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ID PMID Title PublicationDate abstract
21946465 Successful use of tocilizumab in a patient with rheumatoid arthritis following severe panc 2011 Oct Severe cytopenia, including neutropenia and anemia, may occasionally occur during anti-tumor necrosis factor α (TNF-α) therapy. However, its mechanism is poorly understood, and little is known concerning the rationale of the choice of biologic therapy after a severe episode of cytopenia. The authors present the case of a 68-year-old rheumatoid arthritis patient in whom severe pancytopenia developed soon after the initiation of etanercept therapy. After resolution, the interleukin 6 receptor-blocking agent tocilizumab was introduced, which resulted in long-lasting complete remission of the rheumatoid arthritis without any adverse effects. The apoptosis-inducing effects of 3 TNF-α blockers and tocilizumab on peripheral blood mononuclear cells of the patient were compared by means of annexin V and propidium iodide labeling and flow cytometry. In concert with the clinical events, the anti-TNF-α agents demonstrated significantly higher apoptotic activities than that of tocilizumab. Tocilizumab appeared safe after anti-TNF-α-induced cytopenia possibly caused by apoptosis induction.
22197458 Inhibition of hyaluronan synthesis reduced inflammatory response in mouse synovial fibrobl 2012 Feb 1 Hyaluronan (HA) fragments are able to induce inflammation by stimulating both CD44 and toll-like receptor 4 (TLR-4). CD44 and TLR-4 activation stimulates the liberation of NF-kB and pro-inflammatory cytokine responses. The aim of this study was to investigate the effects of hyaluronidase (HYAL) treatment, which depolymerises HA into small fragments, and of the addition of specific hyaluronan synthases-1, 2, and 3 small interference RNA (HASs siRNA), which silence HASs activity, on normal mouse synovial fibroblasts (NSF) and on rheumatoid arthritis synovial fibroblasts (RASF) obtained from mice subjected to collagen induced arthritis (CIA). The addition of HYAL to NSF and/or RASF significantly increased the TLR-4, CD44 and NF-kB activity, as well as the pro-inflammatory cytokines, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-33 (IL-33) in both groups, but to a greater extent in RASF. The addition to NSF and/or RASF of the HASs siRNA, which block HASs activity and therefore the availability of HA substrate for HYAL, was able to reduce HYAL effects in both NSF and RASF. Finally, the HA evaluation confirmed the increment of HA at low molecular weight after HYAL treatment.
22586159 Parental history of lupus and rheumatoid arthritis and risk in offspring in a nationwide c 2013 Apr OBJECTIVES: To examine the familial risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), including juvenile rheumatoid/idiopathic arthritis (JRA), in a population-based setting; and to determine whether patterns of transmission differ according to the sex of the parent or offspring, in order to provide insight into the potential impact of X-chromosomal factors on sex disparities in these autoimmune diseases. METHODS: A population-based cohort of parent-offspring triads from Denmark (1977-2010) was established. SLE and RA incidence rates among offspring were calculated, and Cox regression was performed to assess the sex-specific risk of disease in offspring according to maternal or paternal disease history. RESULTS: Among 3 513 817 parent-offspring triads, there were 1258 SLE cases among offspring (1095 female, 163 male) and 9118 cases of RA/JRA (6086 female, 3032 male). Among female offspring, SLE risk was nearly the same according to maternal (HR 14.1) or paternal (HR 14.5) history (p=NS); likewise among male offspring, risk according to maternal (HR 5.5) and paternal (no cases) history were similar (p=NS). For RA, all risk estimates were similar, regardless of the sex of the offspring or parent (HR 2.6-2.9; p=NS). CONCLUSIONS: The authors quantified the familial risk of SLE and RA in a nationwide cohort study. For both diseases, transmission was comparable among both female and male offspring of maternal and paternal cases. These data provide evidence at the population level that X-chromosomal factors do not play a major role in sex disparities associated with the risk of SLE and RA.
22360989 Development of a patient-reported outcome measure for the foot affected by rheumatoid arth 2012 Apr OBJECTIVE: To develop an idiographic and nomothetic patient-reported outcome measure (PROM) for the assessment and evaluation of patients with feet affected by rheumatoid arthritis (RA). STUDY DESIGN AND SETTING: The development of the Salford Rheumatoid Arthritis Foot Evaluation (SAFE) Instrument PROM was divided into four stages: establishment of the PROM's conceptual basis and content generation, following a descriptive phenomenological study; clinimetric instrument development; instrument pretesting, involving expert reviews and cognitive interviews; and demonstration of instrument measurement properties, including convergent validity and test-retest reliability of the nomothetic scale. RESULTS: A total of 123 items were initially generated for the SAFE, with 25 of them clinimetrically selected for nomothetic scale (SAFE-Part A) and 80 items initially included in the idiographic scale (SAFE-Part B). The pretesting strategy proved effective for improving and refining the SAFE, with the final draft consisting of 19 items in Part A and 42 items in Part B. The SAFE-Part A has strong evidence for convergent validity and test-retest reliability. CONCLUSION: The SAFE features a nomothetic and idiographic assessment strategy that, with further development, will prove to be a valuable tool for clinicians involved in managing the foot health problems associated with RA.
23303013 VEGF and CD31 expression in arthritic synovium and cartilage of human knee joints. 2012 PURPOSE: To determine the histological differences and the particular aspects of local angiogenesis in knee joint of the patients with osteoarthritis (OA) and rheumatoid arthritis (RA). MATERIALS AND METHODS: In 10 cases with RA and five OA, immunohistochemical stains were performed with CD31 and VEGF-A (Vascular Endothelial Growth Factor). All surgical samples provided from total knee joint arthroplasty. Angiogenesis was quantified in both synovial membrane and cartilage. RESULTS: In patients with OA, villous proliferation of the synovial membrane was more prominent that in RA. In the last, invasion of the cartilage by the proliferated synovial tissue was more characteristic. The neovascularization was more intense in RA than in OA, in both synovium and degenerated cartilage. In RA, the vessels were immature in the superficial areas and became larger in the deep synovium. The local angiogenesis was characterized by sprouting and splitting (intussusceptions) mechanisms. In OA, the mature vessels predominated in the subintimal zones. Sprouting or non-sprouting mechanisms of local angiogenesis, which can indicate vascular formation from the resident mature vessels, were not identified in OA. CONCLUSIONS: Angiogenesis seems to have particular behavior in RA and OA. In RA, local active angiogenesis seems to predominate but in OA up taking of the circulating precursors may be more intensely involved. Intra-articular inhibition of local angiogenesis could have therapeutically impact in RA but not in OA. Finally, we can conclude that there probably are many different pathways leading to the same joint damage having certain therapeutic consequences.
21938555 Low-intensity pulsed ultrasound reduces the inflammatory activity of synovitis. 2011 Dec The purpose of this study was to examine the effect of low-intensity pulsed ultrasound (LIPUS) on the cell proliferation and growth of synovial membrane cells stimulated with inflammatory cytokines, and to evaluate the effectiveness of LIPUS treatment of synovitis in the knee joints of animal models for rheumatoid arthritis. The rabbit knee synovial membrane cell line, HIG-82, was cultured in medium with or without IL-1β or TNF-α. Four hours after stimulation with the cytokines, the cells received LIPUS or sham exposure. Cell proliferation and growth were then analyzed. Using MRL/lpr mice, the anti-inflammatory effects of LIPUS were also evaluated in vivo. Stimulation with proinflammatory cytokines significantly up-regulated cell proliferation which was significantly down-regulated by LIPUS exposure. In MRL/lpr mice, exposure of knee joints to LIPUS caused a significant reduction of histological damage compared to the control. Histological lesions were significantly reduced in the joints treated with LIPUS for 3 weeks. Cox-2-positive cells in the knee joints treated with LIPUS were markedly decreased compared to the control joints. Therefore, LIPUS stimulation may be a medical treatment for joint inflammatory diseases, such as synovitis.
21187593 [Anti-RANKL monoclonal antibody Denosumab (AMG162)]. 2011 Jan Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL) which blocks its binding to RANK, inhibiting the development and activity of osteoclasts, followed by suppression of bone resorption. Denosumb given subcutaneously twice yearly for 3 years was associated with a reduction in the risk of vertebral, nonvertebral and hip fractures but not with serious adverse events in women with osteoporosis. New horizon would be brought about by Denosumab, new molecular targeting pharmaceutics in the treatment of osteoporosis as well as rheumatoid arthritis and metastatic bone diseases.
22361690 Rituximab and mycophenolate combination therapy in refractory dermatomyositis with multipl 2011 Dec We report a case of dermatomyositis associated with rheumatoid arthritis, Hashimoto thyroiditis, and diabetes mellitus responsive only to combination of rituximab with mycophenolate. A 42-year-old woman presented with proximal muscle weakness, myalgias, fever, night sweats, and shortness of breath. Creatinine kinase was 8155 IU/L, and muscle biopsy was diagnostic of dermatomyositis. She was started on glucocorticoids; her systemic symptoms improved, but her muscle weakness persisted. She was serially treated with intravenous immunoglobulin, azathioprine, and mycophenolate mofetil without improvement in her weakness. She responded dramatically to combination therapy with rituximab and mycophenolate, with improvement in strength and normalization of creatinine kinase. She has been well controlled on rituximab infusion every 6 months and maintenance mycophenolate mofetil.
22674488 Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients wi 2012 Oct OBJECTIVE: The importance of interleukin-17 (IL-17) is underscored both by its resistance to control by Treg cells and the propensity of Treg cells to produce this highly inflammatory cytokine. This study sought to address whether Th17 cells are inhibited by Treg cells in rheumatoid arthritis (RA) patients responding to anti-tumor necrosis factor (anti-TNF) therapy, and if so defining the underlying mechanisms of suppression. METHODS: Inhibition of Th17 cell responses was determined by Treg cell suppression assays. The Treg cell phenotype was analyzed using flow cytometry and enzyme-linked immunosorbent assay. Mechanisms of suppression were tested by cytokine addition or antibody blockade. RESULTS: Th17 responses were inhibited by Treg cells from RA patients responding to the anti-TNF antibody adalimumab (Treg(ada) ), but not by Treg cells from healthy individuals or patients with active RA. Furthermore, Treg(ada) cells secreted less IL-17, even when exposed to proinflammatory monocytes from patients with active RA. Treg(ada) cells suppressed Th17 cells through the inhibition of monocyte-derived IL-6, but this effect was independent of IL-10 and transforming growth factor β, which mediated the suppression of Th1 responses. Adalimumab therapy led to a reduction in retinoic acid receptor-related orphan nuclear receptor C-positive Th17 cells and an increase in FoxP3+ Treg cells lacking expression of the transcription factor Helios. However, this acquisition of IL-17-suppressor function was not observed in RA patients responding to treatment with etanercept, a modified TNF receptor-Fc fusion protein. Indeed, there was no alteration in Treg cell number, function, or phenotype in etanercept-treated patients, and Th17 responses remained unchecked. CONCLUSION: Th1 and Th17 responses are controlled through distinct mechanisms by Treg cells from patients responding to anti-TNF antibody therapy. Adalimumab therapy, but not etanercept therapy, induces a potent and stable Treg cell population with the potential to restrain the progression of IL-17-associated inflammation in RA via regulation of monocyte-derived IL-6.
23253928 Bone remodelling in inflammatory arthritis. 2013 Apr The inflammatory arthropathies that include rheumatoid arthritis, the seronegative spondyloarthropathies and systemic lupus erythematosus are characterised by marked alterations in the architecture and structural integrity of peri-articular bone; however, the pattern and natural history of the skeletal changes differs in these conditions. In part, this can be attributed to differences in the primary anatomical site of the inflammation, but also there is evidence that there are differences in the biological properties and products produced by inflammatory tissues. This review will focus on recent advances in the understanding of the cellular and molecular mechanisms that contribute to the differential pattern of articular bone remodelling in these prototypical inflammatory forms of arthritis.
21665094 MR imaging assessment of inflammatory, crystalline-induced, and infectious arthritides. 2011 May The role of magnetic resonance imaging in evaluating patients with inflammatory arthritides has evolved with the recent introduction of drugs capable of modifying disease activity and natural history. In conditions like rheumatoid arthritis, active synovitis and bone marrow inflammation precede and predict bone and cartilage erosion. These imaging findings identify patients who can be treated early and aggressively to prevent future morbidity. Similarly, in gout and other crystalline disorders, specific diagnosis aided by imaging may lead to earlier medical and surgical management. Infected joints need the most rapid identification to institute immediate therapy and prevent irreversible cartilage destruction.
21360103 The economic burden of rheumatoid arthritis: beyond health care costs. 2011 Mar Rheumatoid arthritis (RA) not only causes significant morbidity, but also leads to substantial losses in terms of productivity that have a negative impact on the individual and the society. In countries, such as Canada, the US, and the UK, it is known that the costs to the economy in terms of sick leave and work-related disability run into billions of dollars. However, putting an accurate figure on these losses is not entirely straightforward. Most health-related studies use the "human capital" approach, which treats human beings as assets. A figure for lost productivity is calculated by multiplying hours lost by the hourly wage rate. It is a method that is not without its critics because of its emphasis on earning power, which discriminates against non-earners. Another method is the "friction-cost" approach, whereby absenteeism is only recorded if the missed work requires extra hours undertaken, either by the employee himself, or by the others. A third method is the "willingness-to-pay" approach which values life according to an individual's preference to avoid illness with an imputed monetary valuation on the various health outcomes being considered. A number of studies have shown that biologic RA treatments provide productivity benefits in terms of maintaining employment, as well as reducing absenteeism and presenteeism. Going forward, an approach recently adopted by the present authors with encouraging preliminary results, the Valuation of Lost Productivity, takes into account a wide range of factors to provide a measure of productivity that is as accurate as possible.
23242087 Interstitial keratitis and sensorineural hearing loss as a manifestation of rheumatoid art 2012 Dec 14 Cogan's syndrome or non-syphilitic interstitial keratitis with vestibule-auditory dysfunction is a serious and under-recognised complication of rheumatoid arthritis. It is an autoimmune condition characterised by inflammatory infiltrates on the cornea and extensive vestibulocochlear damage. If left untreated, patients progress to develop profound hearing loss. We present a case that was incorrectly diagnosed and treated as conjunctivitis by several emergency departments prior to being correctly recognised as Cogan's syndrome.
21047805 Cytokine pattern in very early rheumatoid arthritis favours B-cell activation and survival 2011 Feb OBJECTIVES: B cells play an important role in the perpetuation of RA, particularly as autoantibody-producing cells. The ICs that further develop deposit in the joints and aggravate the inflammatory process. However, B-cell contribution in the very early stage of the disease remains unknown. The main goal of this work was to determine the concentration of cytokines potentially relevant for B-cell activation in serum from very early polyarthritis patients, with <6 weeks of disease duration, who latter on evolved into very early RA (VERA). METHODS: A proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF) and IL-21 levels were measured by ELISA in the serum of VERA, other very early arthritis (VEA), established RA patients and controls. SF samples of established RA were also analysed. RESULTS: VERA patients have higher levels of APRIL and BAFF as compared with VEA, established RA and controls. Furthermore, APRIL and BAFF levels are also significantly elevated in RA-SF when compared with serum. CONCLUSIONS: The increased levels of APRIL and BAFF in VERA patients suggests that B-cell activation and the development of autoreactive B-cell responses might be crucial in early phases of RA. Therefore, APRIL and BAFF could be promising targets for therapy in the early phase of RA.
23249408 The arthritis severity locus Cia5a regulates the expression of inflammatory mediators incl 2012 Dec 19 BACKGROUND: Cia5a is a locus on rat chromosome 10 that regulates disease severity and joint damage in two models of rheumatoid arthritis, collagen- and pristane-induced arthritis (PIA). In this study, we aimed to identify cellular and molecular processes regulated by Cia5a using microarray-based gene expression analysis of synovial tissues from MHC identical DA (severe erosive disease) and DA.F344(Cia5a) congenics (mild non-erosive disease) rats. RESULTS: Synovial tissues from six DA and eight DA.F344(Cia5a) rats were analyzed 21 days after the induction of PIA using the Illumina RatRef-12 BeadChip (21,922 genes) and selected data confirmed with qPCR. There was a significantly increased expression of pro-inflammatory mediators such as Il1b (5-fold), Il18 (3.9-fold), Cxcl1 (10-fold), Cxcl13 (7.5-fold) and Ccl7 (7.9-fold), and proteases like Mmp3 (23-fold), Mmp9 (32-fold), Mmp14 (4.4-fold) and cathepsins in synovial tissues from DA, with reciprocally reduced levels in congenics. mRNA levels of 47 members of the Spleen Tyrosine Kinase (Syk) pathway were significantly increased in DA synovial tissues compared with DA.F344(Cia5a), and included Syk (5.4-fold), Syk-activating receptors and interacting proteins, and genes regulated by Syk such as NFkB, and NAPDH oxidase complex genes. Nuclear receptors (NR) such as Rxrg, Pparg and Rev-erba were increased in the protected congenics, and so was the anti-inflammatory NR-target gene Scd1 (54-fold increase). Tnn (72-fold decrease) was the gene most significantly increased in DA. CONCLUSIONS: Analyses of gene expression in synovial tissues revealed that the arthritis severity locus Cia5a regulates the expression of key mediators of inflammation and joint damage, as well as the expression of members of the Syk pathway. This expression pattern correlates with disease severity and joint damage and along with the gene accounting for Cia5a could become a useful biomarker to identify patients at increased risk for severe and erosive disease. The identification of the gene accounting for Cia5a has the potential to generate a new and important target for therapy and prognosis.
22584017 Low-dose oral prednisone improves clinical and ultrasonographic remission rates in early r 2012 May 14 INTRODUCTION: In early rheumatoid arthritis (RA), low-dose oral prednisone (PDN) co-medication yields better clinical results than monotherapy with disease-modifying anti-rheumatic drugs (DMARDs). In addition, ultrasonography (US) evaluation reveals rapid and significant effects of glucocorticosteroids on subclinical synovitis. No data currently exist that examine the clinical and US results offered by glucocorticoid co-medication over DMARD monotherapy in early RA patients. METHODS: Two hundred and twenty patients with early RA (< 1 year from clinical onset) were treated according to a low disease activity (LDA) targeted step-up protocol including methotrexate (MTX) and, in the active treatment arm, low-dose (6.25 mg/day) oral PDN over 12 months. Clinical disease activity measures were collected at baseline, 2, 4, 6, 9 and 12 months, and US examination of hands was performed at baseline, 6 and 12 months. Grey-scale and power Doppler (PD) synovitis were scored (0 to 3) for each joint. At 12 months, clinical remission according to the disease activity score among 28 joints was defined as the clinical outcome, and a total joint PD score of 0 (PD negativity) as the imaging outcome. RESULTS: Each group included 110 patients with comparable demographic, clinical, laboratory and US characteristics. At 12 months, the LDA rate was similar in the two groups, whilst the clinical remission rate (risk ratio = 1.61 (95% confidence interval = 1.08, 2.04)) and PD negativity rate (risk ratio = 1.31 (95% confidence interval = 1.04, 1.64)) were significantly higher in the MTX+PDN group. CONCLUSION: In early RA, despite a similar response rate in terms of LDA, low-dose oral PDN co-medication led to a higher proportion of clinical remission and PD negativity compared with MTX monotherapy, thus ensuring a better disease activity control. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN2486111.
22540992 The interferon type I signature towards prediction of non-response to rituximab in rheumat 2012 Apr 27 INTRODUCTION: B cell depletion therapy is efficacious in rheumatoid arthritis (RA) patients failing on tumor necrosis factor (TNF) blocking agents. However, approximately 40% to 50% of rituximab (RTX) treated RA patients have a poor response. We investigated whether baseline gene expression levels can discriminate between clinical non-responders and responders to RTX. METHODS: In 14 consecutive RA patients starting on RTX (test cohort), gene expression profiling on whole peripheral blood RNA was performed by Illumina® HumanHT beadchip microarrays. Supervised cluster analysis was used to identify genes expressed differentially at baseline between responders and non-responders based on both a difference in 28 joints disease activity score (ΔDAS28 < 1.2) and European League against Rheumatism (EULAR) response criteria after six months RTX. Genes of interest were measured by quantitative real-time PCR and tested for their predictive value using receiver operating characteristics (ROC) curves in an independent validation cohort (n = 26). RESULTS: Genome-wide microarray analysis revealed a marked variation in the peripheral blood cells between RA patients before the start of RTX treatment. Here, we demonstrated that only a cluster consisting of interferon (IFN) type I network genes, represented by a set of IFN type I response genes (IRGs), that is, LY6E, HERC5, IFI44L, ISG15, MxA, MxB, EPSTI1 and RSAD2, was associated with ΔDAS28 and EULAR response outcome (P = 0.0074 and P = 0.0599, respectively). Based on the eight IRGs an IFN-score was calculated that reached an area under the curve (AUC) of 0.82 to separate non-responders from responders in an independent validation cohort of 26 patients using Receiver Operator Characteristics (ROC) curves analysis according to ΔDAS28 < 1.2 criteria. Advanced classifier analysis yielded a three IRG-set that reached an AUC of 87%. Comparable findings applied to EULAR non-response criteria. CONCLUSIONS: This study demonstrates clinical utility for the use of baseline IRG expression levels as a predictive biomarker for non-response to RTX in RA.
21898355 Treatment with tumor necrosis factor inhibitors and the risk of acute coronary syndromes i 2012 Jan OBJECTIVE: Rheumatoid arthritis (RA) is associated with an increased risk of ischemic heart disease, in both early and established RA. Data on the risk of ischemic heart disease in relation to therapy with tumor necrosis factor (TNF) antagonists (anti-TNF) are conflicting in patients with established RA and essentially lacking in those with early RA. In established RA, the risk of myocardial infarction has been linked to the response to anti-TNF therapies. The aim of this study was to determine the risk of acute coronary syndromes (ACS) in patients with early RA in relation to treatment with, and response to, anti-TNF. METHODS: A cohort consisting of patients in whom RA was diagnosed between 1999 and 2007 was identified from the Swedish Rheumatology Register (n=6,000), from which information on disease activity and pharmacologic treatments was extracted. In a cohort study, the risk of first occurrence of an ACS was compared between patients treated with anti-TNF and those without exposure to anti-TNF, using hazard ratios (HRs). In a nested case-control study, the relationship between response to anti-TNF according to the European League Against Rheumatism (EULAR) response criteria and the risk of ACS was investigated. RESULTS: In the cohort study, treatment with anti-TNF was not related to any statistically significant alteration in the risk of ACS (HR 0.80, 95% confidence interval [95% CI] 0.52-1.24). In the nested case-control study, a good or moderate EULAR treatment response at 3 months and at 6 months was not associated with a risk of ACS (odds ratio [OR] 1.7, 95% CI 0.5-5.1 and OR 1.5, 95% CI 0.3-6.9, respectively), when adjusted for disease activity before treatment start. CONCLUSION: In this study of patients treated with anti-TNF within the first years of RA, neither treatment with, nor response to, anti-TNF therapy could be linked to any statistically significant decrease in the risk of ACS.
21834066 Interleukin-17A induction of angiogenesis, cell migration, and cytoskeletal rearrangement. 2011 Nov OBJECTIVE: To examine the ability of interleukin-17A (IL-17A) to stimulate angiogenesis, cell migration, and cytoskeletal rearrangement. METHODS: The effect of IL-17A on microvascular tube formation and extracellular matrix invasion by human dermal endothelial cells (HDECs) was assessed using Matrigel matrix and Transwell Matrigel invasion chambers. IL-17A-induced growth-related oncogene α (GROα) and monocyte chemotactic protein 1 (MCP-1) production in rheumatoid arthritis synovial fibroblasts (RASFs) and HDECs was measured by enzyme-linked immunosorbent assay. IL-17A-induced migration was assessed using peripheral blood mononuclear cell (PBMC) migration assays and wound-repair scratch assays, with or without anti-GROα and anti-MCP-1 antibodies. Binding of β1 integrin receptors was assessed using integrin binding assays. Cytoskeletal assembly/disassembly in RASFs and HDECs were assessed by immunofluorescence staining for F-actin. IL-17A-induced cell migration and cytoskeletal disassembly were assessed in the presence of a Rac1 inhibitor (NSC23766). Rac1 activation following IL-17 stimulation in the presence or absence of anti-GROα, anti-MCP-1, or IgG control was assessed by Rac GTPase pull-down assays and Western blotting. RESULTS: IL-17A significantly up-regulated angiogenesis and endothelial cell invasion. It significantly induced GROα and MCP-1 expression in RASFs. Migration of PBMCs, RASFs, and HDECs was induced by IL-17A; these effects were blocked by anti-GROα or anti-MCP-1 antibodies. IL-17A significantly up-regulated β1 integrin receptor binding and induced cytoskeletal disassembly in RASFs and HDECs. Rac1 activation was directly induced by IL-17A. IL-17A-induced wound repair and actin rearrangement were inhibited by a pharmacologic inhibitor of Rac1 (NSC23766). Anti-GROα or anti-MCP-1 antibodies had no effect on IL-17A-induced Rac1 activation. CONCLUSION: IL-17A induces angiogenesis, cell migration, and cell invasion, all of which are key processes in the pathogenesis of rheumatoid arthritis and ones that are mediated in part through chemokine- and cytoskeleton-dependent pathways.
21961943 Increased expression of S100 calcium binding protein A8 in GM-CSF-stimulated neutrophils l 2011 Sep OBJECTIVES: In our previous proteomic surveillance, we found that at least 11 proteins in neutrophils were increased more than 2.5-fold by the stimulation of GM-CSF. In this paper, focusing on one of the 11 proteins, S100 calcium binding protein A8 (S100A8), we tried to elucidate the effect of S100A8 and the cooperative effect of S100A8 and GM-CSF on production and secretion of cytokines of neutrophils. METHODS: S100A8 in neutrophil was detected by western blotting, and concentrations of S100A8 in synovial fluid (SF) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were measured by ELISA. Cytokine levels in the culture medium of neutrophils incubated with and without S100A8 were measured by an antibody array. IL-8 and IL-16 levels in the culture medium of neutrophils stimulated with S100A8, GM-CSF, and the combination of S100A8 and GM-CSF were measured by ELISA. The mRNA levels of IL-8 and IL-16 in the stimulated neutrophils were analysed by real-time PCR. RESULTS: The western blotting analysis confirmed that S100A8 is up-regulated in neutrophil by the stimulation of GM-CSF. Furthermore, the ELISA analysis confirmed that S100A8 was significantly elevated in SF of patients with RA compared to SF of patients with OA. S100A8 induced mRNA expression and secretion of IL-8 and IL-16. S100A8 further enhanced production of IL-8 by GM-CSF but not that of IL-16. CONCLUSIONS: These data suggest that S100A8 may be involved in the exacerbation of RA, and that S100A8 may be a therapeutic target of RA.