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Objective: Phthalates induce inflammation and are ubiquitously used in daily life. We aim to study the impact of di‐(2‐ethylhexyl) phthalate (DEHP) exposure on inflammation and osteoporosis in premenopausal and postmenopausal females. Methods: Female 8‐week‐old C57BL/6JNarl mice received an ovariectomy (OVX) or a sham operation and were fed with DEHP or vehicle by oral gavage for 4 or 8 weeks. Their femurs were isolated for micro‐computed tomography, and their serum was collected for inflammatory cytokine assays. Correlations between urinary phthalate metabolites and the lumbar spine bone mineral density (BMD) in premenopausal and postmenopausal volunteers were performed. Results: Among the OVX mice treated for 4 weeks, significant lower bone volume, bone volume/tissue volume, and trabecular number but significant higher trabecular bone pattern factor and structure model index were identified in the mice treated with DEHP than with vehicle. The OVX mice treated with DEHP for 4 weeks had significantly higher serum interleukin (IL)‐1β, IL‐10, IL‐17A, interferon (IFN)‐γ, tumor necrosis factor (TNF)‐α, and Dickkopf‐1 levels than those treated with vehicle. The sham mice treated with DEHP for 8 weeks showed an impaired femur trabecular microstructure and had significantly higher serum IL‐1β, IL‐6, IL‐10, IL‐17A, IFN‐γ, and TNF‐α than those treated with vehicle. DEHP metabolites were inversely correlated with the BMD of premenopausal women and the T‐score of postmenopausal women. Conclusion: DEHP treatment in OVX and sham mice results in osteoporosis and impairs the microstructure of the femur trabecula through inflammation. Phthalate exposure negatively affects the bone mass in both premenopausal and postmenopausal women. Thus, long‐term avoidance is suggested. [ABSTRACT FROM AUTHOR]

This article discusses a case of a 33-year-old man who presented with fever, bilateral plantar pain, and skin lesions. The patient was diagnosed with keratoderma blennorrhagica, a skin condition associated with reactive arthritis. Reactive arthritis is an inflammatory arthritis that typically occurs after an infection in another part of the body. The exact cause of reactive arthritis is unknown, but it is believed to be related to an abnormal immune response triggered by an infection. Treatment involves managing symptoms with nonsteroidal anti-inflammatory drugs and physical therapy. [Extracted from the article]

Background: Nonradiographic axial spondyloarthropathies (nr-axSpA) are diagnosed by the absence of radiographic sacroiliitis and the presence of bone marrow edema (BME) on magnetic resonance imaging (MRI). According to the classification criteria of the international Assessment of Spondyloarthritis Society (ASAS), structural changes to sacroiliac joints (SIJs) on MRI cannot be used as criteria in the absence of BME. However, less than half the Asian patients with clinically active axSpA show BME. The incidence of human leukocyte antigen (HLA)-B27 is low in Asian populations, which makes it more difficult to identify nr-axSpA. We used MRI to evaluate the structural damage to SIJs in patients with nr-axSpA with and without BME with the aim of identifying the best methodology for accurate diagnosis, especially in populations with less common BME and HLA-B27.Methods: One hundred three patients with inflammatory back pain were included in this prospective study. No patient's radiograph met the definition of positive modified New York criteria. BME and structural damage to SIJ including sclerosis and erosion were assessed independently on coronal and axial short-tau inversion recovery and T1-weighted spin echo MRI scans by two well-trained musculoskeletal radiologists using the Spondyloarthritis Research Consortium of Canada (SPARCC) score. Demographics of patients were collected. Disease characteristics and structural damage were analyzed in patients with and without BME on SIJ MRI. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of structural damage.Results: All individuals in the cohort had at least one abnormal finding on SIJ MRI, including BME or structural damage; 36 of 103 patients had BME. We identified a significant positive correlation between SPARCC scores and severe erosion assessed by focal joint space widening (fJSW) (p = 0.001) in these 36 patients. Fifty-eight of the 103 enrolled patients fulfilled the ASAS criteria for nr-axSpA in the either absence or presence of BME. Of these 58 patients, 57 and 19 had erosions or fJSW, respectively, and the presence of BME was significantly correlated with fJSW (phi score of 0.319 and p = 0.015). We demonstrated a significant positive correlation between fJSW and either the presence or the severity of BME in patients with nr-axSpA who met the ASAS definition. There was a positive correlation between BME and fJSW across the whole study cohort (phi score of 0.389; p < 0.001). The area under the ROC curve (AUC) for fJSW on SIJ MRI was 0.736, p < 0.001. In both HLA-B27-positive and -negative groups, BME was more common in the presence of fJSW (phi scores of 0.370 and 0.377, p = 0.018 and 0.003, respectively) and SPARCC scores were higher in patients with fJSW (p < 0.001 and p = 0.005). We also identified a positive correlation between fJSW and BME in patients with nr-axSpA and normal serum levels of C-reactive protein (phi score of 0.362 and p = 0.001).Conclusion: Structural damage detected on SIJ MRI, sclerosis, erosions and fJSW may be present in patients without detectable inflammation on SIJ MRI. However, fJSW is significantly correlated with the severity of inflammation seen on SIJ MRI, which contributes to the accurate diagnosis of nr-axSpA, and it could be used as an alternative diagnostic test for nr-axSpA in the general population, especially for those who do not carry the HLA-B27 gene, Asian patients without BME, or patients with normal serum inflammatory biomarkers. [ABSTRACT FROM AUTHOR]

Aim: Mood disorders are a serious issue for patients with rheumatoid arthritis (RA) because poor mental health can exacerbate the disease course. This study aimed to identify the effect of proinflammatory cytokines on the mood of patients with RA. Methods: This study was conducted at a rheumatology clinic in Northern Taiwan. In total, 113 patients with RA and 42 healthy controls were assessed for anxiety and depression symptoms using Hospital Anxiety and Depression Scale (HADS). RA was assessed using the Disease Activity Score of 28 joints (DAS28). Serum proinflammatory cytokine levels, including interleukin (IL)‐1β, IL‐6, IL‐17 and tumor necrosis factor alpha (TNF‐α) were measured and compared between different patient groups according to disease activity and pain level. Results: Serum IL‐1β, IL‐6, IL‐17 and TNF‐α levels were significantly higher in patients with RA than in healthy controls, as were the mean anxiety and depression subscale scores. In patients with RA who had different disease activities, pain severity correlated with both anxiety and depression symptoms. When HADS scores were analyzed according to pain levels, age was correlated with depression in the severe pain group. In the mild pain group, patients with higher IL‐6 or higher IL‐17 had a higher risk of depression. There was no correlation between mood symptoms and cytokine levels in healthy controls. Conclusion: Elevated serum IL‐6 and IL‐17 levels in patients with RA induce arthritis and cause mood symptoms, especially depression symptoms. [ABSTRACT FROM AUTHOR]

Objective Deletion of Deltex1 (DTX1) in mice caused hyperactivation of T cells and lupus-like autoimmune syndromes, however, the association of DTX1 with human autoimmune diseases is totally unknown. This study investigated the role of DTX1 in human T cell functions and its correlation with disease activity in patients with SLE. Methods The influence of DTX1 on T cell function was evaluated using human primary cells. DTX1 expression in peripheral blood mononuclear cells (PBMCs) from healthy controls and SLE patients was measured by quantitative real-time PCR and the SLEDAI was used to assess disease activity. Results After stimulation with anti-CD3 and anti-CD28, silencing of DTX1 expression enhanced IFN-γ secretion by human T cells. The expression of DTX1 in PBMCs was significantly lower in 100 SLE patients than in 50 age- and sex-matched healthy controls (DTX1/glyceraldehyde 3-phosphate dehydrogenase, 0.452 vs 1.269, P < 0.001). The area under the receiver operator characteristics curve of the model was 0.737 (95% CI 0.658, 0.815). Intriguingly, a low DTX1 level in T cells led to high IFN-γ production in SLE patients and had a correlation with severe disease activity. In addition, low DTX1 expression in SLE patients was associated with active LN, lung involvement or hypocomplementaemia. Conclusion Knockdown DTX1 expression in human T cells reduced IFN-γ secretion. DTX1 expression in the PBMCs was significantly lower in SLE patients and had an inverse correlation with disease activity, indicating that the DTX1 level may be a good disease marker of SLE. [ABSTRACT FROM AUTHOR]

Objectives. The aims of this study were to investigate the expression of amphiregulin (AREG) and TNF-α-converting enzyme (TACE) in fibroblast-like synoviocytes from humans with RA (FLS-RA) when stimulated with proinflammatory cytokines and to explore whether AREG plays a role in RA.Methods. The effects of cytokines on the expression of AREG and TACE in FLS-RA were measured by quantitative RT-PCR and western blotting. Blockade of IL-1β-mediated pathways was used to verify the involvement of intracellular signal pathways in the induction of AREG and TACE. TAPI-1 and TACE short hairpin RNA (shRNA) infection were used to identify the role of TACE in IL-1β-induced AREG secretion and shedding. AREG-induced production of MMP-1 and cadherin-11 in FLS-RA were measured by ELISA or western blotting. The effect of AREG on FLS-RA invasion was examined using a Transwell invasion assay.Results. IL-1β, but not other tested cytokines, increased the expressions of AREG mRNA and protein in a dose-responsive and time-dependent manner in FLS-RA. IL-1β induced AREG expression via p38 MAPK, NF-κB, JNK and ERK1/2 signalling pathways and induced TACE expression via PI3K, p38MAPK and NF-κB signalling pathways in FLS-RA. TACE mediated AREG secretion and shedding. EGFR (ErbB1) and Her-2 (ErbB2) were expressed in FLS-RA, and AREG increased MMP-1 and cadherin-11 expression in FLS-RA. AREG promoted the FLS-RA invasion ability.Conclusion. AREG and TACE expression were up-regulated by IL-1β and their activations on FLS-RA lead to the matrix degradation by inducing MMP-1 and cadherin-11 production. TACE activity is necessary for IL-1β-induced AREG release. Our results demonstrate that IL-1β-induced AREG release may be involved in the pathogenesis of RA. [ABSTRACT FROM PUBLISHER]

Ascorbigen (ABG) is the predominant indole-derived compound from Brassica vegetables. In this study, we attempted to evaluate the effects of ABG on hair growth. To this end, we examined the proliferation of isolated human dermal papilla (DP) cells and keratinocytes after incubation in various concentrations (0-1.25 mM) of ABG. Furthermore, hair shaft regrowth was monitored in a mouse model of chemotherapy-induced alopecia (CIA), and hematoxylin and eosin staining was performed for histological analyses. We found that 1.25 mM ABG induced a 1.2-fold increase in the growth of DP cells, but not keratinocytes. However, ABG did not exert significant protective effects against CIA in the mouse model. These findings suggest that ABG may not be able to counteract CIA and that further investigation of the therapeutic potential of ABG in disease models is required. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective. Decoy receptor 3 (DCR3) has been known to modulate immune functions of monocyte or macrophage. In the present study, we investigated the mechanism and the effect of DCR3 on RANK ligand (RANKL)-induced osteoclastogenesis.Methods. We treated cells with DCR3 in RANKL-induced osteoclastogenesis to monitor osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. Osteoclast activity was assessed by pit formation assay. The mechanism of inhibition was studied by biochemical analysis such as RT–PCR and immunoblotting. In addition, cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis and apoptosis signalling were evaluated by immunoblotting and using flow cytometry.Results. DCR3 inhibited RANKL-induced TRAP+ multinucleated cells and inhibited RANKL-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) nuclear translocation in RAW264.7 cells. Also, DCR3 significantly inhibited the bone-resorbing activity of mature osteoclasts. Moreover, DCR3 enhanced RANKL-induced cell apoptosis and enhanced RANKL-induced Fas ligand expression. The mechanisms were mediated via the intrinsic cytochrome c and activated caspase 9 apoptosis pathway.Conclusion. We postulated that the inhibitory activity of DCR3 on osteoclastogenesis occurs via down-regulation of RANKL-induced NFATc1 expression and induction of cell apoptosis. Our results postulated DCR3 as a possible new remedy against inflammatory bone destruction. [ABSTRACT FROM PUBLISHER]

Purpose: Using receptor activator of NF-κB ligand (RANKL) induced osteoclast differentiation on RAW264.7 as a screening tool; we synthesize and identify small-molecule inhibitors preserving immunomodulatory effects as therapeutics for rheumatoid arthritis. Methods: Differentiation into osteoclast-like cells was examined by tartrate-resistant acid phosphatase (TRAP) staining and expression of osteoclast differentiation markers. Collagen-induced arthritis (CIA) mice were administered test articles by gavages to assess its efficacy. Then clinical, histological, and biochemical parameters were assessed to determine the effects of N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide (NDMC101) on synovial inflammation and bone erosion by hematoxlin and eosin staining and Enzyme-linked immunosorbent assay (ELISA). Results: NDMC101 markedly inhibited RANKL-induced formation of TRAP+ multinucleated cells in RAW264.7 and bone marrow macrophage cells (BMMs). Moreover, pit formation assay showed that NDMC101 significantly reduced the bone-resorbing activity of mature osteoclasts. In CIA mice, oral administration of NDMC101 reduced arthritic index and mitigated bone erosion. Serum TNF-α and IL-1β concentrations in these mice were decreased significantly at the higher dose of 62.5 mg/kg. Conclusions: Screening of our chemical library, our findings suggest that NDMC101 inhibits osteoclastogenesis which also ameliorates paw swelling and inflammatory bone destruction. Its efficacy is associated with the inhibition of such transcription factors as NF-κB and NFATc1 as well as multiple protein kinases, including p38, ERK, and JNK. There results guarantee further clinical tests of NDMC101 for its therapeutic potential in the treatment of inflammation-induced bone diseases. [ABSTRACT FROM AUTHOR]

Background: Dengue virus (DENV) infection is a serious public health issue without specific treatment. We examined the potential immunomodulatory effects of leflunomide, a dihydroorotate dehydrogenase inhibitor commonly prescribed for arthritis, in DENV-stimulated monocyte-derived dendritic cells (mo-DCs). Methods: mo-DCs were prepared from purified monocytes. Cytokine and chemokine concentrations were determined by enzyme-linked immunosorbent assay. Expression of cell surface markers or viral E protein was measured by flow cytometry. The activation of transcription factors and kinases was determined by electrophoretic mobility shift assays, Western blotting, or immunoprecipitation kinase assays. Chemotaxis assays were used to determine cell migration. Results: Leflunomide at therapeutic concentrations inhibited cytokine and chemokine production from DENV-infected mo-DCs. Leflunomide suppressed mo-DC maturation by downregulating the expression of both CD80 and CD86. In addition, leflunomide inhibited DENV-induced mo-DC migration and mo-DC response to chemoattractants CCL19 and CCL21. Inhibition of mo-DC migration was likely due to the suppression of CCR7 expression on mo-DCs. These events were associated with the suppression of nuclear factor kappa B and activator protein-1 signaling pathways by leflunomide. Conclusions: Leflunomide preserves immunosuppressive effects, inhibiting activation of DENV-stimulated mo-DCs. Leflunomide may be helpful in the development of therapeutics for DENV infection. [ABSTRACT FROM AUTHOR]

Background: Using tumor necrosis factor-alpha (TNF-α)-activated porcine chondrocytes as a screening tool, we aim to synthesize and identify small-molecule inhibitors preserving immunomodulatory effects as therapeutics for osteoarthritis (OA). Methods: Chondrocytes were isolated from pig joints. A minilibrary of 300 benzamide-linked small molecules was established. The levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) were measured by Western blot and Griess reaction, respectively. Proteoglycan degradation in cartilage explants was determined by histochemistry analysis. The activation of transcription factors and protein kinases was determined by electrophoretic mobility shift assays or Western blots. Zymography and real-time reverse transcriptase-polymerase chain reaction were used to determine enzyme activity and expression of matrix metalloproteinases (MMPs) and aggrecanases, respectively. Results: Bioassay screening of benzamide-linked small molecules revealed that 2-hydroxy- N-[3-(trifluoromethyl)phenyl]benzamide (HS-Cf) was a potent inhibitor of NO production and iNOS expression in TNF-α-stimulated porcine chondrocytes. HS-Cf suppressed TNF-α-induced activity of MMP-13 and expressions of several aggrecanases and prevented TNF-α-mediated reduction of collagen II. Histochemistry analysis confirmed that HS-Cf could prevent TNF-α-induced degradation and release of proteoglycan/aggrecan in cartilage explants. Such effects by HS-Cf were likely through suppressing TNF-α-induced interferon regulatory factor-1 (IRF-1) but not nuclear factor-kappaB signaling. The significance of IRF-1 was further confirmed by short hairpin knockdown studies. Conclusions: In a minilibrary containing 300 small molecules, we identified a benzamide-linked small molecule, HS-Cf, that through down-regulating TNF-α-induced IRF-1 activity suppressed chondrocyte activation and prevented cartilage destruction. HS-Cf might be a potential disease-modifying drug for OA therapeutics. [ABSTRACT FROM AUTHOR]

Objective T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac. Methods We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction. Results A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P = 3.8 × 10−7). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ∼2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype ( P = 0.007). Conclusion Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians. [ABSTRACT FROM AUTHOR]

1. Glutamine is an amino acid that is used to treat various diseases. Glutamine has been reported to have protective effects in human pulmonary epithelia-like cells exposed to hyperoxia. However, the effects of glutamine in hyperoxia-induced lung injury have not been investigated in vivo. 2. Mice treated with saline or glutamine [(750 mg/kg) intravenously] were randomly exposed to hyperoxia for 48 or 72 h. Control mice treated with saline or glutamine were exposed to room air. Cytokine levels in bronchoalveolar lavage fluid (BALF), heat shock protein (HSP) 70, the wet/dry (W/D) weight ratio, malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity and pathoglogical findings in lung tissue were evaluated to determine the effects of glutamine on acute lung injury. In addition, survival was monitored. 3. Lung expression of HSP70 was significantly enhanced in both the control (room air) and 48 and 72 h hyperoxic glutamine-treated mice. The W/D ratio, BALF concentrations of tumour necrosis factor-α and interleukin-6, MDA levels, MPO activity, neutrophil infiltration and interstitial oedema in lung tissue were significantly lower at 48 and 72 h of hyperoxia in glutamine-treated mice compared with saline-treated mice. 4. In a separate series of experiments evaluating survival, after 96 h continuous exposure to hyperoxia, all saline-treated mice died. In contrast, all glutamine-treated mice died after 108 h exposure to hyperoxia. 5. The data suggest that glutamine administered to mice during hyperoxia has a protective effect against hyperoxia-induced acute lung injury and improves survival. [ABSTRACT FROM AUTHOR]

A term 'bone-breaking fever' is used in Chinese medicine to describe the symptoms of patients infected with dengue virus (DV). We examined the significance of the COX-prostaglandin pathway in human DC infected by DV. We show that DV infection induced the expression of COX-2 and the production of prostaglandin E (PGE) in DC, and stimulated the DNA binding of NF-κB and the kinase activity of both IκBα kinase (IKK) α and β. DV infection also activated MAPK and AP-1 signaling. Both IκBα kinase-NF-κB and MAPK-AP-1 were upstream of COX-2 activation. Our investigation into the significance of COX-2-PGE pathway also revealed that DV infection enhances DC migration by inducing CC chemokine receptor 7 (CCR7) expression, and that blocking COX-2 or MAPK activity suppresses DV-induced DC migration. Our data also suggest that PGE can induce CCR7 expression on DC and that antagonists of the PGE receptors EP2 and EP4 suppress DV-induced DC migration. We further show that the increased CCR7 expression was observed in both DV-infected and bystander DC, suggesting the presence of secondary effects in inducing CCR7 expression. Collectively, this study reveals not only the pathways involved in COX-2 synthesis in DV-infected DC but also the autocrine action of PGE on the migration of DV-infected DC. [ABSTRACT FROM AUTHOR]

Objective. SLE is an autoimmune disorder characterized by abnormal complement activation. Numerous new biomarkers have recently been used to diagnose or monitor disease activity in patients with SLE. We checked the levels of erythrocyte-bound C4d (E-C4d), an activation-derived fragment of C4 that is deposited on the erythrocytes, under different conditions of SLE in order to correlate these levels with disease activity.Methods. We conducted a cross-sectional investigation of three groups of patients: (i) 63 patients with SLE; (ii) 43 patients with other diseases; and (iii) 26 healthy controls. Erythrocytes were analysed by flow cytometry to determine the levels of E-C4d.Results. We found a significant elevation in the mean levels of E-C4d in SLE patients compared with patients with other diseases or healthy controls. In SLE patients, the levels of E-C4d were correlated with the SLEDAI and inversely correlated with serum C3/C4 levels. In the subgroup of SLE patients with haemolytic anaemia (HA), a significantly higher level of E-C4d was observed than that in SLE patients without HA. However, in SLE patients with HA, there was no correlation between the levels of E-C4d and other markers of disease activity, including SLEDAI and levels of anti-dsDNA, C3 and C4.Conclusion. E-C4d levels are useful diagnostic markers for SLE and can serve as biomarkers of disease activity in patients with SLE. However, E-C4d is of limited value in monitoring disease activity in SLE patients with HA. [ABSTRACT FROM PUBLISHER]

This study aims to investigate the effects and mechanisms of all-trans retinoic acid (t-RA) on interleukin(IL)-1-induced production of several inflammatory mediators in human chondrocytes. The cartilage from OA patients receiving total knee or total hip replacement was obtained and chondrocytes were prepared. Chemokine concentrations were measured by ELISA. The expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was determined by Western blotting and/or RT/PCR. Nitrite levels were measured by Griess assays. The DNA-binding activity and transcriptional activity of activator protein-1 (AP-1) were measured by electrophoresis mobility shift assay and luciferase assay. We showed that t-RA suppressed IL-1-induced release of chemokines, including regulated upon activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein-1alpha (MIP-1α) and MIP-1β. Four different retinoid derivatives all preserved inhibitory effects albeit the potency was different. t-RA potently suppressed IL-1-induced expression of iNOS and COX-2 and production of nitric oxide and prostaglandin E2. In consistent with the results in primary chondrocytes, t-RA down-regulated IL-1-induced AP-1 DNA binding activity and transcriptional activity in a human fibroblast-like (commercially labeled as chondrocyte) cell line. By examining the effect of a c-jun N-terminal kinase (JNK) specific inhibitor, we showed that the suppression of JNK-AP-1 signaling was enough to inhibit IL-1-induced production of chemokines and activation of iNOS and COX-2 pathways. Collectively, our results raise a therapeutic option that intra-articular administration of retinoid derivatives at 10-1000 nanomolar concentrations may be effective to suppress the progression of inflammatory OA. [ABSTRACT FROM AUTHOR]

Objective: Coinhibitory signals mediated via programmed death 1 (PD-1) receptor play a critical role in downregulating immune responses and in maintaining peripheral tolerance. Programmed death 1 ligand 1 (PD-L1), the interacting ligand for PD-1, widely expressed in many cell types, acts as a tissue-specific negative regulator of pathogenic T-cell responses. We investigated the protective potential of PD-L1 on autoimmune diabetes by transgenically overexpressing PD-L1 in pancreatic beta-cells in nonobese diabetic (NOD) mice.Research Design and Methods: We established an insulin promoter-driven murine PD-L1 transgenic NOD mouse model to directly evaluate the protective effect of an organ-specific PD-L1 transgene against autoimmune diabetes. Transgene expression, insulitis, and diabetic incidence were characterized in these transgenic NOD mice. Lymphocyte development, Th1 cells, and regulatory T-cells were analyzed in these transgenic mice; and T-cell proliferation, adoptive transfer, and islet transplantation were performed to evaluate the PD-L1 transgene-mediated immune-protective mechanisms.Results: The severity of insulitis in these transgenic mice is significantly decreased, disease onset is delayed, and the incidence of diabetes is markedly decreased compared with littermate controls. NOD/SCID mice that received lymphocytes from transgenic mice became diabetic at a slower rate than mice receiving control lymphocytes. Moreover, lymphocytes collected from recipients transferred by lymphocytes from transgenic mice revealed less proliferative potential than lymphocytes obtained from control recipients. Transgenic islets transplanted in diabetic recipients survived moderately longer than control islets.Conclusions: Our results demonstrate the protective potential of transgenic PD-L1 in autoimmune diabetes and illustrate its role in downregulating diabetogenic T-cells in NOD mice. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Coinhibitory signals mediated via programmed death 1 (PD-1) receptor play a critical role in downregulating immune responses and in maintaining peripheral tolerance. Programmed death 1 ligand 1 (PD-L1), the interacting ligand for PD-1, widely expressed in many cell types, acts as a tissue-specific negative regulator of pathogenic T-cell responses. We investigated the protective potential of PD-L1 on autoimmune diabetes by transgenically overexpressing PD-L1 in pancreatic β-cells in nonobese diabetic (NOD) mice. RESEARCH DESIGN AND METHODS--We established an insulin promoter-driven murine PD-L1 transgenic NOD mouse model to directly evaluate the protective effect of an organ-specific PD-L1 transgene against autoimmune diabetes. Transgene expression, insulitis, and diabetic incidence were characterized in these transgenic NOD mice. Lymphocyte development, Th1 cells, and regulatory T-cells were analyzed in these transgenic mice; and T-cell proliferation, adoptive transfer, and islet transplantation were performed to evaluate the PD-L1 transgene-mediated immuneprotective mechanisms. RESULTS--The severity of insulitis in these transgenic mice is significantly decreased, disease onset is delayed, and the incidence of diabetes is markedly decreased compared with littermate controls. NOD/SCID mice that received lymphocytes from transgenic mice became diabetic at a slower rate than mice receiving control lymphocytes. Moreover, lymphocytes collected from recipients transferred by lymphocytes from transgenic mice revealed less proliferative potential than lymphocytes obtained from control recipients. Transgenic islets transplanted in diabetic recipients survived moderately longer than control islets. CONCLUSIONS--Our results demonstrate the protective potential of transgenic PD-L1 in autoimmune diabetes and illustrate its role in downregulating diabetogenic T-cells in NOD mice. Diabetes 57:1861-1869, 2008 [ABSTRACT FROM AUTHOR]

Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han-Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulated T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-kappaB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. We showed that Tet inhibited NF-kappaB DNA-binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28-costimulated NF-kappaB activities. Since Tet itself did not affect NF-kappaB binding to its corresponding DNA sequence, the results suggested that Tet might regulate NF-kappaB upstream signaling molecules. Further studies demonstrated that Tet could prevent the degradation of IkappaBalpha and inhibit nuclear translocation of p65 by blocking IkappaBalpha kinases alpha and beta activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signal-regulated kinase and activator protein-1 DNA-binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF-kappaB transcriptional activity by Tet. When four Tet analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-costimulated but not on H(2)O(2)-induced NF-kappaB DNA-binding activities. Our results provide the molecular basis of immunomodulation of Tet for being a potential disease-modifying antirheumatic drug in the therapy of autoimmune disorders like rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

1 Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han-Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. 2 We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulaied T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-κB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. 3 We showed that Tel inhibited NF-κB DNA-binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28-costimulated NF-κB activities. Since Tet itself did not affect NF-κB binding lo its corresponding DNA sequence, the results suggested that Tet might regulate NF-κB upstream signaling molecules. 4 Further studies demonstrated that Tet could prevent the degradation of IκBα and inhibit nuclear translocation of p65 by blocking IκBα kinases α and β activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signalregulated kinase and activator protein-1 DNA-binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF-κB transcriptional activity by Tet. 5 When four Tel analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-coslimulaled but not on H2O2-induced NF-κB DNA-binding activities. 6 Our results provide the molecular basis of immunomodulation of Tet for being a potential diseasemodifying antirheumalic drug in the therapy of autoimmune disorders like rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Dengue viruses(DV) infection is an important public health issue all over the world. Although the pathogenesis remains unclear, the overwhelmingly triggered immune responses have been consistently observed. Recently, we and other researchers demonstrated that the natural hosts for DV are dendritic cells(DC), the primary sentinels of immune system. In light of the significance of T cells in dengue virus pathogenesis, here, we examine the possible consequences of DC-T cell interaction that is supposed to be happening in lymphoid tissues after infection. We showed that DV-infected DC induced the interacting T cells to proliferate, to produce interleukin-2 as well as to express activation markers on cell surface. Compared to mock-infected DC, the infection of DC by DV also induced T cells to produce interleukin-4, interleukin-10 and interferon-gamma, a cytokine pattern suggesting Th0 phenotype. Such an effect was either totally abolished or greatly reduced when DV were pre-inactivated with heat or ultraviolet before infection. In addition, we demonstrated that such a Th0 phenotype shift of T cells was affected neither by different dosages of viruses that infected DC nor by different durations of DC-T cell interaction. Our results provide a basic support for clinical observations and may be of help in understanding the pathogenesis of DV infection. [ABSTRACT FROM AUTHOR]

Objective: The activation of T lymphocytes contributes to the inflammatory process of atherosclerosis. Here we examined the effects of carvedilol, a new β-blocker containing an antioxidative property, on the activation of T cells. Methods: Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA. The NF-κB and related protein activity was determined by electrophoretic mobility shift assays, Western blotting, kinase assays and transfection assays. Results: Carvedilol was nontoxic at concentrations ≦10 μM, however, higher dosages (&ges;20 μM) induced T cell apoptosis. We demonstrated that carvedilol inhibited cytokine production from various stimuli-activated T cells. Carvedilol also suppressed the expression of T cell activation markers, including CD25, CD69 and CD71. Molecular investigation indicated that carvedilol specifically downregulated NF-κB but not activator protein 1 DNA-binding activity in activated T cells. The inhibitory effect was likely due to its antioxidative property. Meanwhile, carvedilol prevented stimuli-induced IκBα degradation. Such an effect was mediated through the inhibition of IκBα kinase activity. The inhibitory specificity on NF-κB by carvedilol was also demonstrated in transfection assays. Conclusions: Our results demonstrated a novel therapeutic mechanism of carvedilol in atherosclerosis, namely the inhibition of T cell activation via downregulating NF-κB activity. [Copyright &y& Elsevier]

Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-10 (IL-10) are important mediators regulating inflammatory responses. Inflammatory processes have an important role in atherogenesis. In this paper, the effects of carvedilol on GM-CSF-induced IL-10 production were examined on human monocytic cell line, U937, and purified human monocytes. First, we showed that one-time carvedilol pretreatment at concentrations 0.3-10 μM dose-dependently inhibited GM-CSF-induced IL-10 production in U937 cells. In addition, we found carvedilol to be non-cytotoxic at concentrations equal to or less than 10 μM. However, at concentrations higher than 10 μM, carvedilol induced programmed cell death in U937 cells. The inhibition of GM-CSF-induced IL-10 production by carvedilol was also observed at the expression of mRNA. Furthermore, the inhibition of IL-10 production was demonstrated in GM-CSF-activated purified human peripheral blood monocytes. Finally, long-term carvedilol pretreatment of U937 cells up to 2 months at concentrations of 1.0 μM mildly enhanced the IL-10 production. Our observations that carvedilol modulated GM-CSF-induced IL-10 production may have some implication in understanding the broad-spectrum effects of carvedilol in regulating inflammatory reactions. [ABSTRACT FROM AUTHOR]

Objective: In the development of autoimmune diseases, dendritic cells (DC) play critical roles. Here, we examined the effect of aspirin on lipopolysaccharide (LPS)-induced DC activation.Methods: The monocyte-derived DC were established. The cytokine production was measured by ELISA, reverse transcriptase/polymerase chain reaction, or intracellular staining analyzed by flow cytometry. The expression of cell surface molecules was determined by flow cytometry.Results: Aspirin inhibited LPS-induced DC maturation and costimulatory molecules expression. Aspirin, at therapeutic concentrations, also decreased LPS-induced IL-12 and IL-10 production. In contrast, the LPS-induced TNF-alpha production was enhanced by aspirin. The differential effects of aspirin on IL-12 and TNF-alpha production may not be due to down-regulation of cyclooxygenase activities.Conclusion: The various effects of aspirin on LPS-stimulated DC may influence the understanding of the diverse immunomodulatory mechanisms of this anti-inflammatory drug. [ABSTRACT FROM AUTHOR]

Adverse drug reactions of non-steroidal anti-inflammatory drugs (NSAIDs) are quite prevalent, but there are few reports about possible adverse psychiatric reactions, which may be ignored or underestimated. We describe here five psychiatric outpatients, two with major depressive disorders, one bipolar disorder, one schizophrenic disorder and one anxiety disorder, who were treated with NSAIDs for pain due to rheumatoid arthritis, osteoarthritis or other painful neuromuscular conditions. All five patients developed a moderate to severe depressive state, three patients became obviously paranoid, and four had either thoughts of suicide or an attempt while undergoing co-administration of NSAIDs. The psychiatric symptoms remitted when the NSAIDs were stopped. The depressive and paranoid symptoms returned on seven occasions of re-use or re-challenge with the same or a different type of NSAID in all five patients. When the NSAIDs were stopped again, the patients had another remission of the adverse psychiatric reactions, and eventually recovered to their baseline mental states in clear temporal relationships. The cases presented suggest that NSAIDs can induce or exacerbate idiosyncratic reproducible adverse psychiatric symptoms in certain vulnerable patients, including those with a variety of psychotic or neurotic disorders, and also in elderly persons, but these undesirable side-effects were generally transient and disappeared on withdrawal of the NSAIDs. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that can lead to damage to several vital organs. Antiphospholipid syndrome (APS), manifesting as vascular thromboembolic events and morbidities of pregnancy in the presence of antiphospholipid antibodies (aPL), has been described in patients with SLE. Catastrophic antiphospholipid syndrome (CAPS), in contradistinction to APS, is defined as three or more organs affected by thrombotic microangiopathy in patients demonstrating aPL and can result in mortality up to 50%. We describe a unique SLE patient who was diagnosed with recurrent APS presented with axillary venous thrombosis and subsequent superficial edema and compartment syndrome. The CAPS followed and revealed thromboses over liver, spleen, and acute pancreatitis. The spontaneous hemorrhage of left fourth intercostal artery (ICA) and left axillary artery occured at the same time without vasculitis or severe trauma. Though emergency transcatheter arterial embolization (TAE) of the left fourth ICA was successfully accomplished by the radiologist. The repeated computed tomography angiogram of chest demonstrated remission of ruptured ICA. Nevertheless, the patient died of diffuse alveolar hemorrhage and respiratory failure and shock. Both disseminated intravascular coagulation (DIC) and CAPS share similar characteristics encompassing thrombotic microangiopathy, bleeding, thromboembolism, and multiple organ dysfunction. It is difficult to distinguish between them, especially in cases such as our uremic SLE patient with a calamitous disease progression. The emphasis of treatment for DIC is on platelet and fresh plasma transfusion, in contrast with anti-coagulant for CAPS. To the best of our knowledge, this is the first report describing ICA hemorrhage in an SLE patient without vasculitis or aneurysm. The lupus flare initiated a pathological immunological cascade and resulted in the CAPS and the vascular damage. [ABSTRACT FROM AUTHOR]

Adult-onset Still’s disease (AOSD) is an inflammatory disorder characterized by high-spiking fever, arthritis, and an evanescent rash. The pattern of chronic arthritis is a universal feature of AOSD. However, chronic bursitis with the formation of numerous rice bodies is a very rare presentation in a patient with AOSD. To our knowledge, no case of formation of numerous rice bodies in AOSD has been reported thus far. We describe the case of a 28-year-old man with AOSD with rice bodies in his left shoulder joint. [ABSTRACT FROM AUTHOR]

Presents several abstracts related to the efficacy and safety of tumor necrosis factor (TNF)-alpha blockers in rheumatoid arthritis. Expression profile analysis by microarray to predict responders to anti-TNF biologics in rheumatoid arthritis; Postmarketing surveillance of etanercept in Australia; Open-label evaluation of the efficacy and safety of etanercept in patients with active rheumatoid arthritis and ankylosing spondylitis.

: We describe a 29-year-old woman who developed pernicious anaemia 2 years after the diagnosis of systemic lupus erythematosus. This is a rare association despite the relationship between the autoimmune aetiologies of these two conditions. Seven other cases have been described, but our report demonstrates a case with an excellent response to steroid and azathioprine. [ABSTRACT FROM AUTHOR]

We describe a patient with polymyositis receiving corticosteroid therapy, who presented with persistent fever and mass lesion at the left thigh. Surgical exploration and mycobacterial culture proved to be Mycobacterium Tuberculosis infection involving the semitendinous muscle of the left thigh. Suitable surgical debridement, anti-TB medications, and sufficient corticosteroid administration resulted in a good control of both polymyositis and the tuberculous infection. [ABSTRACT FROM AUTHOR]

A correction to the article "Deltex1 suppresses T cell function and is a biomarker for diagnosis and disease activity of systemic lupus erythematosus," by Chuen-Miin Leu and colleagues is presented.