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ID PMID Title PublicationDate abstract
12483727 Bcl-3 is an interleukin-1-responsive gene in chondrocytes and synovial fibroblasts that ac 2002 Dec OBJECTIVE: To define the role of Bcl-3, a member of the inhibitor of nuclear factor kappaB (NF-kappaB) family and a known regulator of NF-kappaB, in interleukin-1 (IL-1)-induced matrix metalloproteinase 1 (MMP-1) transcription in chondrocytes and synovial fibroblasts. METHODS: SW-1353 cells, a human chondrosarcoma cell line, were stimulated with IL-1beta, and the harvested RNA was subjected to microarray analysis and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). The SW-1353 cells were stimulated with IL-1 or transfected with a plasmid that constitutively expressed Bcl-3, and then MMP-1 messenger RNA (mRNA) expression was assayed by quantitative real-time RT-PCR. SW-1353 cells were transfected with antisense oligonucleotides to Bcl-3, and IL-1-induced MMP-1 mRNA expression was assayed by quantitative RT-PCR. SW-1353 cells and rabbit synovial fibroblasts were transfected with a 4.3-kb human MMP-1 promoter construct along with Bcl-3 and NF-kappaB1 expression constructs, and MMP-1 transcription was assayed. RESULTS: Microarray analysis and real-time RT-PCR showed Bcl-3 to be an IL-1beta-responsive gene in SW-1353 cells. Exogenous expression of Bcl-3 in SW-1353 cells activated MMP-1 transcription. Endogenous Bcl-3 expression was required for IL-1beta induction of MMP-1 gene expression. Bcl-3 also activated MMP-1 transcription in primary synovial fibroblasts. We showed previously that NF-kappaB1 contributes to IL-1beta induction of MMP-1 transcription in stromal cells. We showed here that Bcl-3 can cooperate with NF-kappaB1 to activate MMP-1 transcription in SW-1353 cells. CONCLUSION: These data define a new role for Bcl-3 in joint cells as an IL-1beta-responsive early gene involved in cell-mediated cartilage remodeling. Our findings implicate Bcl-3 as an important contributor to chronic inflammatory disease states, such as osteoarthritis and rheumatoid arthritis.
12352631 The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflamm 2002 Sep The present report describes and expands the clinical and genetic spectrum of the autoinflammatory disorder, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). A total of 20 mutations have been identified since our initial discovery of 6 missense mutations in TNF receptor super family 1A (TNFRSF1A) in 1999. Eighteen of the mutations result in amino acid substitutions within the first 2 cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation also affects the first CRD by causing the insertion of 4 amino acids. Haplotype analysis of the most commonly occurring and ethnically heterogeneous mutation, R92Q, demonstrates an ancient founder; however, analysis of the T50M mutation, another commonly occurring mutation in Irish and Scottish families, does not, suggesting that T50M is a recurring mutation. Mutations that result in cysteine substitutions demonstrate a higher penetrance of the clinical phenotype (93% versus 82% for noncysteine residue substitutions), and also increase the probability of developing life-threatening amyloidosis (24% versus 2% for noncysteine residue substitutions). Retrospective and prospective evaluation of more than 50 patients, representing 10 of the 20 known mutations, allows us to expand and better define the clinical spectrum of TRAPS. Recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that often last longer than 5 days are the most characteristic clinical features of TRAPS. Defective shedding of TNFRSF1A can only partially explain the pathophysiologic mechanism of TRAPS, since some mutations have normal shedding. Consequently, other mechanisms may be mediating the observed phenotype. We are currently investigating other possible mechanisms using stable and transiently transfected cell systems in vitro, as well as developing a knockin mouse model. Preliminary data suggest that etanercept may be effective in decreasing the severity, duration, and frequency of symptoms in TRAPS patients. Additionally, it provides a viable therapeutic alternative to glucocorticoid therapy, which has numerous serious, long-term adverse effects. Two clinical trials are being conducted to evaluate the efficacy of etanercept in decreasing the frequency and severity of symptoms in TRAPS. Lastly, we have summarized data that R92Q and P46L, and probably as yet undiscovered substitutions, represent very low penetrance mutations that may play a much larger role in more broadly defined inflammatory diseases such as rheumatoid arthritis. Our laboratories are currently undertaking both clinical and basic research studies to define the role of these mutations in more common inflammatory diseases.
15551734 Cutaneous immunocytoma: a clinical, histologic, and phenotypic study of 11 cases. 2004 Sep Immunocytomas represent low grade B cell lymphomas related to marginal zone lymphoma but with a predominance of cells having plasmacytic features. Eleven patients presented with lesions compatible with primary cutaneous immunocytoma. The expression of CD2, CD3, CD5, CD20, CD21, CD23, CD43, CD56, CD79, and bcl-2 was analyzed immunohistochemically and of lambda and kappa light chains by an in situ hybridization assay. There were 6 men and 5 women ranging in age from 43 to 76 years. The most common clinical presentation was as extremity based clustered erythematous brown papules. Therapy with local irradiation or Rituximab resulted in lesional resolution. Underlying illnesses included Sjögren's syndrome, hepatitis C, ulcerative colitis, autoimmune thyroid disease, and rheumatoid arthritis. Four patients were taking medications previously associated with immune dysregulation. In two patients in whom a paraproteinemia was uncovered. The most common pattern light microscopically was perivascular small lymphocytic and plasmacellular infiltrates mimicking architecturally a reactive process. Phenotypic studies revealed a marginal zone (MZL) phenotype amid the small atypical lymphocytic infiltrate and highlighted a reactive background population of non-neoplastic T and B cells; light chain restriction was seen amid the plasma cells. In one case there was EBER staining of plasma cells while in another case in whom there was hepatitis C seropositivity staining of plasma cells for hepatitis C associated RNA transcripts was observed. Primary cutaneous immunocytoma appears to arise from a pre-existing state of reactive lymphoid hyperplasia. latrogenic and endogenous immune dysregulation including in the context of lymphotropic viral infections is implicated.
15548526 Site-directed mutagenesis of CC chemokine receptor 1 reveals the mechanism of action of UC 2005 Feb 11 The chemokine receptor CCR1 and its principal ligand, CCL3/MIP-1alpha, have been implicated in the pathology of several inflammatory diseases including rheumatoid arthritis, multiple sclerosis, and asthma. As such, these molecules are the focus of much research with the ultimate aim of developing novel therapies. We have described previously a non-competitive small molecule antagonist of CCR1 (UCB 35625), which we hypothesized interacted with amino acids located within the receptor transmembrane (TM) helices (Sabroe, I., Peck, M. J., Jan Van Keulen, B., Jorritsma, A., Simmons, G., Clapham, P. R., Williams, T. J., and Pease, J. E. (2000) J. Biol. Chem. 275, 25985-25992). Here we describe an approach to identifying the mechanism by which the molecule antagonizes CCR1. Thirty-three point mutants of CCR1 were expressed transiently in L1.2 cells, and the cells were assessed for their capacity to migrate in response to CCL3 in the presence or absence of UCB 35625. Cells expressing the mutant constructs Y41A (TM helix 1, or TM1), Y113A (TM3), and E287A (TM7) were responsive to CCL3 but resistant to the antagonist, consistent with a role for the TM helices in CCR1 interactions with UCB 35625. Subsequent molecular modeling successfully docked the compound with CCR1 and suggests that the antagonist ligates TM1, 2, and 7 of CCR1 and severely impedes access to TM2 and TM3, a region thought to be perturbed by the chemokine amino terminus during the process of receptor activation. Insights into the mechanism of action of these compounds may facilitate the development of more potent antagonists that show promise as future therapeutic agents in the treatment of inflammatory disease.
15265887 Antisense knockdown of sphingosine kinase 1 in human macrophages inhibits C5a receptor-dep 2004 Aug 1 The anaphylatoxin C5a is produced following the activation of the complement system and is associated with a variety of pathologies, including septic shock and adult respiratory distress syndrome, and with immune complex-dependent diseases such as rheumatoid arthritis. C5a has been shown to regulate inflammatory functions by interacting with its receptor, C5aR, which belong to the rhodopsin family of seven-transmembrane GPCRs. However, the intracellular signaling pathways triggered by C5aR on immune-effector cells are not well understood. In this report we present data showing that, in human monocyte-derived macrophages, C5aR uses the intracellular signaling molecule sphingosine kinase (SPHK)1 to trigger various physiological responses. Our data show that C5a rapidly stimulates the generation of sphingosine-1-phosphate, SPHK activity, and membrane translocation of SPHK1. Using an antisense oligonucleotide against SPHK1, we show that knockdown of SPHK1 abolishes the C5a-triggered intracellular Ca(2+) signals, degranulation, cytokine generation, and chemotaxis. Our study shows for the first time that SPHK1 not only plays a key role in the generation and release of proinflammatory mediators triggered by anaphylatoxins from human macrophages but is also involved in the process of immune cell motility, thus pointing out SPHK1 as a potential therapeutic target for the treatment of inflammatory and autoimmune diseases.
15252211 Influence of human recombinant interferon-alpha2a (rhIFN-alpha2a) on altered lymphocyte su 2004 Oct OBJECTIVE: In Behçet's disease (BD), several abnormalities of lymphocyte subpopulations have been described. Standard treatment comprises immunosuppressive drugs. We successfully treated 50 patients with ocular BD with interferon-alpha2a (IFN-alpha2a) (response rate 92%), although this is counterintuitive because IFN-alpha is immunostimulatory and can sometimes even induce autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. The aim of the present study was to elucidate the immunomodulatory effects that IFN-alpha might exert on peripheral blood mononuclear cells (PBMC) in BD by examining changes in the distribution of lymphocyte subpopulations under IFN-alpha2a treatment. METHODS: Fourteen patients with ocular BD were evaluated before and at weeks 4 and 24 of IFN-alpha treatment and compared with 10 healthy controls. PBMC were stained with monoclonal antibodies and measured by flow cytometry. RESULTS: Compared with the controls there is a significant elevation of monocytes (CD14(+)), CD8(+)/gammadelta T cells, CD3(+)/gammadelta T cells, natural killer (NK) cells (CD56(+)/CD16(+)) and activated/regulatory T cells (CD4(+)/CD25(+) and CD8(+)/CD25(+)) in patients with active BD before treatment with IFN-alpha2a. Numbers of naïve T cells (CD8(+)/CD45(+)RA(+)/RO(-), CD4(+)/CD45(+)RA(+)/RO(-)) were significantly lower. Under therapy, NK cells, CD8(+)/gammadelta T cells and CD3(+)/gammadelta T cells decreased significantly, whereas B cells increased. The previously reduced expression of HLA class I on monocytes in HLA-B51-positive patients rose to levels comparable to HLA-B51-negative patients. CONCLUSION: These results implicate the participation of NK cells and gammadelta T cells, especially CD8(+)/gammadelta T cells, in the pathogenesis of BD and may explain one mechanism by which IFN-alpha2a exerts therapeutic effects. Alternatively, they may result indirectly from remission induction by IFN-alpha2a. The reduced expression of HLA class I on monocytes in HLA-B*51-positive patients might reflect an impaired expression of and antigen presentation by HLA-B*51.
15194006 Effects of the selective COX-2 inhibitors celecoxib and rofecoxib on human vascular cells. 2004 Jul 15 Rheumatoid arthritis (RA) is associated with a reduced life expectancy considered to be partly caused by cardiovascular events. A growing concern is that accelerated atherosclerosis is driven by inflammatory mechanisms similar to those responsible for RA. Therefore, selective COX-2 inhibitors, which are widely used for the symptomatic treatment of pain and inflammation in RA, may have an impact on atherosclerotic processes. Their anti-inflammatory properties might provoke anti-atherogenic effects but on the other hand, selective inhibition of anti-thrombotic prostacyclin and COX-2 independent effects might promote the risk of increased prothrombotic activity. In the current study, the effects of the presently marketed selective COX-2 inhibitors celecoxib and rofecoxib on vascular cells have been investigated. Celecoxib inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. At high concentrations, it induced apoptosis and the modulation of inhibitory cell cycle proteins. In contrast rofecoxib-even at high concentrations-had no effect on cell proliferation, apoptosis or cell cycle distribution indicating that celecoxib and rofecoxib do not affect the same signal transduction pathways in endothelial cells. Both drugs did not affect apoptosis induction or cell cycle proliferation in human vascular smooth muscle cells. The observed effects on endothelial cells appear to be COX-independent since both drugs selectively inhibited COX-2-activity and the applied concentrations lay beyond the IC(50) for inhibition of prostacyclin production. Regarding endothelial apoptosis as a relevant event in the initiation and progression of atherosclerosis the present data put forward the hypothesis that the presently marketed COX-2 inhibitors have a different impact on atherosclerotic processes.
15177278 Characterization and biological activities of recombinant human plasminogen kringle 1-3 pr 2004 Jul Angiogenesis, the formation of new capillaries from preexisting blood vessels, is involved in many pathological conditions, for example, tumorigenesis, diabetic retinopathy, and rheumatoid arthritis. Angiostatin, which contains the kringle 1-4 domains of plasminogen, is known to be a potent inhibitor of angiogenesis and a strong suppressor of various solid tumors. In this study, we expressed recombinant protein containing the kringle 1-3 domains of human plasminogen in Escherichia coli and investigated its biological activities. The protein was successfully refolded from inclusion bodies and purified at a 30% overall yield, as a single peak by HPLC. The purified recombinant protein had biochemical properties that were similar to those of the native form, which included molecular size, lysine-binding capacity, and immunoreactivity with a specific antibody. The recombinant protein was also found to strongly inhibit the proliferation of bovine capillary endothelial cells in vitro, and the formation of new capillaries on chick embryos. In addition, it suppressed the growth of primary Lewis lung carcinoma and B16 melanoma in an in vivo mouse model. Our findings suggest that the recombinant kringle 1-3 domains in a prokaryote expression system have anti-angiogenic activities, which may be useful in clinical and basic research in the field of angiogenesis.
15162344 Smoking and smokeless tobacco: increased risk for oral pain. 2004 May Tobacco has been linked with several pain conditions that include musculoskeletal pain, rheumatoid arthritis, and fibromyalgia. This study documented associations between smoking and smokeless tobacco use and measures of orofacial pain and oral pain impacts (activity reduction and trouble with sleep) assessed during a 48-month time period. These data were collected as part of the Florida Dental Care Study, a longitudinal study of oral health among 873 adults aged 45 years and older at baseline. Twenty-five percent of the study participants were current users of some form of tobacco, and 34% were former users. Separate models were tested for smoking and smokeless tobacco. Current tobacco users were at increased risk of experiencing a range of painful oral symptoms. We also found that behavioral impacts associated with oral pain are sensitive to differences in tobacco use status. Our data also support the supposition that once tobacco cessation occurs, the risk for pain associated with oral disease decreases significantly. No differences were found between former users and those never having used tobacco across any of the pain measures. Strengths of the current study include the longitudinal methodology, assessment of different pain symptoms with potentially differing etiology, and that several markers of tobacco use were used (prevalence, consumption, and duration). PERSPECTIVE: This study considers the harmful effects of tobacco use on oral health. Smokers were at significantly increased risk for oral pain and related limitation of daily activities. The data also suggest that the risk for oral pain associated with tobacco use decreases significantly if tobacco cessation occurs.
15145954 Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed usi 2004 Jul 30 Identification of tumor necrosis factor-alpha (TNF alpha) as the key agent in inflammatory disorders, e.g. rheumatoid arthritis, Crohn's disease, and psoriasis, led to TNF alpha-targeting therapies, which, although avoiding many of the side-effects of previous drugs, nonetheless causes other side-effects, including secondary infections and cancer. By controlling gene expression, TNF alpha orchestrates the cutaneous responses to environmental damage and inflammation. To define TNF alpha action in epidermis, we compared the transcriptional profiles of normal human keratinocytes untreated and treated with TNF alpha for 1, 4, 24, and 48 h by using oligonucleotide microarrays. We found that TNF alpha regulates not only immune and inflammatory responses but also tissue remodeling, cell motility, cell cycle, and apoptosis. Specifically, TNF alpha regulates innate immunity and inflammation by inducing a characteristic large set of chemokines, including newly identified TNF alpha targets, that attract neutrophils, macrophages, and skin-specific memory T-cells. This implicates TNF alpha in the pathogenesis of psoriasis, fixed drug eruption, atopic and allergic contact dermatitis. TNF alpha promotes tissue repair by inducing basement membrane components and collagen-degrading proteases. Unexpectedly, TNF alpha induces actin cytoskeleton regulators and integrins, enhancing keratinocyte motility and attachment, effects not previously associated with TNF alpha. Also unanticipated was the influence of TNF alpha upon keratinocyte cell fate by regulating cell-cycle and apoptosis-associated genes. Therefore, TNF alpha initiates not only the initiation of inflammation and responses to injury, but also the subsequent epidermal repair. The results provide new insights into the harmful and beneficial TNF alpha effects and define the mechanisms and genes that achieve these outcomes, both of which are important for TNF alpha-targeted therapies.
15033519 Development of a microplate bioassay for monocyte chemoattractant protein-1 based on activ 2004 Apr 1 Monocyte chemoattractant protein-1 (MCP-1) is a potential therapeutic target for the treatment of several inflammatory conditions, including rheumatoid arthritis and chronic obstructive pulmonary disease. Current cell-based assays for MCP-1 use monocyte chemotaxis or calcium flux as a readout. Here, we describe an alternative bioassay based on MCP-1-induced phosphorylation of the mitogen-activated protein kinases (MAPK) p44 (ERK1) and p42 (ERK2). Adherent cells expressing the MCP-1 receptor CCR2B are treated with MCP-1 in 96-well plates in the presence or absence of inhibitors, fixed and permeabilized with methanol, and then probed with a monoclonal antibody that selectively recognizes the doubly phosphorylated form of p44/42 MAPK. Bound antibody is detected with a secondary antibody-peroxidase conjugate and a chromogenic substrate. The phosphorylation of p44/42 MAPK as detected in this assay peaks after 3-5 min of MCP-1 treatment, and the concentration of MCP-1 required for half-maximal p44/42 MAPK phosphorylation is 1-3 nM. MCP-1-induced phosphorylation of p44/42 MAPK is dependent upon the expression of CCR2B. The assay can be used for screening and characterization of small molecule inhibitors and antibodies blocking the binding of MCP-1 to its receptor. Since the assay is rapid and simple, it may represent a useful alternative to chemotaxis or calcium mobilization assays for the analysis of MCP-1 inhibitors.
14871297 Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythemato 2004 Feb Recent animal studies have shown that CD4+CD25+ T cells play a crucial role in the suppression of the immune response and that depletion of this subset of T cells might lead to development of autoimmune diseases. The aim of the present study was to investigate the levels of CD4+CD25+ T cells in the peripheral blood of patients with systemic lupus erythematosus (SLE). Ninety-four SLE patients, 52 patients with rheumatoid arthritis (RA) and 50 age- and gender-matched healthy individuals were enrolled in the study. A flowcytometric method was applied in the measurement of CD4+CD25+ T cells. The results showed that patients with SLE had statistically lower levels of CD4+CD25+ T cells than did normal controls, when expressed as either percentages of peripheral blood mononuclear cells (PBMCs) (mean +/- SD, 8.49 +/- 6.36 versus 11.11 +/- 4.58%, P < 0.05) or absolute cell numbers (98.77 +/- 97.52 versus 213.93 +/- 104.52 cells/mm3, P < 0.05). In terms of CD25brightCD4+ T cells, defined as having a fluorescence intensity of CD25 expression exceeding 100, SLE patients still had significantly lower levels than did normal controls expressed as percentages of PBMCs (1.76 +/- 1.32 versus 3.73 +/- 1.30%, P < 0.05). No significant differences could be found between RA patients and normal controls. The overwhelming majority of CD4+CD25+ T cells belonged to CD45RO+ cells and most did not express the CD69 molecule. Although decreased CD4+CD25+ T cells were found in SLE patients, we failed to find a significant correlation between the levels of CD4+CD25+ T cells and disease activities of SLE. To the best of our knowledge, this is the first study to demonstrate that patients with SLE had decreased CD4+CD25+ T cells. However, the exact role of the decreased CD4+CD25+ T cells in the pathogenesis of SLE remains to be elucidated.
14679071 SOX13 autoantibodies are likely to be a supplementary marker for type 1 diabetes in Korea. 2003 Nov The SOX13, one of the family of transcription factors that play key roles in organ development, is reported to be a diabetes autoantigen, islet cell antigen 12 (ICA12). Recently, a study of antibodies to SOX13 was conducted in patients with type 1 diabetes mellitus (T1DM) indicating that these antibodies potentially identified patients without antibodies to the major T1DM-associated autoantigens, insulin, GAD, or IA-2. We know that the prevalence of islet-specific autoantibodies (GAD, IA-2) in Korean patients is much lower than that in white patients. It may be possible that other autoantibodies that could be directed to as yet unknown antigen may play a role in Korean T1DM patients. To investigate this, we measured SOX13 autoantibodies applying a radioligand binding assay using in vitro transcribed and translated antigen in 188 T1DM patients (mean duration, 4.2 years) and 64 T2DM patients and compared the results with those of 101 healthy control subjects. SOX13 autoantibodies occurred at a significantly higher frequency among T1DM patients (55/188, 29.3%) than among T2DM patients (4/64, 6.2%) or healthy adult controls (1/101, 1%). The 55 patients with positive SOX13 antibodies had significantly shorter duration of diabetes than SOX13 antibody-negative patients (3.6 +/- 2.8 vs. 4.5 +/- 3.9 years; p < 0.05). We could detect a prevalence similar to control in patients with Hashimoto's thyroiditis (4.9%, n = 101) and rheumatoid arthritis (6.7%, n = 89). As a whole, 44 of the 55 patients with SOX13 antibodies had at least one or more other autoantibodies to the major T1DM-associated autoantigens. However, SOX13 antibodies were the only antibodies detected as positive in 1 of the 11 new-onset patients. We conclude, therefore, that these antibodies are likely to be one of several epitope-spreading responses to islet- or nonislet-specific autoantigens seen in the development of T1DM, and they may be used as a supplementary marker for investigating T1DM in Korea.
14566819 Autocrine motility factor signaling induces tumor apoptotic resistance by regulations Apaf 2003 Dec 10 Autocrine motility factor (AMF) is a cytokine that regulates locomotion and metastasis of tumor cells. It is well known that expression levels of AMF secretion and its receptor (AMF R) are closely related to tumor malignancy and rheumatoid arthritis. We have established that AMF signaling induced anti-apoptotic activity and that human fibrosarcoma HT-1080 line that secreted high levels of AMF were resistant to drug-induced apoptosis. These cells did not express the apoptotic protease activating factor-1 (Apaf-1) and Caspase-9 genes that encode for the proteins that form the "apoptosome" complex. The disappearance of the Apaf-1 and Caspase-9 gene was recovered by a cellular signaling inhibitor of protein kinase C, phosphatidylinositol 3-phosphate kinase and mitogen-activated protein kinase of the in vitro cultured human fibrosarcoma HT-1080 line. Treatment with these inhibitors favored apoptotic cell death induced by anti-cancer drugs of the murine ascites Ehrlich line. Apoptotic resistance of tumor cells allows them to escape death from cancer chemotherapy, so an understanding of malignant anti-apoptotic activities is important. Antibodies against AMF induced Ehrlich ascites apoptosis in vitro, and effectively aided in vivo apoptosis induced by anti-cancer drugs. The results might indicate a novel route by which tumor cells protect themselves with products, such as AMF, and proliferate despite various stresses and chemical insults; AMF regulates expression of Apaf-1 and caspase-9 genes via a complex signaling pathway and indirectly regulates formation of the apoptosome.
14555214 Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. 2003 Oct 15 Tumor necrosis factor (TNF) was first identified in 1984 as a cytokine with anti-tumor effects in vitro and in vivo. Extensive research since then has shown that there are at least 18 distinct members of the TNF super family and they exhibit 15-25% amino acid sequence homology with each other. These family members bind to distinct receptors, which are homologous in their extracellular domain. These cytokines have been implicated in a wide variety of diseases including tumorigenesis, septic shock, viral replication, bone resorption, rheumatoid arthritis, diabetes, and other inflammatory diseases. TNF blockers have been approved for human use in treating some of these conditions in the United States and other countries. Various members of the TNF super family mediate either proliferation, survival, or apoptosis of cells. Although distinct receptors, all members share a common cell signaling pathway that mediates the activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (e.g. c-jun N-terminal kinase). Regulation of cell growth and activation of NF-kappaB and of c-jun N-terminal kinase by the TNF super family is mediated through sequential activation/association of a set of cell signaling proteins named TNF receptor-associated factors, Fas-associated death domain and FADD-like ICE, caspases, receptor-interacting protein, NF-kappaB-inducing kinases, and IkappaBalpha kinases. Both apoptotic and antiapoptotic signals are activated simultaneously by the same cytokine in the same cell. Together these cytokines regulate cell growth/survival/apoptosis in a complex dance of changing partners and overlapping steps.
12915334 Dietary fatty acids and immune reactions in synovial tissue. 2003 Aug 20 Inflammation of the synovial membrane in rheumatoid arthritis is mediated by specialized cells necessary for immune response. The most prominent features are the accumulation of mononuclear phagocytes, lymphocytes and leukocytes in the proliferating tissue. Pro-inflammatory and proliferative signals are transmitted to the bone marrow and to the synovial membrane. The result is a monoclonal stimulation of specific cell lines, and synovial proliferation in the inflamed joint. Angiogenesis, synovial hypertrophy, and increased perfusion facilitate the accumulation of inflammatory cells. Components of the autoimmune reaction are described in the international system of classification, the CD-System (cluster of differentiation). Pro-inflammatory signals are mediated by metabolites of arachidonic acid. Prostaglandins, leukotrienes, lipoxines and hydroxy fatty acids, derived from this PUFA, stimulate the formation and the activity of adhesion molecules (integrines), cytokines (gamma-interferon, interleukin-1, interleukin-6, tumor-necrosis factor), chemokines (interleukine-8, macrophage-chemotactic peptide, RANTES and colony -stimulating factors ((CSF, granulocytes/ monocytes-CSF, Multi-CSF (= IL-3)). Dietary means to mitigate inflammation comprise reduction of arachidonic acid, and increased intake of eicosapentaenoic acid and antioxidants. In the literature 12 randomized, placebo-controlled double-blind studies, fulfilling GCP-criteria, demonstrate a moderate but consistent improvement of clinical findings and laboratory parameters in patients with RA. A dose-response relationship was established up to an daily dose of 2.6 gram fish oil, equivalent to about 1.6 gram EPA. In these experiments EPA was the omega-3 fatty acid responsible for improvement, with distinct effects on inhibition of cytokines formation (IL-1 to IL-6, IL-8, TFN-alpha, GM-CSF), decreased induction of proinflammatory adhesion molecules (selectines, intercellular adhesions molecule-1 (ICAM-1)), and degrading enzymes (e.g. phospholipase A2, cyclooxygenase-2, inducible NO-synthetase). Only one study reports the relevance of the background diet. From this study it became apparent that reduction of dietary arachidonic acid improves the incorporation and the clinical benefit of EPA.
12781110 [Quality of life evaluation in children and adolescents with chronic and/or incapacitating 2003 Jun OBJECTIVE: To evaluate quality of life in children and adolescents with acute lymphocytic leukemia (ALL) and juvenile rheumatoid arthritis (JRA). MATERIAL AND METHODS: We administered the Children's Global Assessment Scale (CGAS), the Vineland Adaptative Behavior Scale (VABS) and the Autoquestionnaire qualité de vie enfant imagé (AUQEI) to a sample of 28 children with ALL, 28 children with JRA, and 28 healthy controls, aged 4 to 13 years old, who were diagnosed between 1 and 5 years previously. RESULTS: Slight differences were found in age between patients with ALL and those with JRA. No significant differences were found in time since diagnosis or in CGAS scores. A significant difference was found in VABS global scores, as well as in VABS communication domain scores. No significant differences were found in VABS daily living skills domain scores between patients with ARJ and healthy controls. No significant differences were found among the groups in VABS socialization domain scores or in AUQEI scores. CONCLUSION: In our study, chronically ill children clearly performed worse in adaptative behavior development. Nevertheless, their quality of life was similar to that of healthy controls. Appropriate methods to identify pediatric patients' perception of their illnesses and treatment should be urgently developed.
12773510 Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitme 2003 Jun Naïve T cells, when activated by specific antigen and cytokines, up-regulate adhesion molecules as well as chemokine receptors on their surface, which allows them to migrate to inflamed tissues. Human studies have shown that CXCR3 is one of the chemokine receptors that is induced during T cell activation. Moreover, CXCR3-positive T cells are enriched at inflammatory sites in patients with autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. In this study, we use a mouse model of inflammation to demonstrate that CXCR3 is required for activated T cell transmigration to inflamed tissue. Using an anti- mCXCR3 antibody, we have shown that in vitro-differentiated T helper (Th) 1 and Th2 cells up-regulated CXCR3 upon stimulation with specific antigen/major histocompatibility complex. However, only Th1 cells, when adoptively transferred to syngeneic recipients, are efficiently recruited to the peritoneum in an adjuvant-induced peritonitis model. Furthermore, the neutralizing anti-mCXCR3 antibody profoundly inhibits the recruitment of Th1 cells to the inflamed peritoneum. Real-time, quantitative reverse transcriptase-polymerase chain reaction analysis demonstrates that the CXCR3 ligands, interferon (IFN)-inducible protein 10 (CXCL10) and IFN-inducible T cell alpha chemoattractant (CXCL11), are among the many chemokines induced in the adjuvant-treated peritoneum. The anti-mCXCR3 antibody is also effective in inhibiting a delayed-type hypersensitivity response, which is largely mediated by enhanced trafficking of activated T cells to peripheral inflammatory sites. Collectively, our results suggest that CXCR3 has a critical role in T cell transmigration to sites of inflammation and thus, may serve as a molecular target for anti-inflammatory therapies.
12650783 Low dose methotrexate in inflammatory bowel disease: current status and future directions. 2003 Mar Despite many recent advances, some notable limitations exist in the medical management of patients with inflammatory bowel disease. Glucocorticoids suppress active inflammation very effectively, but their long term use is associated with high rates of relapse and unacceptable toxicity. 6-Mercaptopurine and its prodrug azathioprine are effective in inducing and maintaining remission; however, a significant number of patients are resistant or intolerant to thiopurines. Low dose methotrexate, an anti-inflammatory drug, is a well established medication for rheumatoid arthritis and psoriasis. After an initial report in 1989, several clinical trials and analyses of clinical notes have examined the role of methotrexate in patients with ulcerative colitis and Crohn's disease. This review was conducted to summarize the current knowledge about the underlying basic anti-inflammatory mechanisms of methotrexate as well as the pharmacology and toxicology of this drug with particular emphasis on inflammatory bowel disease. It also critically evaluates all existing trials not only in the induction of remission but also in maintenance therapy. We conclude that low dose methotrexate is an effective and safe treatment in glucocorticoid-dependent and thiopurine intolerant patients with Crohn's disease but not ulcerative colitis. It remains to be seen whether low dose methotrexate may also be useful in long term maintenance therapy in patients with inflammatory bowel disease.
20641847 (111)In-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe- 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Janssen et al. (13) reported the development of (111)In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)](2) ((111)In-DOTA-E-[c(RGDfK)](2)) for imaging α(v)β(3) receptors in nude mice bearing ovarian carcinoma tumors.