Home About us Contact
|
Home About us Contact | ||
|
|
||
Cytokines IL-1 (cytokine + il-1)
Kinds of Cytokines IL-1 Selected AbstractsInterferon-, synergistically enhances induction of interleukin-6 by double stranded RNA in HeLa cellsFEBS JOURNAL, Issue 9 2000Jennifer L. Harcourt Double stranded RNA (dsRNA), an intermediate that is common during viral infection, directly induces much higher levels of expression of interleukin-6 (IL-6) mRNA than does the cytokine IL-1,. Interferon , (IFN,) by itself does not induce expression of IL-6; nonetheless, IFN, pretreatment dramatically enhances IL-6 induction by dsRNA but not by IL-1,. Mutation of either the activating transcription factor/cyclic AMP response element binding protein (ATF/CREB) or the NF-IL-6 binding element within the IL-6 promoter eliminates most responsiveness of CAT reporter constructs to either dsRNA or to IL-1,. IFN, pretreatment partially restores responsiveness to dsRNA but not to IL-1, when either the ATF/CREB site or the NF-IL-6 site is mutated, but at least one of these sites must be intact for responsiveness to be restored. Mutation of the ,B binding site in the IL-6 promoter eliminates responsiveness to either IL-1, or to dsRNA, and pretreatment with IFN, does not restore any responsiveness. Incubation with dsRNA leads to a decrease in protein translation, especially in cells that have been pretreated with IFN,. Nonetheless, IFN, pretreatment followed by dsRNA leads to very high IL-6 protein levels. These studies demonstrate that major differences exist in the induction of IL-6 at both the mRNA and protein levels by dsRNA compared to cytokines and that IFN, pretreatment selectively enhances IL-6 induction by dsRNA but not by IL-1,. The high levels of IL-6 expression that result when cells encounter class I IFN prior to dsRNA suggest a mechanism for a heightened host response to viral infection with heightened production of this pleotropic cytokine. [source] Aging Increases the Interleukin-1,,Induced INOS Gene Expression and Nitric Oxide (NO) Production in Vascular Smooth Muscle CellsJOURNAL OF CARDIAC SURGERY, Issue 6 2002Gabriel HH Chan Objectives: Inducible form of nitric oxide synthase (iNOS) is induced by cytokines (e.g. interleukin-1, (IL-1,)) during pathological conditions, such as sepsis. Excessive NO synthesis in blood vessels during sepsis can result in massive vasodilation and life-threatening hypotension. In addition, chronic expression of iNOS contributes to onset of diabetes, autoimmune diseases, arthritis, renal toxicity, and neurodegenerative disorders. The purpose of the present study was to examine the effect of aging on the levels of expression of iNOS induced by a low concentration (5 ng/ml) of IL-1, in VSMCs. Methods: Gene expression of iNOS was determined by RT-PCR and analysis of the PCR products by both agarose gel electrophoresis and capillary electrophoresis with laser-induced fluorescence detector (CE-LIF). This new CE-LIF technique, just developed in our laboratory, provides greater than 1,000 fold better sensitivity compared to agarose gels. The production of nitrite, the stable metabolite of NO, was measured (by a modified Griess reaction) in the media of cultured VSMCs isolated from young and elderly rats (3-month and 20-months old, respectively) of both genders following the exposure to IL-1, (5 ng/ml). VSMCs were used in their 1st passage to avoid phenotypic changes that typically occur in cultures of VSMCs after 3-10 passages. Results: IL-1, (5 ng/ml) caused a much larger increase in iNOS mRNA in VSMCs of elderly rats as compared to young rats. Furthermore, IL-1, (5 ng/ml) had no significant effect on nitrite levels in VSMCs of young, but significantly increased nitrite levels by 7.9 fold in VSMCs from elderly male rats and by 2.6 fold in VSMCs from elderly female rats, as compared to young rats. A report had previously shown that the neuropeptide CGRP could synergistically enhance the expression of iNOS caused by IL-1, in later passages (10-15 passages) of rat aortic VSMCs (i.e. phenotypically modulated VSMCs). We found that IL-1, and CGRP together did not act synergistically to increase production of nitrite in our phenotypically normal (1st passage) VSMCs. Conclusion: IL-1,, at a low concentration (5 ng/ml), preferentially induces iNOS expression and increases production of NO in VSMCs of elderly rats as compared to young rats. The data suggest that aging enhances the responsiveness of VSMCs to the iNOS-inducing actions of the cytokine IL-1,. This may be a contributing factor in the increased risk of developing severe hypotension in elderly patients with sepsis. (Supported by a Direct Grant for Research). [source] Rapid co-release of interleukin 1, and caspase 1 in spinal cord inflammationJOURNAL OF NEUROCHEMISTRY, Issue 3 2006Anna K. Clark Abstract Mounting evidence supports the hypothesis that pro-inflammatory cytokines secreted by astrocytes and microglia modulate nociceptive function in the injured CNS and following peripheral nerve damage. Here we examine the involvement of interleukin-1, (IL-1,) and microglia activation in nociceptive processing in rat models of spinal cord inflammation. Following application of lipopolysaccharide (LPS) to an ex vivo dorsal horn slice preparation, we observed rapid secretion of IL-1, which was prevented by inhibition of glial cell metabolism and by inhibitors of either p38 mitogen-activated protein kinase (MAPK) or caspase 1. LPS superfusion also induced rapid secretion of active caspase 1 and apoptosis-associated speck-like protein containing a caspase recruitment domain from the isolated dorsal horn. Extensive microglial cell activation in the dorsal horn, as determined by immunoreactivity for phosphorylated p38 MAPK, was found to correlate with the occurrence of IL-1, secretion. In behavioural studies, intrathecal injection of LPS in the lumbar spinal cord produced mechanical hyperalgesia in the rat hind-paws which was attenuated by concomitant injections of a p38 MAPK inhibitor, a caspase 1 inhibitor or the rat recombinant interleukin 1 receptor antagonist. These data suggest a critical role for the cytokine IL-1, and caspase 1 rapidly released by activated microglia in enhancing nociceptive transmission in spinal cord inflammation. [source] Inflammatory cytokines in glomerulonephritisNEPHROLOGY, Issue 2002RC ATKINS SUMMARY: The importance of various inflammatory cytokines in mediating renal disease is now recognized, and the potential for the use of cytokine blockade as a therapeutic intervention is under active investigation. Studies in rat anti-glomerular basement membrane (GBM) disease model showed that antagonism of the proinflammatory cytokine IL-1 inhibited induction of glomerulonephritis, and prevented progression of established disease. A second cytokine Tumour Necrosis Factor-alpha (TNF-,) had similar proinflammatory effects to IL-1 in this model. Blocking the actions of both cytokines together, however, had no added benefit. Another cytokine Macrophage Migration Inhibitory Factor (MIF) has been shown to override the anti-inflammatory effects of corticosteriods. Renal MIF is markedly up-regulated in rat anti-GBM disease and blocking studies have demonstrated MIF plays a pathological role in mediating renal injury in this model. the importance of MIF in glomerulonephritis has been demonstrated by the fact that MIF is produced locally within the kidney, that it reflects the severity of the cellular immune response, and can be measured in the urine. Macrophage Migration Inhibitory Factor is up-regulated in human glomerular disease and correlates with loss of renal function and is thus a potential target for therapy for human glomerulonephritis. Thus, the inflammatory cytokines, IL 1, TNF-, and MIF each play a role in the immune/inflammatory process in glomerulonephritis. Blocking their action reduces disease and cytokine blocking agents have therapeutic potential. [source] Knockdown of Fc, receptor III in an arthritic temporomandibular joint reduces the nociceptive response in ratsARTHRITIS & RHEUMATISM, Issue 10 2010Phillip R. Kramer Objective Fc, receptor III (Fc,RIII; CD16) is a receptor expressed on immune cells that selectively binds IgG molecules. IgG binding results in cellular activation and cytokine release. IgG is an important factor in arthritis and can be found in the arthritic temporomandibular joint (TMJ). We undertook this study to test the hypothesis that a reduction in Fc,RIII expression in TMJ tissues would reduce the nociceptive and inflammatory responses in an inflamed joint. Methods Small interfering RNA (siRNA), either naked or complexed with linear polyethyleneimine, was injected into the superior joint space of the TMJ in rats. After administration of siRNA the joint was injected with saline or with Freund's complete adjuvant to induce arthritis. Nociceptive responses were quantitated in the rat by measuring the animal's meal duration. Fc,RIII expression in the TMJ tissue was assayed by immunocytochemistry or Western blotting. Cleavage of Fc,RIII transcript was then assayed by 5, rapid amplification of complementary DNA ends. Interleukin-1, (IL-1,) and IgG content was measured in the TMJ tissue by enzyme-linked immunosorbent assay. Results Injection of Fc,RIII siRNA reduced the amount of Fc,RIII in the TMJ tissues, and the transcript was cleaved in a manner consistent with an RNA interference mechanism. Moreover, injection of Fc,RIII siRNA reduced the nociceptive response of rats with an arthritic TMJ and reduced the amount of the proinflammatory cytokine IL-1,. Conclusion Fc,RIII contributes to the pain resulting from inflammatory arthritis of the TMJ, and siRNA has the potential to be an effective treatment for this disorder. [source] Influenza A viruses with truncated NS1 as modified live virus vaccines: Pilot studies of safety and efficacy in horsesEQUINE VETERINARY JOURNAL, Issue 1 2009T. M. Chambers Summary Reasons for performing study: Three previously described NS1 mutant equine influenza viruses encoding carboxyterminally truncated NS1 proteins are impaired in their ability to inhibit type I IFN production in vitro and are replication attenuated, and thus are candidates for use as a modified live influenza virus vaccine in the horse. Hypothesis: One or more of these mutant viruses is safe when administered to horses, and recipient horses when challenged with wild-type influenza have reduced physiological and virological correlates of disease. Methods: Vaccination and challenge studies were done in horses, with measurement of pyrexia, clinical signs, virus shedding and systemic proinflammatory cytokines. Results: Aerosol or intranasal inoculation of horses with the viruses produced no adverse effects. Seronegative horses inoculated with the NS1-73 and NS1-126 viruses, but not the NS1-99 virus, shed detectable virus and generated significant levels of antibodies. Following challenge with wild-type influenza, horses vaccinated with NS1-126 virus did not develop fever (>38.5°C), had significantly fewer clinical signs of illness and significantly reduced quantities of virus excreted for a shorter duration post challenge compared to unvaccinated controls. Mean levels of proinflammatory cytokines IL-1, and IL-6 were significantly higher in control animals, and were positively correlated with peak viral shedding and pyrexia on Day +2 post challenge. Conclusion and clinical relevance: These data suggest that the recombinant NS1 viruses are safe and effective as modified live virus vaccines against equine influenza. This type of reverse genetics-based vaccine can be easily updated by exchanging viral surface antigens to combat the problem of antigenic drift in influenza viruses. [source] A crucial role for macrophages in the pathology of K/B,×,N serum-induced arthritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2005Samuel Solomon Abstract Autoantibodies in the form of immune complexes are known to be crucial mediators in initiating inflammation in a variety of autoimmune diseases. This has been well documented in the anti-collagen,II antibody-induced arthritis animal model for a long time now. Recently, in the K/B,×,N mouse model (the F1 of the TCR-transgenic KRN and the diabetic NOD mice), anti-glucose-6-phosphate isomerase (GPI) autoantibodies have been shown to induce arthritis. Experimental work in the K/B,×,N model demonstrated key roles of autoantigenic immune complexes activating the alternative pathway of complement, the subsequent association with C5aR and Fc,RIII-mediated cell activation and production of the inflammatory cytokines IL-1 and TNF-,, finally leading to joint destruction. The presence of high amounts of inflammatory cytokines and matrix-degrading proteases at sites of inflammation obviously put the cytokine-producing macrophages as the next target for investigation in this model. Here, we show that mice depleted of macrophages by clodronate liposome treatment are completely resistant to K/B,×,N serum-induced arthritis. Reconstituting clodronate liposome-treated mice with macrophages from naive animals could reverse this resistance. Also, we found that deficiencies in the Wiskott-Aldrich syndrome protein and CD40, which are both implicated in macrophage activation, chemotaxis and phagocytosis, are not essential in serum-induced arthritis. Mast cell degranulation was seen in arthritogenic serum-treated mice even in the absence of macrophages, possibly suggesting that mast cell degranulation/activation acts hierarchically before macrophages in the inflammatory cascade of anti-GPI antibody-induced arthritis. [source] Helicobacter pylori Infection in the Cat: Evaluation of Gastric Colonization, Inflammation and FunctionHELICOBACTER, Issue 1 2001Kenneth W. Simpson Background. Further elucidation of the consequences of Helicobacter pylori infection on gastric mucosal inflammation and gastric secretory function would be facilitated by an animal model that is susceptible to infection with H. pylori, is broadly similar in gastric physiology and pathology to people, and is amenable to repeated non-invasive evaluation. The goal of this study was to examine the interrelationship of bacterial colonization, mucosal inflammation and gastric secretory function in cats with naturally acquired H. pylori infection. Materials and Methods. Twenty clinically healthy cats with naturally acquired H. pylori infection (cagA,, picB) and 19 Helicobacter -free cats were evaluated. Gastric colonization was determined by tissue urease activity, light microscopy, culture and PCR. The mucosal inflammatory response was evaluated by light microscopy, and by RT-PCR of the pro-inflammatory cytokines IL-1,, IL-1,, IL-8 and TNF-, in gastric mucosa. Gastric secretory function was assessed by measuring pentagastrin-stimulated acid secretion, fasting plasma gastrin, and antral mucosal gastrin and somatostatin immunoreactivity. Results. H. pylori colonized the pylorus, fundus and cardia in similar density. Bacteria were observed free in the lumen of gastric glands and were also tightly adherent to epithelial cells where they were associated with microvillus effacement. Mononuclear inflammation, lymphoid follicle hyperplasia, atrophy and fibrosis were observed primarily in H. pylori -infected cats, with the pylorus most severely affected. Neutrophilic and eosinophilic infiltrates, epithelial dysplasia, and up-regulation of mucosal IL-1, and IL-8 were observed solely in infected cats. Fasting plasma gastrin concentrations and pentagastrin-stimulated acid output were similar in both infected and uninfected cats. There was no relationship of bacterial colonization density or gastric inflammation to plasma gastrin concentrations or gastric acid output. Conclusions. The pattern of colonization and the mucosal inflammatory response in cats with naturally acquired H. pylori are broadly similar to those in infected people, particularly children, and non-human primates. The upregulation of IL-8 in infected cats was independent of cagA and picB. Our findings argue against a direct acid-suppressing effect of H. pylori on the gastric secretory-axis in chronically infected cats. Abbreviations: RT-PCR, reverse transcriptase polymerase chain reaction, HLO; Helicobacter -like organisms. [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] An optimized method for intensive screening of molecules that stimulate , -defensin 2 or 3 (hBD2 or hBD3) expression in cultured normal human keratinocytesINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 3 2005I. Pernet Synopsis Normal human skin controls the intrusion of microorganisms by the production of peptide antibiotics such as defensins. The aim of our study was to develop a culture model of normal human keratinocytes for optimal , -defensin mRNA detection which allows the screening of molecules able to stimulate hBD2 and hBD3 without inducing pro-inflammatory cytokines. A keratinocyte culture model in 96-well plates, in high calcium medium (1.7 mm) allowed to analyze hBD2 and hBD3 mRNA expression in basal condition and after cell stimulation by products from diverse vegetal extracts. The release of IL-8 and the chemokine MIP-3, was also evaluated in cell supernatants by ELISA. Among the 184 extracts tested, 75 showed a stimulatory effect on , -defensin expression: 40 on hBD2, 26 on hBD3 and nine on both defensins. Fifteen of these substances which also induced the release of pro-inflammatory cytokines were eliminated. Among the other substances, four were selected and were analyzed in a dose-dependent study (n = 4) by real-time quantitative RT-PCR and completed by a measure of MIP-3,, IL-8 and IL-1, levels. These data underline the important necessity of screening result controls by a quantitative method reproduced at least three times. This new method of intensive screening allowed us to exhibit vegetal extracts that were able to stimulate epidermal , -defensin expression without inducing an up-secretion of pro-inflammatory cytokines. Résumé La peau humaine normale exerce une fonction barrière contre l'intrusion de microorganismes par la production de peptides antibiotiques comme les défensines. Le but de cette étude a consistéà mettre au point un modèle de culture de kératinocytes humains normaux permettant une détection optimale des ARNm des défensines en général, et adapté au screening de molécules aptes à stimuler les défensines épidermiques hBD2 et hBD3 en particulier, sans induire de cytokines pro-inflammatoires. Un modèle de culture de kératinocytes en plaques 96 puits, en milieu riche en calcium (1,7 mm) permet une analyse de l'expression des ARNm de hBD2 et hBD3 en condition basale et après stimulation par divers extraits végétaux. La sécrétion d'IL-8 et de la chimiokine MIP-3, a étéévaluée dans les surnageants de culture par ELISA. Parmi les 184 extraits testés, 75 montrent un effet stimulant sur l'expression des , -défensines : 40 ont un effet sur hBD2, 26 sur hBD3 et 9 sur les 2 types de défensines. Quinze de ces actifs qui induisent aussi la sécrétion de cytokines pro-inflammatoires ont étééliminés. Parmi les autres molécules, 4 ont été sélectionnées pour faire l'objet d'une étude de leurs effets-doses (n = 4) sur l'expression des , -défensines par une technique quantitative de RT-PCR en temps réel. Cette étude est complétée par le dosage des cytokines IL-1,, IL-8 et MIP-3,. Les résultats obtenus soulignent l'importante nécessitée de contrôler au moins trois fois par une méthode quantitative les résultats d'un screening. Cette nouvelle méthode de screening intensif nous a permis de mettre en évidence des extraits végétaux capables de stimuler les défensines épidermiques sans induire de cytokines pro-inflammatoires. [source] c-Jun N-terminal kinase is largely involved in the regulation of tricellular tight junctions via tricellulin in human pancreatic duct epithelial cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010Takashi Kojima Tricellulin (TRIC) is a tight junction protein at tricellular contacts where three epithelial cells meet, and it is required for the maintenance of the epithelial barrier. To investigate whether TRIC is regulated via a c-Jun N-terminal kinase (JNK) pathway, human pancreatic HPAC cells, highly expressed at tricellular contacts, were exposed to various stimuli such as the JNK activators anisomycin and 12- O -tetradecanoylphorbol 13-acetate (TPA), and the proinflammatory cytokines IL-1,, TNF,, and IL-1,. TRIC expression and the barrier function were moderated by treatment with the JNK activator anisomycin, and suppressed not only by inhibitors of JNK and PKC but also by siRNAs of TRIC. TRIC expression was induced by treatment with the PKC activator TPA and proinflammatory cytokines IL-1,, TNF,, and IL-1,, whereas the changes were inhibited by a JNK inhibitor. Furthermore, in normal human pancreatic duct epithelial cells using hTERT-transfected primary cultured cells, the responses of TRIC expression to the various stimuli were similar to those in HPAC cells. TRIC expression in tricellular tight junctions is strongly regulated together with the barrier function via the JNK transduction pathway. These findings suggest that JNK may be involved in the regulation of tricellular tight junctions including TRIC expression and the barrier function during normal remodeling of epithelial cells, and prevent disruption of the epithelial barrier in inflammation and other disorders in pancreatic duct epithelial cells. J. Cell. Physiol. 225: 720,733, 2010. © 2010 Wiley-Liss, Inc. [source] Binding of anti-HLA class I antibody to endothelial cells produce an inflammatory cytokine secretory pattern,JOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 3 2009Eduardo Reyes-Vargas Abstract Current methods are inadequate for the diagnosis of early chronic allograft rejection. The goal of this study was to determine whether ligation of anti-HLA antibodies to endothelial cells is associated with a distinctive cytokine secretory pattern. Human iliac artery endothelial cells (HIAEC) cultured in vitro were incubated with w6/32, an anti-HLA class I mAb. Culture supernatants collected daily for up to 4 days were tested for secretion of 13 cytokines using a multiplexed fluorescent microsphere immunoassay. Culture of HIAEC with medium containing mAb w6/32 supported the growth of HIAEC during the 4-day study period. Levels of the pro-inflammatory cytokines IL-1,, IL-6, IL-8, and TNF-, became significantly increased in supernatants of HIAEC incubated with the mAb w6/32. We conclude that ligation of anti-HLA class I antibodies to HLA class I antigens in endothelial cells initiates an acute inflammatory process and detecting an inflammatory cytokine secretory pattern might be useful to diagnose sub-clinical chronic allograft rejection. J. Clin. Lab. Anal. 23:157,160, 2009. © 2009 Wiley-Liss, Inc. [source] Gene regulation of ,4,2 nicotinic receptors: microarray analysis of nicotine-induced receptor up-regulation and anti-inflammatory effectsJOURNAL OF NEUROCHEMISTRY, Issue 3 2009Vishnu Hosur Abstract ,4,2 Nicotinic acetylcholine receptors play an important role in the reward pathways for nicotine. We investigated whether receptor up-regulation of ,4,2 nicotinic acetylcholine receptors involves expression changes for non-receptor genes. In a microarray analysis, 10 ,M nicotine altered expression of 41 genes at 0.25, 1, 8 and 24 h in h,4,2 SH-EP1 cells. The maximum number of gene changes occurred at 8 h, around the initial increase in 3[H]-cytisine binding. Quantitative RT-PCR corroborated gene induction of endoplasmic reticulum proteins CRELD2, PDIA6, and HERPUD1, and suppression of the pro-inflammatory cytokines IL-1, and IL-6. Nicotine suppresses IL-1, and IL-6 expression at least in part by inhibiting NF,B activation. Antagonists dihydro-,-erythroidine and mecamylamine blocked these nicotine-induced changes showing that receptor activation is required. Antagonists alone or in combination with nicotine suppressed CRELD2 message while increasing ,4,2 binding. Additionally, small interfering RNA knockdown of CRELD2 increased basal ,4,2 receptor expression, and antagonists decreased CRELD2 expression even in the absence of ,4,2 receptors. These data suggest that endoplasmic reticulum proteins such as CRELD2 can regulate ,4,2 expression, and may explain antagonist actions in nicotine-induced receptor up-regulation. Further, the unexpected finding that nicotine suppresses inflammatory cytokines suggests that nicotinic ,4,2 receptor activation promotes anti-inflammatory effects similar to ,7 receptor activation. [source] Advanced glycation endproducts and pro-inflammatory cytokines in transgenic Tg2576 mice with amyloid plaque pathologyJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Gerald Münch Abstract Increased expression and altered processing of the amyloid precursor protein (APP) and generation of ,-amyloid peptides is important in the pathogenesis of amyloid plaques in Alzheimer's disease (AD). Transgenic Tg2576 mice overexpressing the Swedish mutation of human APP exhibit ,-amyloid deposition in the neocortex and limbic areas, accompanied by gliosis and dystrophic neurites. However, murine plaques appear to be less cross-linked and the mice show a lower degree of inflammation and neurodegeneration than AD patients. ,Advanced glycation endproducts (AGEs)', formed by reaction of proteins with reactive sugars or dicarbonyl compounds, are able to cross-link proteins and to activate glial cells, and are thus contributing to plaque stability and plaque-induced inflammation in AD. In this study, we analyze the tissue distribution of AGEs and the pro-inflammatory cytokines IL-1, and TNF-, in 24-month-old Tg2576 mice, and compare the AGE distribution in these mice with a younger age group (13 months old) and a typical Alzheimer's disease patient. Around 70% of the amyloid plaque cores in the 24-month-old mice are devoid of AGEs, which might explain their solubility in physiological buffers. Plaque associated glia, which express IL-1, and TNF-,, contain a significant amount of AGEs, suggesting that plaques, i.e. A, as its major component, can induce intracellular AGE formation and the expression of the cytokines on its own. In the 13-month-old transgenic mice, AGEs staining can neither be detected in plaques nor in glial cells. In contrast, AGEs are present in high amounts in both plaques and glia in the human AD patient. The data obtained in this show interesting differences between the transgenic mouse model and AD patients, which should be considered using the transgenic approach to test therapeutical strategies to eliminate plaques or to attenuate the inflammatory response in AD. [source] Alcohol Consumption Attenuates Febrile Responses to Lipopolysaccharide and Interleukin-1, in Male RatsALCOHOLISM, Issue 1 2002Anna N. Taylor Background: Chronic and acute alcohol use exert profound modulatory effects on the immune system which manifest as impaired host defense against infections. An important feature of this response is the interaction between the immune and the central nervous systems. This study investigated the effects of 14 days of alcohol exposure on cytokine-mediated neuroimmune interactions that affect the febrile component of the host-defense response. Methods: Adult male rats were fed a liquid diet containing ethanol (EtOH, 5% w/v) for 14 days. Pair-fed and normal chow- and water-fed rats served as controls. Continuous biotelemetric recordings of body temperature and locomotor activity commencing after 14 days of EtOH feeding were used to determine the effects of chronic EtOH on the circadian pattern of temperature and activity, on the febrile response to intraperitoneal (ip) administration of lipopolysaccharide (LPS) and interleukin (IL)-1,, and on fever induced by IL-1, administered intracerebroventricularly. We also examined the effects of EtOH consumption on LPS-induced hypothalamic production of the pyrogenic cytokines IL-1, and tumor necrosis factor-, (TNF,) and on the blood levels of IL-1,, TNF,, IL-6, adrenocorticotropin, and corticosterone at 2, 4, and 6 hr after ip LPS. Results: Fourteen days of EtOH consumption blunted the circadian increases in temperature and activity that normally occur in the dark phase of the light/dark cycle without affecting light-phase temperature or activity. EtOH consumption attenuated fever induced by LPS or IL-1, administered ip during the light phase and significantly reduced hypothalamic production of IL-1,. LPS-induced increases in hypothalamic TNF, and blood cytokines, adrenocorticotropin, and corticosterone were unaffected. Central administration of IL-1, produced a normal febrile response in chronic-EtOH rats. Conclusions: The attenuated LPS- and IL-1,,induced febrile responses in EtOH-consuming rats and the corresponding deficit in hypothalamic production of IL-1, suggest that alcohol may impair IL-1,,mediated neuroimmune communication. [source] Tumor necrosis factor , blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cellsARTHRITIS & RHEUMATISM, Issue 2 2010Hak-Ling Ma Objective Patients with psoriasis and psoriatic arthritis respond well to tumor necrosis factor , (TNF,) blockers in general; however, there is now mounting evidence that a small cohort of patients with rheumatoid arthritis who receive TNF, blockers develop psoriasis. This study was undertaken to explore the mechanisms underlying TNF, blockade,induced exacerbation of skin inflammation in murine psoriasis-like skin disease. Methods Skin inflammation was induced in BALB/c scid/scid mice after they received CD4+CD45RBhighCD25, (naive CD4) T cells from donor mice. These mice were treated with either anti,interleukin-12 (anti,IL-12)/23p40 antibody or murine TNFRII-Fc fusion protein and were examined for signs of disease, including histologic features, various cytokine levels in the serum, and cytokine or FoxP3 transcripts in the affected skin and draining lymph node (LN) cells. In a separate study, naive CD4+ T cells were differentiated into Th1 or Th17 lineages with anti-CD3/28 magnetic beads and appropriate cytokines in the presence or absence of TNF,. Cytokine gene expression from these differentiated cells was also determined. Results Neutralization of TNF, exacerbated skin inflammation and markedly enhanced the expression of the proinflammatory cytokines IL-1,, IL-6, IL-17, IL-21, and IL-22 but suppressed FoxP3 expression in the skin and reduced the number of FoxP3-positive Treg cells in the draining LNs. TNF, also demonstrated a divergent role during priming and reactivation of naive T cells. Conclusion These results reveal a novel immunoregulatory role of TNF, on Th17 and Treg cells in some individuals, which may account for the exacerbation of skin inflammation in some patients who receive anti-TNF treatments. [source] Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal,induced murine peritoneal model of acute goutARTHRITIS & RHEUMATISM, Issue 1 2009William John Martin Objective To determine whether infiltrating monocytes, neutrophils, or resident macrophages contribute to the early inflammatory response to monosodium urate monohydrate (MSU) crystals in vivo. Methods MSU crystal,induced inflammation was monitored using a peritoneal model of acute gout. The production of proinflammatory cytokines (interleukin-1, [IL-1,], tumor necrosis factor , [TNF,], IL-6) by resident macrophages, infiltrating monocytes, and neutrophils during the onset of gout was determined by flow cytometry. Infiltrating and resident peritoneal cells were cultured with MSU crystals ex vivo, and proinflammatory cytokine production was determined by multiplex cytokine array. Activated macrophages on the visceral epithelial lining of the peritoneum were identified by immunofluorescence histochemistry. The inflammatory immune response to MSU crystals was then compared with the inflammatory response in mice depleted of resident macrophages by pretreatment with clodronate liposomes. Results The production of cytokines in vivo preceded the influx of Gr-1intermediate7/4+ monocytes. Monocytes and neutrophils recruited during the inflammatory phase of the response to MSU crystals failed to produce proinflammatory cytokines either in vivo, or ex vivo following restimulation with MSU crystals. Stimulation of the naive peritoneal resident cell population with MSU crystals ex vivo resulted in positive staining of resident macrophages for the proinflammatory cytokines IL-1,, TNF,, and IL-6. Depletion of the resident macrophage population resulted in a significant decrease in both MSU crystal,induced neutrophil infiltration and proinflammatory cytokine production in vivo despite the presence of infiltrating monocytes. Conclusion These data indicate that resident macrophages, rather than infiltrating monocytes or neutrophils, are important for initiating and driving the early proinflammatory phase of acute gout. [source] Synthetic double-stranded RNA induces multiple genes related to inflammation through Toll-like receptor 3 depending on NF-,B and/or IRF-3 in airway epithelial cellsCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2006S. Matsukura Summary Background We hypothesized that synthetic double-stranded (ds)RNA may mimic viral infection and induce expression of genes related to inflammation in airway epithelial cells. Objective We analysed what gene was up-regulated by synthetic dsRNA poly I : C and then focused this study on the role of Toll-like receptor 3 (TLR3), a receptor of dsRNA and its transcriptional pathway. Methods Airway epithelial cell BEAS-2B and normal human bronchial epithelial cells were cultured in vitro. Expression of targets RNA and protein were analysed by PCR and ELISA. Localization of TLR3 expression in the cells was analysed with flow cytometry. To analyse the role of TLR3 and transcription factors, knockdown of these genes was performed with short interfering RNA (siRNA). Results Real-time PCR revealed that poly I : C significantly increased the expression of mRNAs for chemokines IP-10, RANTES, LARC, MIP-1,, IL-8, GRO-, and ENA-78 and cytokines IL-1,, GM-CSF, IL-6 and the cell adhesion molecule ICAM-1 in both cell types. Increases in protein levels were also observed. Expression of these genes was significantly inhibited in BEAS-2B cells in which TLR3 expression was knocked down. However, pre-treatment with anti-TLR3 mAb, which interferes with the function of TLR3 expressed on the cell surface, did not inhibit the genes expression and these data were concordant with the results that TLR3 was expressed inside airway epithelial cells. The study of siRNA for NF-,B and IRF3 showed that they transduce the signal of poly I : C, but their roles were different in each target gene. Conclusion TLR3 is expressed inside airway epithelial cells and transduces synthetic dsRNA signals. These signals may increase expression of inflammatory cytokines, chemokines and ICAM-1 through activation of transcription factors NF-,B and/or IRF3 in airway epithelial cells. [source] | |||||||||||||