Symptoms Of Collagen-induced Arthritis Research Articles

Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice

Human and murine lymphocytes express dopamine (DA) D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA) are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th)17/T-regulatory (Treg) cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA) was prepared by intradermal injection of chicken collagen type II (CII) in tail base of DBA/1 mice or Drd2 −/− C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL-) 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF-) β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2 −/− CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1 −/− CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.

Parthenolide inhibits pro-inflammatory cytokine production and exhibits protective effects on progression of collagen-induced arthritis in a rat model

Objectives: Progressive destruction of synovial joint cartilage and bone occurs in pathological conditions such as rheumatoid arthritis (RA) because of the overproduction of pro-inflammatory cytokines and activation of nuclear factor kappa B (NF-κB). Through the screening of NF-κB inhibitors by a luciferase reporter gene assay, we identified parthenolide (PAR) as the most potent NF-κB inhibitor, among several PAR analogue compounds. This study was undertaken to determine whether PAR inhibits pro-inflammatory cytokine production, cartilage degradation, and inflammatory arthritis.Method: The mRNA levels of pro-inflammatory cytokines were examined by real-time polymerase chain reaction (PCR). Proteoglycan content and release were determined by measuring glycosaminoglycan (GAG) levels using the dimethylmethylene blue (DMMB) dye-binding assay. The potential role of PAR in treatment of arthritis was studied using a collagen-induced arthritis (CIA) model.Results: We established that PAR, as a prototype compound, suppressed lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-α-induced increases in matrix metalloproteinase (MMP)-1, MMP-3, inducible nitric oxide synthase (iNOS), and interleukin (IL)-1β mRNA in chondrocytes. In addition, PAR prevented proteoglycan degradation triggered by pro-inflammatory cytokines. PAR treatment at the onset of CIA symptoms significantly reduced synovitis, inflammation, and pannus formation scores. Reduced synovial inflammation after PAR treatment was also reflected in significantly less bone erosion and cartilage damage.Conclusions: These data indicate a protective effect of PAR on the catabolic insults of pro-inflammatory cytokines on chondrocyte metabolism and GAG release in vitro and in CIA. PAR had anti-inflammatory and structure-modifying effects on experimental arthritis, suggesting that PAR may be useful as a potential alternative or adjunct therapy for inflammatory arthritis.

In vivo expression of recombinant pregnancy-specific glycoprotein 1a inhibits the symptoms of collagen-induced arthritis.

The contribution of Pregnancy-specific glycoproteins (PSG), the major variant of PSG released into the circulation during pregnancy, to the pregnancy-dependent improvement of rheumatoid arthritis (RA) has still not been elucidated. Collagen-induced arthritis (CIA) was used to test the hypothesis that PSG1a when released into circulation has a modulatory role on the Th1-pathogenic response, thus improving the CIA symptoms. In vivo expression of PSG1a was induced by injection of the vaccinia (Vac)-based expression vector harboring the complete open-reading frame of PSG1a cDNA. In vivo PSG1a expression during the induction of CIA ameliorated the clinical symptoms, thereby reducing the arthritis score and incidence. Significantly lower levels of IL-17, IL-6, and IFN-γ, but higher levels of TGF-β and IL-10 were secreted by collagen type II-stimulated spleen mononuclear cells from Vac-PSG1a-treated mice compared with control mice. Moreover, Vac-PSG1a treatment promoted the increase in splenic CD4+CD25+Foxp3+ Treg cells. Pre-clinical Vac-PSG1a treatment suppressed the Th1- and Th17-type-specific responses, leading to an increase in splenic Treg cells as well as IL-10- and TGF-β-secreting cells, with the CIA symptoms being ameliorated.

A1.55 Development of antibodies specific for carbamylated protein precedes disease onset in MICE with collagen-induced arthritis

BackgroundAntibodies against citrullinated proteins are a characteristic of rheumatoid arthritis (RA). Recently, we demonstrated that autoantibodies recognizing homocitrulline containing proteins are present in sera of RA patients and predict joint...

Anti-inflammatory effects of WF10 in a mouse model of rheumatoid arthritis (P5185)

Abstract The purpose of our study was to investigate whether the immune modulator WF10 has an impact on clinical signs of experimentally induced rheumatoid arthritis in DBA/1 mice. Female DBA/1 mice were sensitized with a collagen II emulsion on day 0 and boosted on day 21. The animals were scored from day 17 for clinical signs of collagen induced arthritis (CIA). If the evaluated score exceeded a value of 5, CIA was considered to be established. From the day of CIA onset animals were treated with WF10 or saline in different doses and treatment regimens. Scoring was done for a total of 21 days after CIA onset. Animals which developed CIA within the first 35 days after the immunization were included into the study. Control animals as well as mice treated with WF10 exhibited CIA and showed an increasing score within the observation period, whereas animals treated with the compound showed a reduction of clinical symptoms. 21 days after CIA onset, animals were sacrificed and samples were preserved for further investigations like cytokine measurements, histology and mRNA expression analyses. In conclusion, WF10 had a reducing effect on the severity of CIA symptoms in mice and may therefore present a novel therapeutic approach for patients suffering from rheumatoid arthritis and other inflammatory autoimmune diseases.

Helminth Antigens Enable CpG-Activated Dendritic Cells to Inhibit the Symptoms of Collagen-induced Arthritis through Foxp3+ Regulatory T Cells

Dendritic cells (DC) have the potential to control the outcome of autoimmunity by modulating the immune response. In this study, we tested the ability of Fasciola hepatica total extract (TE) to induce tolerogenic properties in CpG-ODN (CpG) maturated DC, to then evaluate the therapeutic potential of these cells to diminish the inflammatory response in collagen induced arthritis (CIA). DBA/1J mice were injected with TE plus CpG treated DC (T/C-DC) pulsed with bovine collagen II (CII) between two immunizations with CII and clinical scores CIA were determined. The levels of CII-specific IgG2 and IgG1 in sera, the histological analyses in the joints, the cytokine profile in the draining lymph node (DLN) cells and in the joints, and the number, and functionality of CD4+CD25+Foxp3+ T cells (Treg) were evaluated. Vaccination of mice with CII pulsed T/C-DC diminished the severity and incidence of CIA symptoms and the production of the inflammatory cytokine, while induced the production of anti-inflammatory cytokines. The therapeutic effect was mediated by Treg cells, since the adoptive transfer of CD4+CD25+ T cells, inhibited the inflammatory symptoms in CIA. The in vitro blockage of TGF-β in cultures of DLN cells plus CII pulsed T/C-DC inhibited the expansion of Treg cells. Vaccination with CII pulsed T/C-DC seems to be a very efficient approach to diminish exacerbated immune response in CIA, by inducing the development of Treg cells, and it is therefore an interesting candidate for a cell-based therapy for rheumatoid arthritis (RA).

Moxibustion at Mingmen Reduces Inflammation and Decreases IL-6 in a Collagen-Induced Arthritis Mouse Model

The purpose of this study was to compare the effectiveness of moxibustion (MOX) treatment at the GV4 and CV12 acupoints, and to determine the correlations between MOX treatment and interleukin (IL)-6 and corticosterone levels in a collagen-induced arthritis (CIA) mouse model. CIA mice were immunized twice intradermally over a 3-week interval with bovine type II collagen. After the second immunization (day 21), MOX was applied to the mouse equivalent of the GV4 and CV12 acupoints with a 1mg moxa cone five times/day. Clinical symptoms of CIA were observed three times/week until day 35. The concentrations of IL-6 and corticosterone in the blood samples were measured by immunoassay kits. At day 35, the incidence of CIA was significantly decreased in mice treated with MOX at the GV4 acupoint (78%, n=23, p<0.05), compared to untreated CIA mice (100%) and mice treated with MOX at the CV12 acupoint (100%). IL-6 and corticosterone levels were significantly increased by immunization. IL-6 levels significantly decreased in mice treated with MOX at the GV4 acupoint. These results suggest that MOX treatment suppressed CIA at the GV4 acupoint, not at the CV12 acupoint, possibly through inhibition of IL-6 production.

Suppression of inflammatory responses after onset of collagen-induced arthritis in mice by oral administration of the Citrus flavanone naringin

Rheumatoid arthritis (RA) is closely related to the pathogenesis of tumor necrosis factor α in lesions. We investigated the suppressive effects of a Citrus flavanone naringin on inflammatory responses in mice with collagen-induced arthritis (CIA), a mouse model for RA. To investigate potential preventive and therapeutic effects of naringin, mice were given naringin orally three times a week from the second immunization with collagen (day 21) and from day 31, when symptoms of CIA had reached a plateau, respectively. In both cases, inflammation-related clinical scores for knee joints were significantly reduced by administration of naringin. Histological analyses demonstrated that representative phenomena, such as damage to interchondral joints, infiltration of inflammatory cells and pannus formation, were significantly depressed by treatment with naringin. In addition, increases in the expression of high-mobility group box-1 protein in the joints of mice with CIA were suppressed by naringin. These results suggest that oral administration of naringin might be effective for treating human patients with RA.

Cytokine-Modulatory Activity and Therapeutic Efficacy of 7-Amino-4-Methylcoumarin in Murine Collagen-Induced Arthritis

Amino-4-methylcoumarin (AMC) was previously shown to suppress pro-inflammatory cytokine production and prevent death in an endotoxic shock model in mice. In the present study, we investigated the effectiveness of AMC as a potential cytokine modulator in alleviating autoimmune diseases. We examined the efficacy and cytokine-modulatory activity of AMC in collagen-induced arthritis (CIA) in mice. Mice were immunized with type II collagen. AMC at 0, 3, or 30 mg/kg was administered orally to the immunized mice once daily for three weeks before and/or three times daily for two weeks after the onset of CIA. The development of arthritis of the paws and cytokine levels in serum were examined. AMC significantly reduced the incidence and severity of CIA prophylactically and therapeutically, and suppressed the rise of systemic interleukin-6 and interferon-� �to the basal levels in the early phase of CIA. AMC also significantly suppressed the level of tumor necrosis factor-� in the severe phase of CIA. However, the levels of interleukin-10 and anti-collagen antibody were not affected by AMC. In the early phase of CIA, the suppression of interleukin-6 and interferon-� � by AMC correlated with the amelioration of symptoms of CIA in a dose-dependent manner. AMC may inhibit the onset of cytokine-mediated disease rather than suppressing disease progression without toxicity or affecting anti-collagen antibody production. AMC was significantly effective against CIA in mice and confirmed to possess cytokine-modulatory activity in vivo. The results suggest that AMC is a potential therapeutic agent for autoim- mune diseases.

Inhibition of the development of collagen-induced arthritis in Wistar rats through vagus nerve suspension: a 3-month observation

In this study, we have investigated the effects of vagus nerve suspension in a rat model of collagen-induced arthritis (CIA) . CIA was induced in male Wistar rats and vagus nerve suspension or sham operation was performed on day 10 after the second immunization. All rats were monitored for macroscopic signs of clinical arthritis and cytokine titres within 2 months after the second immunization. Radiological and histological examination were performed 3 months after the second immunization. Rats subjected to vagus nerve suspension (the test group) showed nerve activities that resemble electrical stimulation of the vagus nerve in the control group. Compared to control, the test group had reduced soft-tissue swelling, arthritic scores, TNF-alpha level and Collagen-II antibody titre, throughout the course of the experiment. Sham operation produced similar suppression on the CIA symptoms as the test group but most of the effects produced by sham operation subsided after 27 or 35 days. Vagus nerve suspension is a novel approach to achieve sustained long-term stimulation of the vague nerve. This procedure can suppress the development of CIA in rats.

Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis

Objectives:Patients with rheumatoid arthritis (RA) have defective CD4+CD25+ regulatory T (Treg) cells and increased osteoclastogenesis. A similar situation has been described in collagen-induced arthritis (CIA). In this study, it was...

Placental secreted factors: Their role in the regulation of anti-CII antibodies and amelioration of collagen induced arthritis in rats

Pregnancy induces collagen-induced arthritis (CIA) remission in rats. Placental hormones, cytokines and growth factors can regulate immune cell activity at the feto–maternal interface as well as at the systemic level. We assessed the effect of placental culture supernatants (PS) in CIA developed in rats after the inoculation of collagen type II (CII) in complete Freund's adjuvant. After the onset of CIA, animals were injected by ip route with seven doses of PS. On the 18th day of treatment with PS, serum anti-CII antibody (total IgG, IgG 1, IgG 2a, IgG 2b, IgG asymmetric molecules) and cytokine levels were determined by ELISA. An arthritic index was used by daily measure of joint swelling and visual signs of arthritis. Our results demonstrated that the PS treatment diminished CIA symptoms, reduced TNF-α, INF-γ and anti-CII antibody serum levels, increased the proportion of asymmetric IgG anti-CII antibodies and affected IgG 1/IgG 2a and IgG 1/IgG 2b ratio. Two weeks after the last PS inoculation there was a recurrence of arthritis, a rise in IgG anti-CII and, simultaneously, the percentage of asymmetric IgG anti-CII fell. We concluded that PS have an effective CIA suppressor activity partly due to the modulation of humoral immune response and may be closely related to an inhibitory effect on TNF-α and INF-γ production.

Adaptor Wars

Fas, a receptor associated with apoptosis triggering, is reported to be an enhancer of signaling through members of the Toll-interleukin 1 (TIR) family (Ma et al. ), and ST2, which is a member of the TIR family, is reported to be an inhibitor of TIR signaling (Brint et al. ). Cytokine production by joint macrophages contributes to chronic inflammation associated with rheumatoid arthritis. Ma et al. showed that collagen-induced arthritis symptoms were reduced in mice deficient for Fas (DBA/1 lpr/lpr mice) compared with heterozygous littermates. Despite having increased levels of interleukin 1β (IL-1β) and its receptor IL-1R in the paws of the Fas-deficient animals, there was less IL-6, an inflammatory mediator produced in response to IL-1β. Disruption of Fas activation in isolated macrophages resulted in decreased production of IL-6 and activation of nuclear factor κB (NF-κB) in response to IL-1R activation by IL-1β or TLR4 (Toll-like receptor 4) in response to lipopolysaccharide (LPS). Crosstalk between Fas signaling and TIR signaling occurred at the level of the adaptor proteins. MyD88, which mediates IL-R1 and TLR4 signaling, and FADD (Fas-associated protein with death domain), which mediates Fas signaling, interact and the outcome is that in the absence of Fas signaling, FADD sequesters MyD88, making it less available for TIR signaling. In the presence of Fas activation, FADD is recruited to the Fas signaling complex and MyD88 is free to mediate TIR signaling. Brint et al. reported that ST2 also acts to sequester the TIR adaptors MyD88 and Mal. In macrophages from ST2-deficient mice, there was enhanced cytokine production in response to stimuli that activate TLR4, TLR9, TLR2, or IL-R1. The TIR domain of ST2 binds the adaptors MyD88 and Mal, which results in decreased availability of these adaptors for mediating TLR signaling. ST2 is not abundant in macrophages from unchallenged mice, and ST2-deficient mice showed the same mortality to LPS as wild-type mice. However, cytokine production and mortality were decreased in ST2-deficient macrophages and mice, respectively, compared with wild type if there was a sublethal LPS exposure before the LPS challenge. Thus, ST2 is stimulated in response to TLR signaling and can then attenuate subsequent responses, which contributes to endotoxin tolerance. Y. Ma, H. Liu, H. Tu-Rapp, H.-J. Thiesen, S. M. Ibrahim, S. M. Cole, R. M. Pope, Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation. Nat. Immunol. 5 , 380-387 (2004). [Online Journal] E. K. Brint, D. Xu, H. Liu, A. Dunne, A. N. J. McKenzie, L. A. J. O'Neill, F. Y. Liew, ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat. Immunol. 5 , 373-379 (2004). [Online Journal]

Adenovirus-Mediated Transfer of Viral IL-10 Gene Inhibits Murine Collagen-Induced Arthritis

IL-10 is a potent anti-inflammatory cytokine that has received growing attention for its therapeutic potential. We examined the efficiency of adenoviral-mediated gene transfer of IL-10 on the incidence and severity of murine collagen-induced arthritis (CIA). Male DBA1 mice immunized with collagen II were treated by systemic administration of 10(9) plaque-forming units of replication-defective adenoviral vector expressing viral IL-10 (vIL-10) on day 30, when clinical symptoms of arthritis start. The transgene was shown to inhibit the onset of CIA, to decrease severity, and profoundly suppress the overall joint histopathology of the experimental arthritis. Significant IL-10 concentrations were obtained in the serum of injected animals for 7 days. Inhibition of arthritis was enhanced by administration of increasing doses of adenovirus-vIL-10. In addition, the local immunosuppressive effect of gene-delivered vIL-10 could be neutralized by a monoclonal anti-vIL-10 Ab. The CIA symptoms in the group treated with the same construct expressing inactive vIL-10 (vIL-10 mut) were similar to those in untreated animals. Our data indicate that a single systemic administration of an adenoviral vector encoding vIL-10 may be a good candidate to suppress arthritis.

Dietary n‐3 fatty acids and arthritis

We have evidence that dietary fish oil (FO) decreases severity of collagen-induced arthritis (CIA), changes the fatty acid composition of macrophage (M phi) membrane phospholipids, decreases M phi synthesis of prostaglandins (PGs), changes chemotactic ability of M phi s, and affects metabolism of acute phase proteins. Gender also has pronounced effects on susceptibility to CIA and M phi prostaglandin profiles. The mechanisms by which dietary n-3 fatty acids may act to alleviate symptoms of CIA, as well as interactions of dietary n-3 and n-6 fatty acids and gender are discussed. We suggest that the ability of FO diets to influence favourably the course of chronic inflammatory diseases is mediated via alterations in n-6 fatty acid metabolism and that intrinsic differences in n-6 fatty acid metabolism may account not only for our reported gender differences in incidence and severity of CIA, but also the well-documented sexual dimorphism in immune/inflammatory responses in general.