In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis

Interleukin (IL)-27 is a novel cytokine of the IL-6/IL-12 family that has been reported to be involved in the pathogenesis of autoimmune diseases and has a pivotal role as both a pro- and anti-inflammatory cytokine. We investigated the in vivo effects of IL-27 on arthritis severity in a murine collagen-induced arthritis (CIA) model and its mechanism of action regarding control of regulatory T (Tregs) and IL-17-producing T helper 17 (Th17) cells. IL-27-Fc-treated CIA mice showed a lower severity of arthritis. IL-17 expression in the spleens was significantly decreased in IL-27-Fc-treated CIA mice compared with that in the CIA model. The Th17 population was decreased in the spleens of IL-27-Fc-treated CIA mice, whereas the CD4+CD25+Foxp3+ Treg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4+ T cells, and the effect was associated with retinoic acid-related orphan receptor gammaT and signal transducer and activator of transcription 3 inhibition. In contrast, fluorescein isothiocyanate-labeled forkhead box P3 (Foxp3) and IL-10 were profoundly augmented by IL-27 treatment. Regarding the suppressive capacity of Treg cells, the proportions of CTLA-4+ (cytotoxic T-lymphocyte antigen 4), PD-1+ (programmed cell death protein 1) and GITR+ (glucocorticoid-induced tumor necrosis factor receptor) Tregs increased in the spleens of IL-27-Fc-treated CIA mice. Furthermore, in vitro differentiated Treg cells with IL-27 exerted a more suppressive capacity on T-cell proliferation. We found that IL-27 acts as a reciprocal regulator of the Th17 and Treg populations in CD4+ cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs. Our study suggests that IL-27 has the potential to ameliorate overwhelming inflammation in patients with RA through a reciprocal regulation of Th17 and Treg cells.

Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis

Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P < 0.05). GSPE reduced the loss of chondrocytes and proteoglycan, the production of MMP13, nitrotyrosine and IL-1beta and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA.

Grape seed proanthocyanidin extract ameliorates monosodium iodoacetate-induced osteoarthritis

Osteoarthritis (OA) is an age-related joint disease that is characterized by degeneration of articular cartilage and chronic pain. Oxidative stress is considered one of the pathophysiological factors in the progression of OA. We investigated the effects of grape seed proanthocyanidin extract (GSPE), which is an antioxidant, on monosodium iodoacetate (MIA)-induced arthritis of the knee joint of rat, which is an animal model of human OA. GSPE (100 mg/kg or 300 mg/kg) or saline was given orally three times per week for 4 weeks after the MIA injection. Pain was measured using the paw withdrawal latency (PWL), the paw withdrawal threshold (PWT) and the hind limb weight bearing ability. Joint damage was assessed using histological and microscopic analysis and microcomputerized tomography. Matrix metalloproteinase-13 (MMP13) and nitrotyrosine were detected using immunohistochemistry. Administration of GSPE to the MIA-treated rats significantly increased the PWL and PWT and this resulted in recovery of hind paw weight distribution (P < 0.05). GSPE reduced the loss of chondrocytes and proteoglycan, the production of MMP13, nitrotyrosine and IL-1beta and the formation of osteophytes, and it reduced the number of subchondral bone fractures in the MIA-treated rats. These results indicate that GSPE is antinociceptive and it is protective against joint damage in the MIA-treated rat model of OA. GSPE could open up novel avenues for the treatment of OA.

Induction of Macrophage Migration Inhibitory Factor in ConA-Stimulated Rheumatoid Arthritis Synovial Fibroblasts through the P38 MAP Kinase-Dependent Signaling Pathway

BACKGROUND/AIMS: This study was undertaken to identify the intracellular signaling pathway involved in induction of macrophage migration inhibitory factor (MIF) in human rheumatoid arthritis (RA) synovial fibroblasts. METHODS: Human RA synovial fibroblasts were treated with concanavalin A (ConA), various cytokines, and inhibitors of signal transduction molecules. The production of MIF by synovial fibroblasts was measured in culture supernatants by ELISA. The expression of MIF mRNA was determined using reverse transcriptase polymerase chain reaction (RT-PCR) and real-time PCR. Phosphorylation of p38 mitogen-activated protein (MAP) kinase in synovial fibroblasts was confirmed using Western blotting. The expression of MIF and p38 MAP kinase in RA synovium was determined using dual immunohistochemistry. RESULTS: The production of MIF by RA synovial fibroblasts increased in a dose-dependent manner after ConA stimulation. MIF was also induced by interferon-gamma, CD40 ligand, interleukin-15, interleukin-1beta, tumor necrosis factor-alpha, and transforming growth factor-beta. The production of MIF by RA synovial fibroblasts was significantly reduced after inhibition of p38 MAP kinase. The expression of MIF and p38 MAP kinase was upregulated in the RA synovium compared with the osteoarthritis synovium. CONCLUSIONS: These results suggest that MIF production was induced through a p38 MAP-kinase-dependent pathway in RA synovial fibroblasts.

The Th17 and Autoimmune Arthritis

Autoimmune arthritis, such as rheumatoid arthritis (RA), is a chronic inflammatory disorder that primarily affects the joints and then results in their progressive destruction. Effector Th cells have been classified as Th1 and Th2 subsets based on their cytokine expression profiles and immune regulatory function. Another subset of T cells termed Th17 was recently discovered and known to selectively produce IL-17. Also, Th17 was shown to be generated by TGFbeta and IL-6 and maintained by IL-23. IL-17 is a proinflammatory cytokine that is considered to involve the development of various inflammatory autoimmune diseases such as RA, asthma, lupus, and allograft rejection. IL-17 is present in the sera, synovial fluids and synovial biopsies of most RA patient. IL-17 activates RA synovial fibroblasts to synthesize IL-6, IL-8 and VEGF via PI3K/Akt and NF-kappaB dependent pathway. IL-17 increases IL-6 production, collagen destruction and collagen synthesis. In addition, it not only causes bone resorption but also increases osteoclastogenesis and fetal cartilage destruction. Inhibition of the IL-17 production may contribute a novel therapeutic approach along with potent anti-inflammatory effect and with less immunosuppressive effect on host defenses.

Macrophage Migration Inhibitory Factor (MIF) Induced Stromal Cell-derived Factor 1 (SDF-1) Production Via Nuclear Factor KappaB (NF-kappaB) Signaling in Rheumatoid Arthritis Fibroblast Like Synoviocytes (RA-FLS)

BACKGROUND: Stromal cell-derived factor (SDF)-1 is a potent chemoattractant for activated T cells into the inflamed Rheumatoid arthritis (RA) synovium. To determine the effect of macrophage migration inhibitory factor (MIF) on the production of SDF-1 in the inflamed RA synovium. METHODS: The expression of SDF-1 and MIF in RA and Osteoarthritis (OA) synovium was examined by immunohistochemical staining. The SDF-1 was quantified by RT-PCR and ELISA after RA fibroblast like synoviocyte (FLS) were treated with MIF in the presence and absence of inhibitors of intracellular signal molecules. The synovial fluid (SF) and serum levels of MIF and SDF-1 in RA, OA and healthy control were measured by ELISA. RESULTS: Expression of SDF-1 and MIF in synovium was higher in RA patients than in OA patients. The production of SDF-1 was enhanced in RA FLS by MIF stimulation. Such effect of MIF was blocked by the inhibitors of NF-kappaB. Concentrations of SDF-1 in the serum and SF were higher in RA patients than in OA patients and healthy control. SDF-1 and MIF was overexpressed in RA FLS, and MIF could up-regulate the production of SDF-1 in RA FLS via NF-kappaB- mediated pathways. CONCLUSION: These results suggest that an inhibition of interaction between MIF from T cells and SDF-1 of FLS may provide a new therapeutic approach in the treatment of RA.

The Approximate Entropy in Maternal Anemia during Pregnancy according to Gestational Age / 대한주산의학회잡지

OBJECTIVES: Maternal anemia is common hematologic disorders during pregnancy. Although mild maternal anemia is not associated with fetal anemia, neonatal morbidity including fetal anemia are common with severe maternal anemia during pregnancies. We aim to analyze each variable of FHR using linear and nonlinear methods to detect maternal anemia during pregnancies. METHODS: Seventy antepartal anemic pregnant women(Hb<10.0g/dL) and the contrast group, 70 normal pregnant women were selected among the women who underwent nonstress test(NST) during 3rd trimester in Hanyang University Hospital. The calculated FHR parameters(NST time=20 min) from collected FHR data(40-50min) were made by HYFM II data file. To assess the difference between the anemic and normal pregnancy group, the parameters such as baseline FHR, variability (AMP, MMR), acceleration and deceleration(15bpm-15seconds), gestational age at the time of NST, loss of record, the number of fetal movement, FHR were evaluated. We compared the canonical correlation between each groups using variables of NST. The overall complexity of each FHR time series was quantified by its approximate entropy(ApEn), measure of regularity derived from nonlinear dynamics, "chaos theory". Finally we extract the value of ApEn and were compared between two groups, normal and anemic pregnant women. RESULTS: There were significant decrease of FHR variability(amplitude and mean minute interval) in anemic group. Canonical correlation ensemble was significantly high in 36th-37th and 38th-39th gestational weeks in anemic group(p-value=0.03048 and 0.03421). The value of ApEn was significantly low(0.68+0.26) in anemic group comparing with normal pregnant group(0.95+0.08), respectively. CONCLUSIONS: This study shows that FHR of maternal anemia is different from that of normal pregnant women, and that subtle behavioral differences could be demonstrated in uterus using computerized FHR analysis. The anemic women during pregnancy have more linear and less complicated FHR than the normal pregnancy group. ApEn, which is bound to be used as an index of fetal well-being would be used as an evaluating tool of intrauterine fetal function in the near future.

A Case of Acute Monoblastic Leukemia developed during Pregnancy / 대한주산의학회잡지

Acute leukemias are among the most common malignant neoplasms of young woman, but paradoxically, their incidence complicating pregnancy is cited to be very low. In most situations, the course of the pregnancy does not seem to be affected by the presence of the leukemia. So early diagnosis and treatment of acute leukemia might be very important., since acute leukemia in a pregnant young woman poses an immediate threat to life and any treatment delay would significantly worsen the patient's prognosis. We report a 37-year-old female who had symptoms and signs of acute leukemia such as vaginal spotting and leukemia cutis and was diagnosed as acute monoblastic leukemia M5(FAB) in January 2002 with 25 weeks' pregnancy. This case represents the use of combination chemotherapy successfully resulted in complete remission in the second trimester without any adverse impact on the fetus in uterus.

A Clinical Significance of Second-look Laparotomy in Patients with Epithelial Ovarian Cancer / 대한산부인과학회잡지

OBJECTIVE: To evaluate pathological complete remission rate (pCR), survival rate, recurrence rate, 91 patients who had clinical complete remission with epithelial ovarian cancer were studied. METHODS: From 1983 to 2002, 91 consecutive patients with epithelial ovarian cancer underwent surgical cytoreduction followed by platinum-based chemotherapy at the Department of Obstetrics and Gynecology, Hanyang University Hospital. At the conclusion of chemotherapy, all patients who were clinically disease free and whose CA 125 was 2 cm with advanced stage at primary surgery and negative second-look findings should be the focus of future protocols for consolidation chemotherapy.

A Significance of Thrombocytosis as a Prognostic Factor in Patient with Epithelial Ovarian Cancer / 대한산부인과학회잡지

OBJECTIVE: We tried to determine the relevance of thrombocytosis as a possible prognostic factor in patient with epithelial ovarian cancer. METHODS: One hundred and eighty-three (183) patients with epithelial ovarian cancer had been surgically treated in our hospital between January 1984 and December 2001. Uni- and multivariate analyses were performed of 9 clinical variables including age, FIGO stage, histologic subtype, grade, volume of residual tumor, presence of ascites, pretreatment levels of hemoglobin, platelet, and tumor marker (CA 125). The Kaplan-Meier method and log-rank test were used for univariate analysis and a multiple regression analysis based on the Cox proportional hazards model was done to find the independent prognostic variables. RESULTS: Prevalence of thrombocytosis was 20.8% and significantly correlated with FIGO stage (p=0.015), tumor grade (p=0.029), presence of ascites (p=0.001) and volume of residual tumor (p=0.032). Significant difference in survival between patients with or without thrombocytosis was found (p=0.006). Multivariate analysis model was used and only volume of residual tumor (p=0.004) was significant independent prognostic variable. Thrombocytosis (p=0.041) was significant independent prognostic variable in patients with early FIGO stage of disease. CONCLUSION: Thrombocytosis is a useful prognostic factor in epithelial ovarian cancer and significantly independent prognostic factor in patients with early FIGO stage of disease.

Statistical Analysis of Twin Pregnancy for 10 Years (1993~2002) / 대한산부인과학회잡지

OBJECTIVE: Our purpose was to evaluate the clinical aspects of twin pregnancy and its outcome. METHODS: From January 1993 to December 2002, we reviewed the medical records of 249 cases of twin birth at least weighed 500 g or more and over 20 weeks of gestation among 14,273 deliveries at Hanyang University Hospital. Paired sample t test and linear regression test were used for statistical analysis. p<0.05 was defined significantly. RESULTS: The incidence of twin births was one in 59.6 birth, and the annual rate of twin births has increased since last 10 years (p<0.05). The predominant age group was 25-29 (47.0%) and mean age was 29.8 +/- 3.9 years old. According to parity, primipara (63.9%) was the most frequent. The predominant gestational age of twin births was 37-38 weeks (42.2%) and mean gestational weeks of twin births was 36.3 +/- 2.9 weeks. The ratio of spontaneous and iatrogenic twinning were 73.1% vs 26.9%. The cephalic-cephalic combination (49.8%) was the predominant presentation. The most common mode of twin delivery was cesarean section (76.5%) and its main indication was "elective" (33.5%). The mean interval between 1st and 2nd baby deliveries among normal spontaneous vaginal delivery was 6 minute 28 seconds. Both male group (43.0%) was predominant. The mean birth weights of 1st and 2nd baby were 2341 +/- 592 grams and 2200 +/- 594 grams respectively. No significant differences were seen in one minute and five minute Apgar scores between 1st and 2nd baby. The most common type of placental membrane was single placenta, two chorion, two amnion (40.6%). The most frequent maternal complication during pregnancy was anemia (41.8%), followed by preterm labor (39.0%) and preeclampsia (20.9%). The perinatal mortality rate was 50 per 1000 newborns and 2 cases (0.8%) of maternal death were encountered. The risk of intrauterine fetal death and abortion was 2.4% and 0.8% respectively. CONCLUSION: Recently, although the incidence of twin pregnancy has been increased, it has greater risks of obstetrical complications and higher perinatal mortality than singleton pregnancy. Therefore, further prospective studies of twin pregnancy are needed for counselling and effective management about perinatal prognosis.