Cytokine의 세포 내 신호전달 과정의 억제 기전 (Jak-STAT Signaling을 중심으로)

지종대 ( Jong Dae Ji ),이영호 ( Young Ho Lee ),송관규 ( Gwan Gyu Song ) 대한류마티스학회 2003 대한류마티스학회지 Vol.10 No.1

Cytokines are secreted proteins and interact with their specific cell surface receptors, triggering intracellular signal transduction pathways that activate a number of genes crucial for the biological functions of cytokines. These cytokine signal transduction pathways are tightly regulated processes. The negative regulations of cytokine signaling are achieved by receptor internalization and degradation, dephosphorylation of signaling intermediates, expression of protein inhibitors such as suppressor of cytokine signaling (SOCS) and protein inhibitors of activated STAT (PIAS). The observation that cytokines are central to the inflammatory and destructive process in several autoimmune diseases suggests that interventions targeting the cytokine intracellular signaling will be a new therapeutic strategy in autoimmune diseases. We review the current knowledge about negative regulation of cytokine signal transduction.

건강 검진 환자에서 만성 피로 증후군의 발생 빈도와 임상양상

지종대(Jong Dae Ji),천병철(Byung Chul Chun),최윤선(Youn Seon Choi),최성재(Seong Jae Choi),이영호(Young Ho Lee),송관규(Gwan Gyu Song) 대한내과학회 2000 대한내과학회지 Vol.59 No.5

N/A Background : To determine the prevalence of chronic fatigue syndrome and idiopathic chronic fatigue in Korea and to describe demographic, clinical, and psychological differences among those with chronic fatigue syndrome (CFS), those with idiopathic chronic fatigue, and healthy controls. Methods : 1,526 persons aged 18-76 years who visited Korea university hospital health management center for general check-up between December 1998 and August 1999 were participated in the study. The questionnaire made according to the Centers for Disease Control and Prevention criteria was administered to the recruited persons and patients with chronic fatigue syndrome were diagnosed by questionnaire, physical examination and laboratory tests. The Korean version of the Center for Epidemiological Studies-Depression Scale (CES-D) was used to assess depression. Results : Of the 1,526 persons studied, 433 (29.4 %) reported severe fatigue lasting at least 6 months. Of the 202 persons with unexplained chronic fatigue, 31 persons (2.0% of the study population) were classified as CFS cases. The prevalence of CFS was 2.81% in women, 1.49% in men respectively (p<0.05). When CES-D cut-off score of 25 was used, 30.43% of persons with CFS and 5.93% of persons without chronic fatigue had scores suggestive of depression. CFS patients had higher mean scores on CES-D than persons without chronic fatigue (p<0.05). Conclusion : Persons who met the criteria for chronic fatigue syndrome were found in 2.0%. The prevalence of chronic fatigue syndrome in our study were high, compared with previous studies in other countries. CFS patients had higher mean scores on CES-D than persons without chronic fatigue.(Korean J Med 59:529-534, 2000)

Network Analysis을 이용한 류마티스관절염 활액 대식세포에서 유전자 발현 연구

지종대 ( Jong Dae Ji ),김태환 ( Tae Hwan Kim ),이빛나라 ( Bit Na Ra Lee ),최성재 ( Sung Jae Choi ),이영호 ( Young Ho Lee ),송관규 ( Gwan Gyu Song ) 대한류마티스학회 2011 대한류마티스학회지 Vol.18 No.2

Objective. We wanted to investigate the mechanisms that could account for the pathogenesis of rheumatoid arthritis, so we examined the different expressions of the genes in rheumatoid arthritis (RA) synovial fluid macrophages as compared with that of normal peripheral blood (PB) monocyte-derived macrophages using microarray and bioinformatic analysis. Methods. We examined the expression of genes by using a gene expression oligonucleotide microarray. The differences of the gene expressions between the RA synovial macrophages and the normal PB monocytes-derived macrophages were analyzed using bioinformatic tools, including cytoscape and its plugin. Results. In this study, we found that 899 genes (464 genes up-regulated and 435 genes down-regulated) were differentially expressed between the two groups. Among the 899 genes, 552 genes were included for gene ontology analysis and network analysis. Based on biological process ontology, they were categorised mainly into immune response processes, responses to stimulus and signaling and regulation of biological processes. In addition to the genes related with STAT1 and AP-1 signaling, we found that the genes involved in the antigen processing and the cell cycle are abundantly expressed in RA synovial macrophages, suggesting that these genes may play an important role in the pathogenesis of RA. Conclusion. Our study suggest that this approach using integration of the gene expression profile with the protein interaction data may help to find several important pathogenic mechanisms in RA.

섬유 조직염환자에서 만성피로 증후군이 동반되는 빈도와 임상양상

지종대(Jong Dae Ji),이영호(Young Ho Lee),송관규(Gwan Gyu Song) 대한내과학회 1998 대한내과학회지 Vol.55 No.5

N/A Objectives: Fibromyalgia is a common rheumatologic disease characterized by chronic myalgia, fatigue, and sleeq disturbance. Chronic fatigue syndrome is chracterized by debilitating fatigue of at least 6 months duration accompenied by other symptoms such as fever, pharyngitis, painful lymph nodes, headache, myalgia, sleep disturbances, neurocognitive complaints, and depression. There has reported that 70% of patients with fibromyalgia met the centers for Disease Control and Prevention symptom criteria for chronic fatigue syndrome. The objectives of this study were to determine how frequently patients with fibromyalgia met the criteria for and chronic fatigue syndrome and what syndrome were manifested. Methods: 34 patients diagnosed with fibromyalgia were participated in the study. The questionnaire made according to the Centers for Disease Control and Prevention criteria was administerd and patients with chronic fatigue syndrome were diagnosed by this questionnaire, physical examination and laboratory tests. Results: 21%(7 patients) of patients with fibromyalgia met the criteria for chronic fatigue syndrome. The symptoms in patients with chronic fatigue syndrome were memory loss/forgetfullness(100%), sore throat(57%), painful lymph node(29%), myalgia(100%), multiple arthralgia(57%), headache(57%), unrefreshing sleep(86%), postexertional malaise(86%). Conclusion: 21% of patients diagnosed with fibromyalgia met the criteria for chronic fatigue syndrome, The incidence of chronic fatigue syndrome in our study is low as compared with the previous study(70%) in 1996.

류마티스 관절염 환자에서 간질성 폐질환 유무에 대한 임상 양상의 비교

지종대 ( Jong Dae Ji ),이영호 ( Young Ho Lee ),송관규 ( Gwan Gyu Song ) 대한류마티스학회 1998 대한류마티스학회지 Vol.5 No.2

Objective: To determine the clinical, laboratory and radiologic factors related to interstitial lung disease in patients with rheumatoid arthritis. Method: 10 patients with rheumatoid arhritis and interstitial lung disease, and 20 patients with rheumatoid arthritis as controlled group were included in this study. Interstitial lung disease was diagnosed by pulmonary function test and high resolution computed tomography. We evaluated the importance of rheumatoid arthritis-specific factors on the interstitial lung disease. Results: 1) patients with interstitial lung disease(mean, 64.40±8.38) were older than those without interstitial lung disease(52.5±14.0). 2) The sex ratio, duration of disease and smoking history were similar between two groups. 3) The incidence of subcutaneous nodule(15 vs 0%, p<0.05) and sputum (15 vs 0%, p<0.05) was different between two groups. The number of joints with swelling(8.62±8.37 vs 3.25±1.59, p<0.05) and tenderness(14.1±10.1 vs 7.10±4.04, p<0.05) was different. But the incidence of cough, fever, dyspnea and chest pain was not different between two groups. 4) C-reactive protein(51.5±35.9mg/l vs 18.9±17.9mg/l, p<0.05) was different between two groups. Hematocrit, platelet, erythrocyte sedimentation rate, hand radiographic evidence of bone erosion was not different. Titer of rheumatoid factors(235±192IU/ml vs 115±158IU/ml, p=0.09) was different between two groups, but was not statistically significant. Conclusion: We found that the incidence of subcutaneous nodule, sputum, number of tenderness and swelling of the joints, C-reactive protein in group with interstitial lung disease was higher than group without interstitial lung disease.

인간 대식세포에서 1,25(OH)2D3에 의한 CYP24 유전자 발현에 있어 MAPK의 역할

지종대 ( Jong Dae Ji ),이빛나라 ( Bit Na Ra Lee ),김태환 ( Tae Hwan Kim ),우진현 ( JIn Hyun Woo ),최성재 ( Sung Jae Choi ),이영호 ( Young Ho Lee ),송관규 ( Gwan Gyu Song ) 대한류마티스학회 2010 대한류마티스학회지 Vol.17 No.3

Objective: Several important roles of 1,25(OH)2D3 have been recognized in the immune system. The availability of 1,25(OH)2D3 at the cellular level is significantly influenced by the relative abundance of enzymes to synthesize (CYP27B1) and catabolize (CYP24) 1,25(OH)2D3. In this study, we examined the effect of 1,25(OH)2D3 on the expression of the CYP24 gene and the role of MAPK for the induction of CYP24 by 1,25(OH)2D3 in activated human macrophages. Methods: For obtaining human activated macrophages, we treated U937 cells with PMA and we cultured these cells for 24 hours to adhere. After 24 hours treatment with PMA, the differentiated cells were washed with phosphate buffered saline (PBS), and then they were used for examining the effect of 1,25(OH)2D3 on the expression of the CYP24 gene. The mRNA expressions of the vitamin-D3 inducible genes were measured by real-time PCR, and the change of the protein expression by 1,25(OH)2D3 was measured by immunoblotting. Results: 1,25(OH)2D3 significantly induced the expression of CYP24 in the U937 cells and the 1,25(OH)2D3-induced expression of CYP24 was strongly augmented in the PMA-differentiated U937 cells. The 1,25(OH)2D3-induced expression of CYP24 was mediated by Erk1/2 and p38 MAPKs. Parallel to the induced expression of CYP24, 1,25(OH)2D3 induced the expression and phosphorylation of the CCAAT enhancer-binding protein (C/EBPβ). Conclusion: In this study, we found that 1,25(OH)2D3 inducedthe expression of CYP24 via activation of MAPKs. These results suggest that MAPK inhibitors may be useful for the treatment of inflammatory conditions, in which active vitamin D3 can be used as the therapeutic molecule, by increasing the availability of 1,25(OH)2D3.

류마티스 관절염에서 활막세포의 세포사멸

지종대 ( Jong Dae Ji ),유대현 ( Dae Hyun Yoo ) 대한류마티스학회 2001 대한류마티스학회지 Vol.8 No.1

Rheumatoid arthritis is characterized by a chronic inflammatory synovitis, eventually leading to destruction of bone and cartilage. Significant hyperplasia and infiltration of activated inflammatory cells play a major role in the destruction of joint. The proliferation of synovial cells could be derived from imbalance between apoptotic cell death and excessive proliferation of synovial cells. However, many reports regarding on the apoptosis or proliferation of synovial cells showed a little bit contradictory up to date. Induction of synovial cell apoptosis could be an interesting and attractive way of treatment by way of many signal transduction pathway, such as NFkB, P53, sentrin, FADD, etc. We discussed on the apoptosis and proliferation of synovial cells, and focused on the proposed mechanisms of resistance for apoptosis. Here, we reviewed literatures on the apoptosis and abnormal proliferation of synovial cells, and focused on the proposed mechanisms of resistance against apoptosis. In addition, we mentioned about the possibility of apoptosis induction as a modality of treatment against rheumatoid arthritis in future.

Prostaglandin E2 면역 및 염증반응에서의 역할

지종대 ( Jong Dae Ji ),이영호 ( Young Ho Lee ),송관규 ( Gwan Gyu Song ) 대한류마티스학회 2004 대한류마티스학회지 Vol.11 No.4

Prostaglandins have numerous biologic effects on a variety of physiological and pathological activities such as inflammation, platelet aggregation, neurotransmitter release, smooth muscle contraction, and so forth. PGE2 is one of the well-studied inflammatory prostaglandins and causes vasodilatation, edema, fever and pain. Also PGE2 induces the production of matrix metalloproteinases (MMPs) which involve in destruction of tissue. In rheumatoid arthritis, macrophages isolated from patients secrete large amounts of PGE2 and PGE2 promote inflammation and participate in destructive mechanisms of the rheumatoid joint. In addition to its proinflammatory effects, PGE2 acts also as an immunomodulator, promote humoral and Th2-type immune responses and inhibit Th1-type immune responses. Also PGE2 inhibits the production of tumor necrosis factor (TNF-α), IL-1β, IL-8 and IL-12 and stimulates the production of IL-10 by macrophages. Thus PGE2 should be regarded not as proinflammatory molecule but as modulator of immune responses. In this review, we will focus on the current knowledge about PGE2 as the modulator of immune responses and summarize the effects of PGE2 on the immune systems and inflammation.

인터페론을 사용한 만성 B 형 간염환자에서 인터페론 중화항체의 발현

지종대(Jong Dae Ji),이신형(Sin Hyeung Lee),김연수(Yun Soo Kim),서동진(Dong Jin Suh) 대한내과학회 1994 대한내과학회지 Vol.46 No.2

N/A Background: It has been suggested that the deveolpment of neutralizing antibody to interferon (anti-IFN) in patients treated with recombinant IFN-α may decrease the therapeutic effect of interferon. We studied the incidence of development and the clinical significance of interferon neutralizing antibody in patients with chronic HBV infection treated with recombinant interferon α-2b (intron A). Methods: 32 patients with chronic HBV infection, who had been positive for HBeAg and HBV DNA for more than twelve months were studied. Serum samples were collected before IFN trial, within 1~2 months after administration and 1 month after cessation of therapy. When duration of treatment were long, serum samples were collected repeatedly within 4~5 months after administation. Sera were stored at -20℃ and subsequently tested for anti-IFN. Test for anti-IFN were performed by an assay which measures the neutralization of the antiviral activity of interferon alfa-2b in a system using EMC virus and FS-4 cells (strain of dipoloid fibroblsasts derived from a neonatal foreskin). Results: 1) 1nterferon neutralizing antibody developed in 6(18.6%) of 32 patients treated with interfern α-2b and titers of anti-IFN were low at 10~20. 2) No correlation was seen between sex, age, or pretreatment serum ALT level and the development of anti-IFN. But anti-INF was significantly more likely to develop in patients who received lower dose (3 MU) of IFN than in those patients received higher doses (5 MU or 6 MU): 36% VS 5% (p=0.04). 3) HBV DNA became negative in 5(19%) patients without anti-IFN and in 1(17%) patients with anti-IFN (p=0.46, not significant). 4) HBeAg was seroconverted in 8(31%) patients with- out anti-IFN and in 1(17%) patients with anti-IFN (p= 0.41, not significant). Conclusion: It is suggested that interferon neutralizing antibody would not influence the therapeutic effect of interferon in chronic HBC infection.

임상적 관해 상태에 있는 류마티스관절염 환자에서 높은 적혈구침강속도의 의의

지종대 ( Jong Dae Ji ) 대한류마티스학회 2014 대한류마티스학회지 Vol.21 No.2