well as MBL accumulation was found in most activated C3-positive patients. Strikingly, 50% of activated C3-positive patients also displayed MAC-associated C9 deposition. Deposition of complement factors was predominantly seen around hepatocytes with macrovesicular steatosis. Subjects showing accumulation of activated C3 displayed increased numbers of apoptotic cells. Importantly, hepatic neutrophil infiltration as well as interleukin (IL)-8 and IL-6 expression was significantly higher in patients showing activated C3 deposition, whereas patients with C9 deposition additionally had increased IL-1, expression. Moreover, nonalcoholic steatohepatitis (NASH) was more prevalent in patients showing hepatic C9 or activated C3 deposition. Conclusion: There is widespread activation of the complement system in NAFLD, which is associated with disease severity. This may have important implications for the pathogenesis and progression of NAFLD given the function of complement factors in clearance of apoptotic cells, hepatic fibrosis, and liver regeneration. (HEPATOLOGY 2009.) [source] Interleukin 18 causes hepatic ischemia/reperfusion injury by suppressing anti-inflammatory cytokine expression in miceHEPATOLOGY, Issue 3 2004Dan Takeuchi Hepatic ischemia/reperfusion injury is a clinically important problem. While the mechanisms of the initial event and subsequent neutrophil-dependent injury are somewhat understood, little is known about the regulation of endogenous hepatoprotective effects on this injury. Interleukin 12 (IL-12) plays a role in the induction of this injury, but involvement of interleukin 18 (IL-18) has not been clarified. Using a murine model of partial hepatic ischemia and subsequent reperfusion, the aim of the current study was to determine whether IL-18 is up-regulated during hepatic ischemia/reperfusion and to determine the role of endogenous IL-18 in the development and regulation of inflammatory hepatic ischemia/reperfusion injury. Hepatic IL-18 expression was up-regulated from 1 to 8 hours after reperfusion. Hepatic ischemia/reperfusion induced nuclear factor-,B (NF-,B) and activator protein 1 (AP-1) activation, as defined by electrophoretic mobility shift assay, and caused significant increases in liver neutrophil recruitment, apoptosis, hepatocellular injury, and liver edema as defined by liver myeloperoxidase content, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labeling (TUNEL) staining, serum aminotransferase levels, and liver wet-to-dry weight ratios. In mice treated with neutralizing antibody to IL-18, ischemia/reperfusion-induced increases in CXC chemokine expression, activation of NF-,B and AP-1, and apoptosis were greatly reduced. Furthermore, under blockade of IL-18, anti-inflammatory cytokines such as IL-4 and IL-10 were greatly up-regulated. Signal transducer and activator of transcription 6 (STAT6) was significantly activated under blockade of IL-18. These conditions also caused significant reduction in liver neutrophil sequestration and liver injury. In conclusion, the data suggest that IL-18 is required for facilitating neutrophil-dependent hepatic ischemia/reperfusion injury through suppressing anti-inflammatory cytokine expression. (HEPATOLOGY 2004;39:699,710.) [source] Decay-accelerating factor 1 (Daf1) deficiency exacerbates xenobiotic-induced autoimmunityIMMUNOLOGY, Issue 1 2010Christopher B. Toomey Summary Absence of decay-accelerating factor 1 (Daf1) has been shown to enhance T-cell responses and autoimmunity via increased expression of specific cytokines, most notably interferon (IFN)-,. To determine if Daf1 deficiency can exacerbate IFN-,-dependent murine mercury-induced autoimmunity (mHgIA), C57/BL6 Daf1+/+ and Daf1,/, mice were exposed to mercuric chloride (HgCl2) and examined for differences in cytokine expression, T-cell activation and features of humoral autoimmunity. In the absence of Daf1, mHgIA was exacerbated, with increased serum immunoglobulin G (IgG), anti-nuclear autoantibodies (ANAs) and anti-chromatin autoantibodies. This aggravated response could not be explained by increased T-cell activation but was associated with increased levels of IFN-,, interleukin (IL)-2, IL-4 and IL-10 but not IL-17 in Daf1-deficient mice. Anti-CD3/anti-CD28 costimulation of Daf1,/, CD4+ T cells in vitro was also found to increase cytokine expression, but the profile was different from that of mHgIA, suggesting that the cytokine changes observed in Daf1 deficiency reflect a response to mercury. The role of Daf1 in influencing cytokine expression was further examined by stimulation of CD4+ T cells in the presence of anti-CD3 and CD97, a molecular partner for Daf1. This resulted in increased IL-10, decreased IL-17 and IL-21 and decreased IFN-,. These findings demonstrate that the absence of Daf1 exacerbates mHgIA, with changes in the profile of expressed cytokines. Interaction between Daf1 and its molecular partner CD97 was found to modify expression of mHgIA-promoting cytokines, suggesting a possible approach for the suppression of overaggressive cytokine production in autoimmunity. [source] Lymphoid enhancer factor interacts with GATA-3 and controls its function in T helper type 2 cellsIMMUNOLOGY, Issue 3 2008Mohammad B. Hossain Summary GATA-3 is the master transcription factor for T helper 2 (Th2) cell differentiation and is critical for the expression of Th2 cytokines. Little is known, however, about the nature of the functional molecular complexes of GATA-3. We identified a high-mobility group (HMG)-box type transcription factor, lymphoid enhancer factor 1 (LEF-1), in the GATA-3 complex present in Th2 cells using a Flag-calmodulin-binding peptide (CBP)-tag based proteomics method. The interaction between GATA-3 and LEF-1 was confirmed by co-immunoprecipitation experiments using LEF-1-introduced T-cell lineage TG40 cells. The HMG-box domain of LEF-1 and two zinc finger domains of GATA-3 were found to be important for the physical association. The introduction of LEF-1 into developing Th2 cells resulted in the suppression of Th2 cytokine production. The suppression was significantly lower in the cells into which a HMG-box-deleted LEF-1 mutant was introduced. Moreover, LEF-1 inhibited the binding activity of GATA-3 to the interleukin (IL)-5 promoter. These results suggest that LEF-1 is involved in the GATA-3 complex, while also regulating the GATA-3 function, such as the induction of Th2 cytokine expression via the inhibition of the DNA-binding activity of GATA-3. [source] Interferon-,-dependent inhibition of late allergic airway responses and eosinophilia by CD8+,, T cellsIMMUNOLOGY, Issue 2 2007Susumu Isogai Summary We have previously shown that CD8+,, T cells decrease late allergic airway responses, airway eosinophilia, T helper 2 cytokine expression and increase interferon-, (IFN-,) expression. We hypothesized that the effects of CD8+,, T cells were IFN-, mediated. Brown Norway rats were sensitized to ovalbumin on day 1. Cervical lymph node CD8+,, T cells from sensitized animals were treated with antisense oligodeoxynucleotide (5 µmol/l) to inhibit IFN-, synthesis or control oligodeoxynucleotide and 3·5 × 104 CD8+,, T cells were injected intraperitoneally into sensitized recipients on day 13. Rats were challenged with aerosolized ovalbumin on day 15 and lung resistance was monitored over an 8 hr period, after which bronchoalveolar lavage was performed. Control oligodeoxynucleotide treated ,, T cells decreased late airway responses and eosinophilia in bronchoalveolar lavage. There was a complete recovery of late airway responses and a partial recovery of airway eosinophilia in recipients of antisense oligodeoxynucleotide treated cells. Macrophage ingestion of eosinophils was frequent in rats administered ,,T cells but reduced in recipients of antisense oligodeoxynucleotide treated cells. These results indicate that CD8+,, T cells inhibit late airway responses and airway eosinophilia through the secretion of IFN-,. Defective or altered ,, T-cell function may account for some forms of allergic asthma. [source] Periapical lesion progression and cytokine expression in an LPS hyporesponsive modelINTERNATIONAL ENDODONTIC JOURNAL, Issue 7 2001A. F. Fouad Abstract Aim The purpose of this study was to compare periapical lesion progression and the expression of the bone modulating cytokines IL-1,, TNF-,, IL-4, IL-6 and IL-11 in periapical lesions of normal and C3H/HeJ (LPS hyporesponsive) mice. Methodology Pulps of both mandibular first molars from C3H/HeJ and BALB/c (normal) mice were exposed and inoculated with normal mouse oral microorganisms for 2, 4, 6, and 8 weeks. After euthanasia, specimens were prepared for histological examination. A quantitative evaluation of the lesional area and immunohistochemical stain counts was performed. Results There were no statistically significant differences in progression of periapical lesions for both mouse strains with time (two-factor anova, P > 0.05). The immunohistochemical staining revealed no overall differences between the two strains in levels of expression of the cytokines (P > 0.05). IL-11 expression did not change from control levels in BALB/c mice, but correlated with the expression of IL-6 and IL-4 in C3H/HeJ mice. Conclusion Responsiveness to LPS may not be significant in the pathogenesis of periapical lesions and in cytokine expression within the lesions, when the lesions are induced by non-specific oral flora. [source] Analysing the effect of novel therapies on cytokine expression in experimental arthritisINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 5 2005Richard O. Williams Summary Type II collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis that has been used extensively to address questions of disease pathogenesis and to validate novel therapeutic targets. Susceptibility to CIA is strongly associated with major histocompatibility complex class II genes, and the development of arthritis is accompanied by a robust T- and B-cell response to type II collagen. The main pathological features of CIA include proliferative synovitis with infiltration of inflammatory cells, pannus formation, cartilage degradation, erosion of bone and fibrosis. Pro-inflammatory cytokines, such as tumour necrosis factor , and interleukin-1,, are expressed in the arthritic joints in both murine CIA and human rheumatoid arthritis, and blockade of these molecules results in amelioration of disease. Hence, there is a great deal of interest in the development of small-molecular-weight inhibitors of pro-inflammatory cytokines. There is also interest in the development and testing of drugs with the capacity to modulate the immune pathways involved in driving the inflammatory response in arthritis. For these reasons, there is a need to monitor the effect of novel treatments on cytokine expression in vivo. In this review, we outline the various techniques used to detect cytokines in experimental arthritis and describe how these techniques have been used to quantify changes in cytokine expression following therapeutic intervention. [source] Exercise Training as a Therapy for Chronic Heart Failure: Can Older People Benefit?JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 5 2003Miles D. Witham BM Despite recent advances in pharmacological therapy, chronic heart failure remains a major cause of morbidity and mortality in older people. Studies of exercise training in younger, carefully selected patients with heart failure have shown improvements in symptoms and exercise capacity and in many pathophysiological aspects of heart failure, including skeletal myopathy, ergoreceptor function, heart rate variability, endothelial function, and cytokine expression. Data on mortality and hospitalization are lacking, and effects on everyday activity, depression, and quality of life are unclear. Exercise therapy for patients with heart failure appears to be safe and has the potential to improve function and quality of life in older people with heart failure. To realize these potential benefits, exercise programs that are suitable for older, frail people need to be established and tested in an older, frail, unselected population with comorbidities. [source] Phosphorylcholine-Coated Circuits Improve Preservation of Platelet Count and Reduce Expression of Proinflammatory Cytokines in CABG: A Prospective Randomized TrialJOURNAL OF CARDIAC SURGERY, Issue 4 2009Costas J. Schulze M.D. Phosphorylcholine (PC) is a new-generation coating material designed to ameliorate biocompatibility and thereby to reduce the detrimental interactions of CPB. We studied the effects of PC-coated perfusion circuits on platelet function and the humoral and cellular response to CPB. Methods: Thirty patients undergoing coronary artery bypass grafting were randomized to PC-coated (PC group, n = 15) and noncoated (control group, n = 15) circuit groups. Clinical data, total blood loss, and pre- and postoperative platelet counts were recorded and IL-6 and TNF-,, CD41a, CD42b, and CD62p were measured at induction of anesthesia, after the initiation of CPB and at termination of CPB. Results: There was a significantly improved preservation of platelet count following CPB in the PC group (p = 0.028), which was sustained over a period of 72 hours. The use of PC-coated circuits further resulted in a significant attenuation of TNF-, and IL-6 expression (p < 0.05 and p < 0.01); however, we were unable to detect any differences in clinical outcomes. Conclusions: Despite similar clinical outcome, the obvious reduction of cytokine expression and improved preservation of platelet count suggest superior biocompatibility of PC-coated circuits. 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