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Interleukin
Kinds of Interleukin Selected AbstractsRole of interleukin-15 in the development of mouse olfactory nerveCONGENITAL ANOMALIES, Issue 4 2009Tsuyoshi Umehara ABSTRACT Interleukin (IL)-15 interacts with components of the IL-2 receptor (R) and exhibits T cell-stimulating activity similar to that of IL-2. In addition, IL-15 is widely expressed in many cell types and tissues, including the central nervous system. We provide evidence of a novel role of IL-15 in olfactory neurogenesis. Both IL-15 and IL-15R, were expressed in neuronal precursor cells of the developing olfactory epithelium in mice. Adult IL-15R, knockout mice had fewer mature olfactory neurons and proliferating cells than wild-type. Our results suggest that IL-15 plays an important role in regulating cell proliferation in olfactory neurogenesis. [source] Polymorphisms in the interleukin-1 gene influence the stratum corneum interleukin-1, concentration in uninvolved skin of patients with chronic irritant contact dermatitisCONTACT DERMATITIS, Issue 5 2008Cindy M. DeJongh Background:, Interleukin (IL)-1, and its receptor antagonist IL-1ra play a role in skin inflammation. Several polymorphisms in the IL1 gene cluster, coding for IL-1,, IL-1ra, and IL-1,, influence their protein expression. Within this cluster, strong linkage disequilibrium has been shown. Objective:, We studied the association between the polymorphisms IL1A -889 (C,T) and IL1B -31 (T,C) and the concentration of IL-1, and IL-1ra in the stratum corneum (SC). Method:, In 124 patients with chronic irritant contact dermatitis, we genotyped the IL1A -889 and IL1B -31 polymorphisms and determined the amount of IL-1, and IL-1ra on tape strips obtained from uninvolved skin of the volar forearm. Results:, The SC IL-1, concentration was 23% and 47% lower in subjects with IL1A -889 C/T genotype and T/T genotype, respectively, compared with wild-type genotype. In subjects with IL1B -31 C/C genotype, the IL-1, concentration was 51% lower compared with C/T and T/T genotypes. The ratio IL-1ra/IL-1, increased twofold in IL1A -889 C/T genotype and threefold in T/T genotype compared with wild type. Conclusions:, We have shown a clear effect of IL1 genotype on protein expression in the SC. This altered expression may be responsible for the interindividual differences in the inflammatory response of the skin. [source] A region on equine chromosome 13 is linked to recurrent airway obstruction in horsesEQUINE VETERINARY JOURNAL, Issue 3 2007U. JOST Summary Reasons for study: Equine recurrent airway obstruction (RAO) is probably dependent on a complex interaction of genetic and environmental factors and shares many characteristic features with human asthma. Interleukin 4 receptor , chain (IL4RA) is a candidate gene because of its role in the development of human asthma, confirmation of this association is therefore required. Methods: The equine BAC clone containing the IL4RA gene was localised to ECA13q13 by the FISH method. Microsatellite markers in this region were investigated for possible association and linkage with RAO in 2 large Warmblood halfsib families. Based on a history of clinical signs (coughing, nasal discharge, abnormal breathing and poor performance), horses were classified in a horse owner assessed respiratory signs index (HOARSI 1,4: from healthy, mild, moderate to severe signs). Four microsatellite markers (AHT133, LEX041, VHL47, ASB037) were analysed in the offspring of Sire 1 (48 unaffected HOARSI 1 vs. 59 affected HOARSI 2,4) and Sire 2 (35 HOARSI 1 vs. 50 HOARSI 2,4), age ,7 years. Results: For both sires haplotypes could be established in the order AHT133-LEX047-VHL47-ASB37. The distances in this order were estimated to be 2.9, 0.9 and 2.3 centiMorgans, respectively. Haplotype association with mild to severe clinical signs of chronic lower airway disease (HOARSI 2,4) was significant in the offspring of Sire 1 (P = 0.026) but not significant for the offspring of Sire 2 (P = 0.32). Linkage analysis showed the ECA13q13 region containing IL4RA to be linked to equine chronic lower airway disease in one family (P<0.01), but not in the second family. Conclusions: This supports a genetic background for equine RAO and indicates that IL4RA is a candidate gene with possible locus heterogeneity for this disease. Potential relevance: Identification of major genes for RAO may provide a basis for breeding and individual prevention for this important disease. [source] Functional epitope of common , chain for interleukin-4 bindingFEBS JOURNAL, Issue 5 2002Jin-Li Zhang Interleukin 4 (IL-4) can act on target cells through an IL-4 receptor complex consisting of the IL-4 receptor , chain and the common , chain (,c). An IL-4 epitope for ,c binding has previously been identified. In this study, the ,c residues involved in IL-4 binding were defined by alanine-scanning mutational analysis. The epitope comprises ,c residues I100, L102, and Y103 on loop EF1 together with L208 on loop FG2 as the major binding determinants. These predominantly hydrophobic determinants interact with the hydrophobic IL-4 epitope composed of residues I11, N15, and Y124. Double-mutant cycle analysis revealed co-operative interaction between ,c and IL-4 side chains. Several ,c residues involved in IL-4 binding have been previously shown to be mutated in X-linked severe combined immunodeficiency. The importance of these binding residues for ,c function is discussed. These results provide a basis for elucidating the molecular recognition mechanism in the IL-4 receptor system and a paradigm for other ,c -dependent cytokine receptor systems. [source] Interleukin 15 expression in the CNS: Blockade of its activity prevents glial activation after an inflammatory injuryGLIA, Issue 5 2008Diego Gómez-Nicola Abstract Although reactive glia formation after neuronal degeneration or traumatic damage is one of the hallmarks of central nervous system (CNS) injury, we have little information on the signals that direct activation of resting glia. IL-15, a pro-inflammatory cytokine involved in regulating the response of T and B cells, may be also key for the regulation of early inflammatory events in the nervous system. IL-15 was expressed in the CNS, most abundantly in cerebellum and hippocampus, mainly in astrocytes and in some projection neurons. Using a rodent model of acute inflammatory injury [lipopolysaccharide (LPS) injection], we found enhanced expression of IL-15 in both reactive astroglia and microglia, soon after CNS injury. Blockade of IL-15 activity with an antibody to the cytokine, reversed activation of both glial types, suggesting that IL-15 has a major role in the generation of gliotic tissue and in the regulation of neuroimmune responses. Because IL-15 appears to modulate the inflammatory environment acutely generated after CNS injury, regulating IL-15 expression seems a clear antiinflammatory therapy to improve the outcome of neurodegenerative diseases and CNS trauma. © 2008 Wiley-Liss, Inc. [source] Interleukin 6 alleviates hepatic steatosis and ischemia/reperfusion injury in mice with fatty liver diseaseHEPATOLOGY, Issue 4 2004Feng Hong Fatty liver, formerly associated predominantly with excessive alcohol intake, is now also recognized as a complication of obesity and an important precursor state to more severe forms of liver pathology including ischemia/reperfusion injury. No standard protocol for treating fatty liver exists at this time. We therefore examined the effects of 10 days of interleukin 6 (IL-6) injection in 3 murine models of fatty liver: leptin deficient ob/ob mice, ethanol-fed mice, and mice fed a high-fat diet. In all 3 models, IL-6 injection decreased steatosis and normalized serum aminotransferase. The beneficial effects of IL-6 treatment in vivo resulted in part from an increase in mitochondrial , oxidation of fatty acid and an increase in hepatic export of triglyceride and cholesterol. However, administration of IL-6 to isolated cultured steatotic hepatocytes failed to decrease lipid contents, suggesting that the beneficial effects of IL-6 in vivo do not result from its effects on hepatocytes alone. IL-6 treatment increased hepatic peroxisome proliferator-activated receptor (PPAR) , and decreased liver and serum tumor necrosis factor (TNF) ,. Finally, 10 days of treatment with IL-6 prevented the susceptibility of fatty livers to warm ischemia/reperfusion injury. In conclusion, long-term IL-6 administration ameliorates fatty livers and protects against warm ischemia/reperfusion fatty liver injury, suggesting the therapeutic potential of IL-6 in treating human fatty liver disease. Supplementary material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2004;40:933,941.) [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] Roles of the novel interleukin-12-associated cytokine, interleukin-23, in the regulation of T-cell-mediated immunityHEPATOLOGY RESEARCH, Issue 2007Masanori Matsui Interleukin (IL)-12 is a heterodimeric proinflammatory cytokine formed by a 35-kDa light chain (p35) and a 40-kDa heavy chain (p40). This cytokine is a key regulator of cell-mediated immunity, and therefore should have therapeutic potential in infectious diseases and tumors. Recently, a novel IL-12-associated cytokine, IL-23 has been discovered. IL-23 is also a heterodimer that consists of the p40 subunit of IL-12 and a novel subunit, p19. Several studies have shown that IL-23 possesses immunoadjuvant activity against tumor and infectious diseases as well as IL-12. On the other hand, there is increasing evidence that IL-12 and IL-23 have discrete roles in the regulation of T-cell-mediated immunity despite their structural similarities. IL-12 leads to the development ofinterferon-,-producing T-helper type 1 (Th1) cells, whereas IL-23 amplifies and stabilizes a new CD4+ T-cell subset, Th17 producing IL-17. The IL-23/Th17 axis rather than the IL-12/Th1 axis contributes to several immune-mediated inflammatory autoimmune diseases. Furthermore, IL-23/IL-17 promotes tumor incidence and growth. Therefore, IL-23 and Th17 are attracting considerable attention at present. Taken together, these findings suggest that IL-23 may be an immunoadjuvant against infectious diseases and tumors, and a viable target for the treatment of inflammatory diseases. [source] Interleukin-17 as a new marker of severity of acute hepatic injuryHEPATOLOGY RESEARCH, Issue 4 2007Yuki Yasumi Aim:, To determine cytokines associated with the progression of acute hepatic injury (AHI), we comprehensively evaluated the serum levels of 17 cytokines. Methods:, We simultaneously measured serum levels of 17 cytokines on admission using a newly developed suspension array protein assay system in 51 patients with AHI, including 15 conventional AHI (CAHI), 15 severe AHI (SAHI) and 21 fulminant hepatic failure (FHF). Results:, Interleukin (IL)-6, IL-8 and IL-17 levels were significantly different among the three disease types as determined by one-way analysis of variance, and only the IL-17 level showed a significant elevation in SAHI and FHF than in CAHI. Namely, the IL-17 levels in SAHI and FHF patients were 4.4 (2.0,11.0) (mean [1 .s.d. range]) and 5.6 (2.0,18.5) pg/mL, respectively, whereas all CAHI patients showed levels lower than the lower limit of detection (2.0 pg/mL). In multiple regression analysis for each factor of model for end-stage liver disease (MELD) score, only IL-10 level was selected as the significant independent variable for total bilirubin level, only IL-17 level for prothrombin time, and TNF-, and IL-1, levels for creatinine level. Conclusion:, These data suggest the usefulness of serum IL-17 level in evaluating the severity of AHI, thus emphasizing the necessity for the basic investigation of the pathological role of IL-17 in acute hepatitis. [source] Elemental signals regulating eosinophil accumulation in the lungIMMUNOLOGICAL REVIEWS, Issue 1 2001Paul S. Foster Summary: In this review we identify the elemental signals that regulate eosinophil accumulation in the allergic lung. We show that there are two interwoven mechanisms for the accumulation of eosinophils in pulmonary tissues and that these mechanisms are linked to the development of airways hyperreactivity (AHR). Interleukin-(IL)-5 plays a critical role in the expansion of eosinophil pools in both the bone marrow and blood in response to allergen provocation of the airways. Secondly, IL-4 and IL-13 operate within the allergic lung to control the transmigration of eosinophils across the vascular bed into pulmonary tissues. This process exclusively promotes tissue accumulation of eosinophils. IL-13 and IL-4 probably act by activating eosinophil-specific adhesion pathways and by regulating the production of IL-5 and eotaxin in the lung compartment. IL-5 and eotaxin co-operate locally in pulmonary tissues to selectively and synergistically promote eosinophilia. Thus, IL-5 acts systemically to induce eosinophilia and within tissues to promote local chemotactic signals. Regulation of IL-5 and eotaxin levels within the lung by IL-4 and IL-13 allows Th2 cells to elegantly co-ordinate tissue and peripheral eosinophilia. Whilst the inhibition of either the IL-4/IL-13 or IL-5/ eotaxin pathways resulted in the abolition of tissue eosinophils and AHR, only depletion of IL-5 and eotaxin concurrently results in marked attenuation of pulmonary inflammation. These data highlight the importance of targeting both IL-5 and CCR3 signalling systems for the resolution of inflammation and AHR associated with asthma. S.M. is a Postdoctoral Fellow funded by a grant from the Human Frontiers Foundation to P.S.F. and M.E.R. J.M. is supported by the German Research Association (grant MA 2241/1-1) and S.P.H by a NH&MRC CJ Martin Postdoctoral Fellowship. [source] Elevation of interleukin-18 in chronic hepatitis C: implications for hepatitis C virus pathogenesisIMMUNOLOGY, Issue 1pt2 2009Arpita Sharma Summary The outcome of hepatitis C virus (HCV) infection is determined by the interplay between the virus and the host immune response. Interleukin (IL)-18, an interferon-,-inducing factor, plays a critical role in the T helper type 1 (Th1) response required for host defence against viruses, and antibodies to IL-18 have been found to prevent liver damage in a murine model. The present study was conducted to investigate the possible role of IL-18 in the pathogenesis and persistence of HCV. IL-18 levels were measured in sera of 50 patients at various stages of HCV infection (resolved, chronic and cirrhosis) and compared with those of normal controls. IL-18 gene expression was studied in peripheral blood mononuclear cells (PBMC) from each group, and in liver biopsy tissue from patients with chronic hepatitis C. The mean levels of IL-18 in sera were markedly elevated in patients with chronic hepatitis and cirrhosis, and were reduced in patients with resolved HCV infection. The serum IL-18 concentrations were related to the Child,Pugh severity of liver disease in cirrhotic patients. There also existed a strong positive correlation of IL-18 levels with histological activity score and necrosis. IL-18 mRNA expression was significantly up-regulated in the PBMC of cirrhotic patients when compared with other groups, while in the liver, higher levels of IL-18 transcripts were expressed in patients with chronic hepatitis C. The results of our study indicate that IL-18 levels reflect the severity and activity of HCV infection, and may contribute to the pathogenesis and progression of liver disease associated with HCV. [source] Epidermal keratinocytes do not activate peripheral T-cells: interleukin-10 as a possible regulatorIMMUNOLOGY, Issue 3 2008Rocío Isabel Domínguez-Castillo Summary The immunogenicity of allogeneic cultured human epidermal keratinocytes (cHEKs) has been studied in several models with contradictory results. We studied human T-cell activation in an in vitro assay by incubating, for 4 and 24 hr, cHEK confluent sheets with human peripheral blood mononuclear cells (PBMC); parallel HEK cultures were incubated with interferon (IFN)-, to induce the expression of major histocompatibility complex (MHC) molecules before their interaction with PBMC. T-cell activation was evaluated by flow cytometry. T cells neither expressed the early and late activation markers CD69 and CD25, respectively, nor proliferated after incubation with the epidermal sheets, despite the IFN-,-induced expression of MHC and adhesion molecules in cHEKs. Interleukin (IL)-10 was detected in the medium from the co-cultured PBMC and HEK sheets, but not from HEK alone. The results suggest that HEKs are unable to stimulate T lymphocytes through secretion of cytokines that might contribute to the immunosuppressive effect in this in vitro model. [source] Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere lengthIMMUNOLOGY, Issue 2 2006Diana L. Wallace Summary Interleukin (IL)-7 and IL-15 are cytokines implicated in homeostatic control of the peripheral CD8 T-cell pool. We compared the effects of IL-7 and IL-15 on survival and proliferation of purified human CD8+ T-cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl-2 up-regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL-15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up-regulation of telomerase and the maintenance of telomere length. These data show that IL-7 and IL-15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset-dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T-cell pool. [source] Functional characterization of human natural killer cells responding to Mycobacterium bovis bacille Calmette-GuérinIMMUNOLOGY, Issue 1 2004Semih Esin Summary The kinetics of activation and induction of several effector functions of human natural killer (NK) cells in response to Mycobacterium bovis bacille Calmette-Guérin (BCG) were investigated. Owing to the central role of monocytes/macrophages (MM) in the initiation and maintenance of the immune response to pathogens, two different experimental culture conditions were analysed. In the first, monocyte-depleted nylon wool non-adherent (NW) cells from healthy donors were stimulated with autologous MM preinfected with BCG (intracellular BCG). In the second, the NW cells were directly incubated with BCG, which was therefore extracellular. In the presence of MM, CD4+ T lymphocytes were the cell subset mainly expressing the activation marker, CD25, and proliferating with a peak after 7 days of culture. In contrast, in response to extracellular BCG, the peak of the proliferative response was observed after 6 days of stimulation, and CD56+ CD3, cells (NK cells) were the cell subset preferentially involved. Such proliferation of NK cells did not require a prior sensitization to mycobacterial antigens, and appeared to be dependent upon contact between cell populations and bacteria. Following stimulation with extracellular BCG, the majority of interferon-, (IFN-,)-producing cells were NK cells, with a peak IFN-, production at 24,30 hr. Interleukin (IL)-2 and IL-4 were not detectable in NK cells or in CD3+ T lymphocytes at any time tested. IL-12 was not detectable in the culture supernatant of NW cells stimulated with extracellular BCG. Compared to the non-stimulated NW cells, the NW cells incubated for 16,20 hr with BCG induced the highest levels of expression of apoptotic/death marker on the NK-sensitive K562 cell line. BCG also induced expression of the activation marker, CD25, and proliferation, IFN-, production and cytotoxic activity, on negatively selected CD56+ CD3, cells. Altogether, the results of this study demonstrate that extracellular mycobacteria activate several NK-cell functions and suggest a possible alternative mechanism of NK-cell activation as the first line of defence against mycobacterial infections. [source] Interleukin 21 expression is increased in rectal biopsies from patients with ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 7 2010Jesús K. Yamamoto-Furusho MD No abstract is available for this article. [source] Role of the novel Th17 cytokine IL-17F in inflammatory bowel disease (IBD): Upregulated colonic IL-17F expression in active Crohn's disease and analysis of the IL17F p.His161Arg polymorphism in IBDINFLAMMATORY BOWEL DISEASES, Issue 4 2008Julia Seiderer MD Abstract Background: Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member of the IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), we characterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17F p.His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) and ulcerative colitis (UC). In addition, we analyzed the IL17F p.His161Arg polymorphism for potential epistasis with IL23R and NOD2/CARD15 variants. Methods: Intestinal IL-17F mRNA expression was measured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n = 499; UC: n = 216; controls: n = 967) was analyzed for the presence of the IL17F p.His161Arg polymorphism, the 3 NOD2 variants, p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008, and 10 CD-associated IL23R variants. Results: Intestinal IL-17F mRNA expression was 4.4-fold increased in inflamed colonic lesions compared to uninflamed biopsies in CD (P = 0.016) but not in UC. However, the mean intestinal IL-17F mRNA expression was higher in UC than in CD (P < 0.0001). The IL17F p.His161Arg substitution was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P = 0.009) and an earlier age of disease onset (P = 0.039) in UC. There was no evidence for epistasis between the IL17F p.His161Arg polymorphism and IBD-associated single nucleotide polymorphisms within the IL23R gene. Conclusions: Intestinal IL17F gene expression is increased in active CD. The IL17F p.His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CD-associated IL23R variants. (Inclamm Bowel Dis 2007) [source] Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibodyINFLAMMATORY BOWEL DISEASES, Issue 1 2006Ivan J Fuss MD Abstract Background: Interleukin (IL)-12p70 and IL-23 are key T helper-1 (TH1) cytokines that drive the inflammation seen in numerous models of intestinal inflammation. These molecules contain an identical p40 chain that is bound to a p35 chain in IL-12 and a p19 chain in IL-23, making both potentially susceptible to modulation by an anti-IL-12p40 monoclonal antibody (mAb). Methods: In the present study, we sought to determine whether active inflammation in Crohn's disease (CD) is associated with the increased synthesis of both of these cytokines and whether patients treated with an anti-IL-12p40 mAb down-regulate IL-23 as well as IL-12p70 as previous reported. Results: To this end we initially determined that IL-12p70 secretion by control and CD antigen-presenting cells (macrophages) in lamina propria mononuclear populations is optimized by stimulation with CD40L and interferon-,. In subsequent studies using these stimulation conditions we found that patients with CD manifested both increased IL-12p70 and IL-23 secretion before anti-IL-12p40 mAb treatment and normal levels of secretion of these cytokines following cessation of treatment. Antigen-presenting cells in lamina propria mononuclear cells from ulcerative colitis patients, in contrast, produced only baseline levels of IL-23. Finally, we found that IL-23-induced T cell production of IL-17 and IL-6 are also greatly reduced after antibody treatment. The latter data are parallel to those from previous studies showing that anti-IL-12p40 down-regulates IFN-, and tumor necrosis factor-, secretion. Conclusions: We conclude that CD but not ulcerative colitis is associated with high levels of both IL-12p70 and IL-23 secretion as well as the secretion of downstream effector cytokines, and that this cytokine production is down-regulated following administration of IL-12p40 mAb. [source] Stepwise regulation of TH1 responses in autoimmunity: IL-12-related cytokines and their receptorsINFLAMMATORY BOWEL DISEASES, Issue 8 2005Christoph Becker PhD Abstract Interleukin (IL)-12 is a key cytokine of cell-mediated immune responses. Until recently, IL-12 was believed to be unique in its ability to induce the differentiation of naive T cells toward the TH1 phenotype and in its pathogenic activity, as shown in various disease models including inflammatory bowel disease. However, recently, 2 additional cytokines closely related to IL-12, IL-23 and IL-27, were discovered. Until then, the role of IL-12 was overestimated because it was believed that the p40 subunit was unique to IL-12. The discovery that IL-12 shares p40 with IL-23 and that IL-23 but not IL-12 is essential in models of chronic inflammation and autoimmunity led to a model in which IL-12 is essential to induce interferon-,-producing TH1 cells, whereas IL-23 mediates effector functions. The latest cytokine added to this cytokine family is IL-27. IL-27 has the unique feature to act on naive T cells, rendering them susceptible to IL-12 signaling. Thus, IL-27 may be essential for the early events of a cell-mediated immune response. This review focuses on these novel cytokines and their role in cell-mediated immune responses and discusses differences and common features within the family of IL-12-related cytokines. [source] Anti-inflammatory role of interleukin-15 in Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 3 2005Manuel A Silva MD Abstract Background: Interleukin (IL)-15 is overexpressed in intestinal tissue with active Crohn's disease (CD). However, its role in the pathogenesis of the disease remains uncertain. We studied the effects of IL-15 on colonic mucosal proinflammatory cytokine response in vitro using organ culture of human colonic explants. Methods: Colonic tissue was obtained from (1) resections in pediatric CD patients (inflamed and noninflamed) and (2) rectal biopsies in patients with CD undergoing colonoscopy (n = 31) and controls (n = 9). In preliminary experiments, explants from the resections were cultured in the presence or absence of a simulated TH1 stimulation using ionomycin (Io) and phorbol-myristate-acetate (PMA), with or without IL-15, or in medium alone. Rectal biopsies were cultured in the same conditions as above, with or without adding a monoclonal anti-IL-15 neutralizing antibody (mAb). Levels of interferon (IFN)-,, tumor necrosis factor (TNF)-,, and IL-2R, were measured by enzyme-linked immunosorbent assay. Results: IL-15, in the absence of Io + PMA, did not induce the expression of IFN-,, TNF-,, or IL-2R,. Only inflamed explants from resections stimulated with Io + PMA expressed IFN-,, TNF-,, and IL-2R,. This TH1 stimulatory effect was inhibited by IL-15 in a dose-dependent fashion. In rectal biopsy explants, inflamed, noninflamed CD, and control tissue responded to stimulation with Io + PMA (P < 0.05) with increased IFN-, and TNF-, (P < 0.05). This response was again inhibited by IL-15. The inhibitory effect of IL-15 was specifically reversed by anti-IL-15 mAb (P < 0.05). The data for the CD group were also analyzed according to the severity of colonic inflammation and medication use. Conclusions: Our results suggest a possible anti-inflammatory role for IL-15 in CD. We postulate that its overexpression in CD potentially represents a protective mechanism against the exaggerated TH1 immune response. [source] Lactobacillus plantarum 299V in the treatment and prevention of spontaneous colitis in interleukin-10-deficient miceINFLAMMATORY BOWEL DISEASES, Issue 2 2002Michael Schultz Abstract Interleukin (IL)-10-deficient (IL-10,/,) mice develop colitis under specific pathogen-free (SPF) conditions and remain disease free if kept sterile (germ free [GF]). We used four different protocols that varied the time-points of oral administration of Lactobacillus plantarum 299v (L. plantarum) relative to colonization with SPF bacteria to determine whether L. plantarum could prevent and treat colitis induced by SPF bacteria in IL-10,/, mice and evaluated the effect of this probiotic organism on mucosal immune activation. Assessment of colitis included blinded histologic scores, measurements of secreted colonic immunoglobulin isotypes, IL-12 (p40 subunit), and interferon (IFN)-, production by anti-CD3-stimulated mesenteric lymph node cells. Treating SPF IL-10,/, mice with L. plantarum attenuated previously established colonic inflammation as manifested by decreased mucosal IL-12, IFN-,, and immunoglobulin G2a levels. Colonizing GF animals with L. plantarum and SPF flora simultaneously had no protective effects. Gnotobiotic IL-10,/, mice monoassociated with L. plantarum exhibited mild immune system activation but no colitis. Pretreatment of GF mice by colonization with L. plantarum, then exposure to SPF flora and continued probiotic therapy significantly decreased histologic colitis scores. These results demonstrate that L. plantarum can attenuate immune-mediated colitis and suggest a potential therapeutic role for this agent in clinical inflammatory bowel diseases. [source] Role of interleukin-18 and its receptor in hepatocellular carcinoma associated with hepatitis C virus infectionINTERNATIONAL JOURNAL OF CANCER, Issue 3 2006Masami Asakawa Abstract Interleukin (IL)-18 is a proinflammatory cytokine that is up-regulated in patients with hepatitis C virus (HCV) infection, which is the most common underlying disease in hepatocellular carcinoma (HCC). The purpose of our study was to investigate the role of IL-18 in HCC associated with HCV infection. Sixty-five patients with HCC and HCV infections who received curative surgical resections were examined in our study. The expression of the IL-18 receptor was investigated in HCC tissues obtained from these patients and in 2 HCC cell lines. Nuclear factor (NF)-,B activity and the expression of Bcl-xL and xIAP mRNA were tested in the cell lines using recombinant human (rh) IL-18. The IL-18 receptor was expressed in both the HCC tissues and the cell lines. NF-,B activation and the expression of Bcl-xL and xIAP mRNA were increased by rhIL-18. Moreover, rhIL-18 suppressed the apoptosis of HCC cells which was induced by etoposide in vitro. The overall survival rate (55.4%) was significantly worse in the IL-18 receptor-positive patients than in the IL-18 receptor-negative patients (p = 0.015). In a Cox multivariate analysis, the expression of the IL-18 receptor was found to be a significant predictor of a poor outcome in HCC patients. The expression of the IL-18 receptor and an antiapoptotic mechanism involving NF-,B activation in HCC cells may be implicated in a poor patient outcome. © 2005 Wiley-Liss, Inc. [source] Interleukin-10 gene promoter polymorphism in Polish rheumatoid arthritis patientsINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2010A. Paradowska-Gorycka Summary Interleukin (IL)-10 is an important multifunctional cytokine with both anti-inflammatory and immunoregulatory effects in rheumatoid arthritis (RA). In the present study, we evaluated the frequency and potential impact of IL-10 promoter polymorphisms on susceptibility to and severity of RA in Polish in , patients with a high disease activity (mean DAS 28 C-reactive protein 5.25). DNA was obtained from 244 RA patients and 106 healthy controls. The ,592C/A and ,1082G/A IL-10 gene polymorphisms were amplified by polymerase chain reaction with restriction endonuclease mapping. The frequency of the IL-10-592CA, -592AA genotypes (respectively: 30% vs 5% and 7% vs 0%) and allele ,592A (37% vs 5%) were significantly higher in RA patients as compared with a control group. We did not find any association of the IL-10-592C/A genotype distribution with disease parameters, except for an increased ESR (erythrocyte sedimentation rate) in patients with the ,592CC genotype as compared with those with ,592CA or ,592AA genotypes (P = 0.01). The frequency of the IL-10-1082GG genotype was lower (P = 0.0001), and that of the IL-10-1082GA genotype was higher (P = 0.009) in RA patients comparing with the control group. In RA patients with ,1082GA or ,1082AA genotypes the time duration of the disease (P = 0.03), Health Assessment Questionnaire (HAQ) Score (P = 0.04) and PLT count (P = 0.001) were significantly increased as compared with subjects with ,1082GG genotype. Presented findings indicate that IL-10-592C/A and IL-10-1082G/A polymorphisms may be considered genetic risk factors for RA susceptibility and severity. [source] The interleukin-6 (IL6),174 G/C promoter genotype is associated with the presence of septic shock and the ex vivo secretion of IL6INTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 6 2007J. J. W. Tischendorf Summary Septic shock is associated with a high mortality and an excessive activation of immune cascades. Interleukin (IL)-6 has been found to be a key cytokine in the pathogenesis of severe sepsis, but the importance of a regulatory polymorphism within the IL6 promoter has been controversial in these patients. The aim of the study was therefore to systematically investigate the IL6,174 G/C promoter genotype with regard to the presence of shock in patients with sepsis, the IL6 serum levels, and the ex vivo secretion of IL6, respectively. Overall, 112 consecutive subjects with severe sepsis and septic shock according to consensus criteria were enrolled. The ex vivo secretion of IL6 after stimulation with lipopolysaccharide (LPS) in a whole blood assay and the IL6 serum concentrations were determined after admission of the patients. Among the 112 subjects with severe sepsis, 85 patients fulfilled the criteria of septic shock. In these patients, the frequency of the mutated C-allele of the IL6 promoter polymorphism was significantly (P = 0.04) higher compared to that in individuals without shock. IL6 serum concentrations were highest in patients with the GG genotype (mean 2209 pg mL,1), followed by CG genotype (mean 1113 pg mL,1), and lowest in individuals with the CC genotype (mean 256 pg mL,1). Interestingly, a significantly (P = 0.005) higher ex vivo secretion of IL6 is detected in heterozygote individuals (535 pg mL,1) and patients with the IL6 CC genotype (555 pg mL,1) compared to patients with the ,174 GG genotype (276 pg mL,1). In conclusion, the IL6,174 G/C promoter genotype is associated with shock in patients with sepsis. Functionally, the mutated C-allele is correlated with low IL6 serum concentrations, but a high ex vivo secretion after LPS stimulation. These results further indicate a complex regulation of the expression of IL6 during infection and have implications for the design of immune intervention trials. [source] IL-18 gene promoter ,137C/G and ,607C/A polymorphisms in Chinese Han children with type 1 diabetes mellitusINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 2 2007G. P. Dong Summary Type 1 diabetes mellitus (T1DM) is a heterogeneous autoimmune disease, and both environmental and genetic factors play a role in its pathogenesis. Interleukin (IL)-18 is a potent pro-inflammatory cytokine capable of inducing interferon-gamma production that is associated with the development of T1DM. The gene for IL-18 is located on chromosome 11q22.2-q22.3 and has been reported to be associated with a susceptibility to T1DM. To test the putative involvement between IL-18 gene polymorphism and predisposition to T1DM, we conducted a case-control study in Chinese Han children. The single nucleotide polymorphisms at position ,607(C/A) and ,137(C/G) in the promoter region of the IL-18 gene were analysed by sequence-specific primers-polymerase chain reaction in 118 patients with T1DM and 150 healthy controls. (1) The allele frequency of ,607A was 41.2% and 53.0%, respectively, in patients and in control subjects (P = 0.01), but the allele frequency of ,137C/G was not statistically significant (P = 0.37). (2) The distribution of CC genotype at position ,607 was significantly different between patients and normal controls (P = 0.03), while the distribution of AA genotype in patients was significantly lower than that in the controls (P = 0.03). (3) Furthermore, there was a significant increase in haplotype (,137C/,607G) and genotype combination (,137GG/ ,607CC) in patients compared with controls (P = 0.03 and P = 0.04, respectively). The results of this study show that IL-18 gene promoter polymorphisms confer susceptibility to T1DM in Chinese Han children. Moreover, subjects carrying AA genotype at position ,607 of the promoter of IL-18 gene may be a low risk of T1DM development. [source] Immunotoxicity of acute acephate exposure in control or IL-1-challenged rats: correlation between the immune cell composition and corticosteroid concentration in bloodJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2002Ashok K. Singh Abstract Corticosterone concentration and the immune cell composition were measured in rats exposed by intraperitoneal (i.p.) injection to different doses (10,500 mg kg,1) of acephate (Ace) and 250 µg kg,1 of interleukin 1 (IL-1), either alone or in combination. Two different combination protocols were used: IL-1 and Ace were administered simultaneously; and IL-1 was injected 60 min after Ace administration (sequential exposure). Ace, in a dose- and time-dependent manner, inhibited blood and brain acetylcholinesterase (AChE) activities, increased blood corticosterone concentrations, suppressed blood CD4, CD8, B cell and monocyte contents and increased blood neutrophil counts. The Ace-induced changes lasted for up to 24 h after Ace exposure. Interleukin 1 increased blood corticosterone concentrations without affecting blood or brain AChE activities. The IL-1-induced corticosterone concentration returned to the basal level within 3,10 h after IL-1 exposure. The CD4, CD8, B cell and monocyte counts increased significantly at 10 min after IL-1 exposure. The cell counts decreased gradually thereafter and returned to the basal level within 30 min after IL-1 exposure. Simultaneous exposure of rats to Ace and IL-1 partially suppressed the IL-1-induced increase in the immune cell counts and decreased the immune cell numbers below the basal values. Sequential injection of Ace and IL-1 blocked the IL-1-induced increase in the immune cell numbers. Thus, Ace exposure would impair the normal distribution of immune cells and deregulate the IL-1 response in rats. This study therefore suggests that Ace would suppress the immune cell numbers in blood, thus decreasing an organism's immunity. Ace exposure occurring concurrent with injury would augment the acute-phase response, which would augment the toxic effects of IL-1 and other cytokines, and Ace exposure occurring prior to the injury would suppress or abolish the initial stimulatory effects of IL-1, which would decrease an organism's ability to combat infection or injury. Copyright © 2002 John Wiley & Sons, Ltd. [source] Quantitative Analysis of Cytokine mRNA Expression in Hearts from Patients with Nonischemic Dilated Cardiomyopathy (DCM)JOURNAL OF CARDIAC SURGERY, Issue 2003Akira Ukimura To evaluate the role of cytokines in nonischemic DCM, we analyzed the relative quantity of cytokine mRNA expression in the hearts from DCM patients with refractory heart failure, using the ABI PRISM7700 real-time PCR system. We used heart tissues resected from 32 DCM patients at the time of elective partial ventriculectomy (PLV), and five biopsy specimens with normal histological findings as control. Results and Discussion: Interleukin (IL)-1,, IL-10, and Tumor Necrosis Factor (TNF)-, mRNA were expressed at low levels in all normal hearts. The number of IL-10-positive DCM cases was significantly smaller than normal controls (P = 0.0036). One (10%) of 10 DCM patients with IL-10 mRNA expression died after PLV, and 10 (45%) of 22 DCM patients without IL-10 mRNA expression died. IL-1, mRNA was overexpressed (over twice the mean of control subjects) in 15 of 32, and TNF-, mRNA in 10 of 32 patients. We propose the classification of DCM patients into subgroups on the basis of cytokine mRNA expression. Anticytokine therapy or cytokine therapy may have potential in improving the condition of heart failure in certain subgroups of DCM patients. Conclusions: We suggest that DCM patients with heart failure deteriorate without IL-10 mRNA expression in the myocardium. The classification of DCM patients into subgroups on the basis of cytokine mRNA expression may have great value in considering the treatment of this heterogeneous disease state. (J CARD SURG 2003;18 (Suppl 2):S101-S108) [source] Matrix metalloproteinase (MMP)-12 regulates MMP-9 expression in interleukin-1,-treated articular chondrocytesJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2008Hwanhee Oh Abstract Limited information is available on the expression and role of matrix metalloproteinase (MMP)-12 in chondrocytes. We characterized the expression mechanism of MMP-12 and possible function in chondrocytes. Interleukin (IL)-1, induced the expression and activation of MMP-12 in primary culture chondrocytes and cartilage explants via mitogen-activated protein (MAP) kinase signaling pathways. Among MAP kinases, extracellular signal-regulated kinase and p38 kinase are necessary for MMP-12 expression, whereas c-jun N-terminal kinase is required for the activation of MMP-12. The possibility that MMP-12 acts as a modulator of other MMP was examined. MMP-12 alone did not affect other MMP expressions. However, MMP-12 enhanced expression and activation of MMP-9 in the presence of IL-1,. Our results indicate that IL-1, in chondrocytes induces the expression and activation of MMP-12, which, in turn, augments MMP-9 expression and activation. J. Cell. Biochem. 105: 1443,1450, 2008. © 2008 Wiley-Liss, Inc. [source] Usefulness of high-sensitivity IL-6 measurement for clinical characterization of patients with coronary artery diseaseJOURNAL OF CLINICAL LABORATORY ANALYSIS, Issue 3 2005Valter Lubrano Abstract Interleukin 6 (IL-6) may represent an early marker of inflammatory activation and may be useful to ameliorate risk stratification in patients with ischemic heart disease. The aim of this study was to verify the performance characteristics of an ultrasensitive immunoassay (Biosource International, Camarillo, CA) for high-sensitivity (hs)-IL-6 measurement in comparison with hs-R&D Systems (Abingdon, United Kingdom) and Immulite System (Diagnostic Products Corporation [DPC], Los Angeles, CA) methods in patients with ischemic heart disease. In addition, hs,C-reactive protein (hs-CRP) concentrations were measured, to evaluate the correlation with hs-IL-6 levels. We measured IL-6 and CRP serum levels in 39 patients with ischemic heart disease and in 12 controls. Out of the 39 patients studied, 13 were affected by unstable angina, 13 by post,acute myocardial infarction (AMI) unstable angina, and 13 by stable angina. The imprecision profile and functional sensitivity were performed measuring 9 different serum pools in 10 runs. The Biosource method had the best performance characteristics as compared to the others. Mean IL-6 level was higher in patients with unstable and post-AMI unstable angina with respect to controls. CRP levels were elevated in patients with post-AMI. In the whole population a high significant linear regression was observed between Biosource hs-IL-6 and hs-CRP serum levels. The Biosource method for IL-6 measurement is characterized by a high functional sensitivity that allows a better stratification of patients with ischemic heart disease. J. Clin. Lab. Anal. 19:110,114, 2005. © 2005 Wiley-Liss, Inc. [source] Transforming growth factor- , stimulates Interleukin-11 production by human periodontal ligament and gingival fibroblastsJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 3 2006R. Yashiro Abstract Background: Transforming growth factor (TGF)- , is a potent multifunctional polypeptide, abundant in the bone matrix. Interleukin (IL)-11 is a pleiotropic cytokine with effects on multiple cell types. The present study was performed to evaluate the regulatory effects of TGF- , on IL-11 production by human periodontal ligament cells (PDL) and human gingival fibroblasts (HGF). Material and Methods: The expression of TGF- , receptor in PDL and HGF were observed using flow cytometry. PDL and HGF were stimulated with TGF- , with or without protein kinase C (PKC) inhibitors and activator. IL-11, bone morphogenetic protein-2 (BMP-2) and TGF- , mRNA expression was quantified by real-time polymerase chain reaction (PCR). IL-11 production was measured using enzyme-linked immunosorbent assay. Results: PDL and HGF expressed both TGF- , receptor I and TGF- , receptor II on the cell surfaces. IL-11 mRNA expression and IL-11 production were augmented by TGF- , in both PDL and HGF, with higher values in PDL. PKC inhibitors partially suppressed TGF- , -induced IL-11 production in PDL and HGF, whereas activator enhanced it. TGF- , mRNA and BMP-2 mRNA expression were up-regulated by TGF- , in PDL. Conclusion: These results suggest that PDL produce IL-11 in response to TGF- ,. [source] Long-term effect of full-mouth tooth extraction on the responsiveness of peripheral blood monocytesJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 8 2003Schelte J. Fokkema Abstract Background: As some residual inflammation may remain after periodontal therapy, the present pilot study investigated the long-term effect of full-mouth tooth extraction therapy on the responsiveness of peripheral blood monocytes in a case with generalized terminal adult periodontitis. Methods: Before and 3, 9, 20 and 32 months after therapy, venous blood was collected. Total and differential white blood cell counts were determined and whole blood cell cultures (WBCC) were incubated with lipopolysaccharide (LPS) to stimulate the production of inflammatory mediators by monocytes. Results: After full-mouth tooth extraction, the numbers of total peripheral white blood cells and neutrophils decreased over time. The release of the chemokines interleukin (IL)-8 and macrophage chemoattractant protein (MCP)-1 in the cultures decreased twofold over time, whereas no changes were seen for the other studied cytokines, chemokines and prostaglandin E2. Conclusion: On the basis of previous studies and the present case, the high production of IL-8 and MCP-1 by monocytes in LPS-stimulated WBCC from periodontitis patients is most likely acquired, as their levels decrease over time when the periodontal infection is controlled. The possible connection between periodontitis and atherosclerosis through IL-8 and MCP-1 is discussed. Zusammenfassung Hintergrund: Da nach der parodontalen Therapie eine restliche Entzündung zurückbleiben kann, untersucht die vorliegende Studie den Langzeiteffekt einer vollständigen Zahnextraktion auf die Ansprechbarkeit der peripheren Blutmonozyten in einem Fall mit generalisierter unheilbarer Erwachsenen-Parodontitis. Methoden: Vor und 3, 9, 20 und 32 Monaten nach der Therapie wurde venöses Blut gesammelt. Der totale und differenzierte weiße Blutzellgehalt wurden bestimmt, und eine gesamte Blutzellkultur (WBCC) wurde mit Lipopolysaccharid inkubiert, um die Produktion von Entzündungsmediatoren durch Lymphozyten zu stimulieren. Ergebnisse: Nach der vollständigen Zahnextraktion verringerte sich die Zahl der totalen peripheren weißen Blutzellen und der Neutrophilen über die Zeit. Die Freisetzung des Chemokins Interleukin 8 (IL-8) und des Makrophagen chemoattraktanten Proteins (MCP) ,1 in den Kulturen verringerte sich zweifach über die Zeit, während für die anderen beobachteten Cytokine, Chemokine und Prostaglandin E2 keine Veränderungen festgestellt wurden. Schlussfolgerung: Auf der Basis vorheriger Studien und des vorliegenden Falls ist die hohe Produktion von IL-8 und MCP-1 durch Monozyten in LPS stimulierten WBCC von Parodontitis-Patienten sehr wahrscheinlich anzunehmen, da ihr Level über die Zeit abnimmt, wenn die parodontale Infektion kontrolliert ist. Die mögliche Verbindung zwischen Parodontitis und Arteriosklerose durch IL-8 und MCP-1 wird diskutiert. Résumé Contexte: Puisqu'après traitement parodontal, une inflammation résiduelle peut subsister, cette étude se propose de rechercher les effets à long terme de l'extraction complète des dents sur la réponse des monocytes périphériques dans un cas de parodontite de l'adulte terminale généralisée. Méthodes: Des prélèvements sanguins veineux ont été réalisés avant et 3, 9, 20 et 32 mois après traitement. Les comptages totaux et relatifs des cellules blanches sanguines furent déterminés et les cultures complètes de cellules sanguines (WBCC) furent incubées avec du lipopolysaccharide pour stimuler la production des médiateurs de l'inflammation par les monocytes. Résultats: Après l'extraction complète des dents, les nombres de cellules sanguines blanches totales périphériques et des neutrophiles diminuaient au cours du temps. Le relargage des chimiokines interleukine (IL)-8 et protéine chimio-attractante du macrophage (MCP)-1 dans les cultures diminuait deux fois au cours du temps, alors qu'aucun changement n'était observé pour les autres cytokines étudiées, chimiokines et prostaglandine E2. Conclusion: Sur la base d'études préalables, et les résultats issus de ce cas présent, la forte production d'IL-8 et de MCP-1 par les monocytes dans les WBCC stimulés par le LPS chez des patients atteints de parodontite semble être vraisemblablement acquise puisque leurs niveaux diminuent lorsque l'infection parodontale est contrôlée. La relation possible entre parodontite et l'athérosclérose par IL-8 et MCP-1 est discutée. [source] | |||||||||||||||||||||||||||||||||||||||||||