1.Isolated Tuberculous Myositis: A Systematic Review and Multicenter Cases
Ji Hyoun KIM ; Jeong Seok LEE ; Byoong Yong CHOI ; Yun-Hong CHEON ; Su-Jin YOO ; Ji Hyeon JU ; Kichul SHIN ; Eu Suk KIM ; Han Joo BAEK ; Won PARK ; Yeong Wook SONG ; Woi-Hyun HONG ; Yun Jong LEE
Journal of Rheumatic Diseases 2022;29(4):243-253
		                        		
		                        			 Objective:
		                        			To investigate the clinical features and associated underlying conditions of isolated tuberculous myositis (ITBM), a rare extrapulmonary tuberculosis (TB). 
		                        		
		                        			Methods:
		                        			A systematic literature search and a multicenter survey were performed using a triangulation strategy. Data from the identified ITBM cases were extracted and analyzed to determine the underlying conditions, clinical presentations, treatments, and outcomes. 
		                        		
		                        			Results:
		                        			Based on the systematic review, we identified 58 ITBM, including 9 pediatric, cases in the literature published from 1981 to 2021: 25 (43.1%) immunocompromised and 33 (56.9%) non-immunocompromised patients. Immunocompromised cases had a significant shorter symptom duration (median 30.0 vs. 75.0 days) and a higher prevalence of multilocular involvement (20.8% vs. 0%). Among 24 immunocompromised adult patients, dermatomyositis/polymyositis (DM/PM; n=10, 41.7%) were the most common underlying diseases in adults with ITBM identified in the systematic review. Over the past 20 years, 11 Korean adults with ITBM were identified in the multicenter survey. Of 7 immunocompromised cases, two (28.6%) were DM/PM patients. TB death rate of immunocompromised patients was 0.0% and 5/23 (21.7%) in the pediatric and adult ITBM cases identified in the systematic review, respectively, and 3/7 (42.9%) in survey-identified ITBM cases. 
		                        		
		                        			Conclusion
		                        			ITBM has a unique clinical presentation including fever, tenderness, local swelling, overlying erythema, abscess formation and was associated with a grave outcome, especially in immunocompromised hosts. DM/PM was a highly prevalent underlying disease in both systematic review-identified and survey-identified immunocompromised ITBM patients. 
		                        		
		                        		
		                        		
		                        	
2.Clinical and Virologic Effectiveness of Remdesivir Treatment for Severe Coronavirus Disease 2019 (COVID-19) in Korea: a Nationwide Multicenter Retrospective Cohort Study
Eun-Jeong JOO ; Jae-Hoon KO ; Seong Eun KIM ; Seung-Ji KANG ; Ji Hyeon BAEK ; Eun Young HEO ; Hye Jin SHI ; Joong Sik EOM ; Pyoeng Gyun CHOE ; Seongman BAE ; Sang Hyun RA ; Da Young KIM ; Baek-Nam KIM ; Yu Min KANG ; Ji Yeon KIM ; Jin-Won CHUNG ; Hyun-Ha CHANG ; Sohyun BAE ; Shinhyea CHEON ; Yoonseon PARK ; Heun CHOI ; Eunjung LEE ; Bo young LEE ; Jung Wan PARK ; Yujin SOHN ; Jung Yeon HEO ; Sung-Han KIM ; Kyong Ran PECK
Journal of Korean Medical Science 2021;36(11):e83-
		                        		
		                        			Background:
		                        			Remdesivir is widely used for the treatment of coronavirus disease 2019 (COVID-19), but controversies regarding its efficacy still remain. 
		                        		
		                        			Methods:
		                        			A retrospective cohort study was conducted to evaluate the effect of remdesivir on clinical and virologic outcomes of severe COVID-19 patients from June to July 2020. Primary clinical endpoints included clinical recovery, additional mechanical ventilator (MV) support, and duration of oxygen or MV support. Viral load reduction by hospital day (HD) 15 was evaluated by calculating changes in cycle threshold (Ct) values. 
		                        		
		                        			Results:
		                        			A total of 86 severe COVID-19 patients were evaluated including 48 remdesivirtreated patients. Baseline characteristics were not significantly different between the two groups. Remdesivir was administered an average of 7.42 days from symptom onset. The proportions of clinical recovery of the remdesivir and supportive care group at HD 14 (56.3% and 39.5%) and HD 28 (87.5% and 78.9%) were not statistically different. The proportion of patients requiring MV support by HD 28 was significantly lower in the remdesivir group than in the supportive care group (22.9% vs. 44.7%, P = 0.032), and MV duration was significantly shorter in the remdesivir group (average, 1.97 vs. 5.37 days; P = 0.017). Analysis of upper respiratory tract specimens demonstrated that increases of Ct value from HD 1–5 to 11–15 were significantly greater in the remdesivir group than the supportive care group (average, 10.19 vs. 5.36; P = 0.007), and the slope of the Ct value increase was also significantly steeper in the remdesivir group (average, 5.10 vs. 2.68; P = 0.007). 
		                        		
		                        			Conclusion
		                        			The remdesivir group showed clinical and virologic benefit in terms of MV requirement and viral load reduction, supporting remdesivir treatment for severe COVID-19.
		                        		
		                        		
		                        		
		                        	
3.Clinical and Virologic Effectiveness of Remdesivir Treatment for Severe Coronavirus Disease 2019 (COVID-19) in Korea: a Nationwide Multicenter Retrospective Cohort Study
Eun-Jeong JOO ; Jae-Hoon KO ; Seong Eun KIM ; Seung-Ji KANG ; Ji Hyeon BAEK ; Eun Young HEO ; Hye Jin SHI ; Joong Sik EOM ; Pyoeng Gyun CHOE ; Seongman BAE ; Sang Hyun RA ; Da Young KIM ; Baek-Nam KIM ; Yu Min KANG ; Ji Yeon KIM ; Jin-Won CHUNG ; Hyun-Ha CHANG ; Sohyun BAE ; Shinhyea CHEON ; Yoonseon PARK ; Heun CHOI ; Eunjung LEE ; Bo young LEE ; Jung Wan PARK ; Yujin SOHN ; Jung Yeon HEO ; Sung-Han KIM ; Kyong Ran PECK
Journal of Korean Medical Science 2021;36(11):e83-
		                        		
		                        			Background:
		                        			Remdesivir is widely used for the treatment of coronavirus disease 2019 (COVID-19), but controversies regarding its efficacy still remain. 
		                        		
		                        			Methods:
		                        			A retrospective cohort study was conducted to evaluate the effect of remdesivir on clinical and virologic outcomes of severe COVID-19 patients from June to July 2020. Primary clinical endpoints included clinical recovery, additional mechanical ventilator (MV) support, and duration of oxygen or MV support. Viral load reduction by hospital day (HD) 15 was evaluated by calculating changes in cycle threshold (Ct) values. 
		                        		
		                        			Results:
		                        			A total of 86 severe COVID-19 patients were evaluated including 48 remdesivirtreated patients. Baseline characteristics were not significantly different between the two groups. Remdesivir was administered an average of 7.42 days from symptom onset. The proportions of clinical recovery of the remdesivir and supportive care group at HD 14 (56.3% and 39.5%) and HD 28 (87.5% and 78.9%) were not statistically different. The proportion of patients requiring MV support by HD 28 was significantly lower in the remdesivir group than in the supportive care group (22.9% vs. 44.7%, P = 0.032), and MV duration was significantly shorter in the remdesivir group (average, 1.97 vs. 5.37 days; P = 0.017). Analysis of upper respiratory tract specimens demonstrated that increases of Ct value from HD 1–5 to 11–15 were significantly greater in the remdesivir group than the supportive care group (average, 10.19 vs. 5.36; P = 0.007), and the slope of the Ct value increase was also significantly steeper in the remdesivir group (average, 5.10 vs. 2.68; P = 0.007). 
		                        		
		                        			Conclusion
		                        			The remdesivir group showed clinical and virologic benefit in terms of MV requirement and viral load reduction, supporting remdesivir treatment for severe COVID-19.
		                        		
		                        		
		                        		
		                        	
4.Autoimmune Hepatitis-systemic Lupus Erythematosus Overlap Syndrome Diagnosed after Tapering Immunosuppressive Therapy.
Bho Hyeon LEE ; Seung Ah PARK ; Joo Kyung KIM ; Dae Young CHEON ; Seong Hun KANG ; Nan Young CHOI ; Ji Won PARK ; Mi Jung KWON ; Young Il SEO ; Sung Eun KIM
Keimyung Medical Journal 2016;35(1):44-49
		                        		
		                        			
		                        			The differential diagnosis of systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) is difficult due to the resemblance of these two disorders. However, the accurate diagnosis is important for prognosis and treatment that are different from each other. We report a case of AIH-SLE overlap syndrome which tapering of prednisone and azathioprine therapy deteriorated the condition of a patient due to flare up of SLE. The patient was a 28-year-old woman diagnosed as AIH. After administrations of prednisone and azathioprine, her condition was improved. During dose reduction, she was admitted to our hospital as fever and dyspnea. She diagnosed as lupus nephritis. After high dose treatment with corticosteroids and azathioprine, she recovered. Once the diagnosis of autoimmune disease such as SLE or AIH has been made, clinicians should also be fully aware of concomitant other autoimmune disease.
		                        		
		                        		
		                        		
		                        			Adrenal Cortex Hormones
		                        			;
		                        		
		                        			Adult
		                        			;
		                        		
		                        			Autoimmune Diseases
		                        			;
		                        		
		                        			Azathioprine
		                        			;
		                        		
		                        			Diagnosis
		                        			;
		                        		
		                        			Diagnosis, Differential
		                        			;
		                        		
		                        			Dyspnea
		                        			;
		                        		
		                        			Female
		                        			;
		                        		
		                        			Fever
		                        			;
		                        		
		                        			Hepatitis, Autoimmune
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Lupus Erythematosus, Systemic
		                        			;
		                        		
		                        			Lupus Nephritis
		                        			;
		                        		
		                        			Prednisone
		                        			;
		                        		
		                        			Prognosis
		                        			
		                        		
		                        	
5.The Effects of Different Noise Types on Heart Rate Variability in Men.
Chang Sun SIM ; Joo Hyun SUNG ; Sang Hyeon CHEON ; Jang Myung LEE ; Jae Won LEE ; Jiho LEE
Yonsei Medical Journal 2015;56(1):235-243
		                        		
		                        			
		                        			PURPOSE: To determine the impact of noise on heart rate variability (HRV) in men, with a focus on the noise type rather than on noise intensity. MATERIALS AND METHODS: Forty college-going male volunteers were enrolled in this study and were randomly divided into four groups according to the type of noise they were exposed to: background, traffic, speech, or mixed (traffic and speech) noise. All groups except the background group (35 dB) were exposed to 45 dB sound pressure levels. We collected data on age, smoking status, alcohol consumption, and disease status from responses to self-reported questionnaires and medical examinations. We also measured HRV parameters and blood pressure levels before and after exposure to noise. The HRV parameters were evaluated while patients remained seated for 5 minutes, and frequency and time domain analyses were then performed. RESULTS: After noise exposure, only the speech noise group showed a reduced low frequency (LF) value, reflecting the activity of both the sympathetic and parasympathetic nervous systems. The low-to-high frequency (LF/HF) ratio, which reflected the activity of the autonomic nervous system (ANS), became more stable, decreasing from 5.21 to 1.37; however, this change was not statistically significant. CONCLUSION: These results indicate that 45 dB(A) of noise, 10 dB(A) higher than background noise, affects the ANS. Additionally, the impact on HRV activity might differ according to the noise quality. Further studies will be required to ascertain the role of noise type.
		                        		
		                        		
		                        		
		                        			Adaptation, Psychological
		                        			;
		                        		
		                        			Confounding Factors (Epidemiology)
		                        			;
		                        		
		                        			Environment
		                        			;
		                        		
		                        			Heart Rate/*physiology
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Male
		                        			;
		                        		
		                        			*Noise
		                        			;
		                        		
		                        			Questionnaires
		                        			;
		                        		
		                        			Stress, Psychological/physiopathology
		                        			;
		                        		
		                        			Young Adult
		                        			
		                        		
		                        	
6.Association between cord blood 25-hydroxyvitamin D concentrations and respiratory tract infections in the first 6 months of age in a Korean population: a birth cohort study (COCOA).
Youn Ho SHIN ; Jinho YU ; Kyung Won KIM ; Kangmo AHN ; Seo Ah HONG ; Eun LEE ; Song I YANG ; Young Ho JUNG ; Hyung Young KIM ; Ju Hee SEO ; Ji Won KWON ; Byoung Ju KIM ; Hyo Bin KIM ; Jung Yeon SHIM ; Woo Kyung KIM ; Dae Jin SONG ; So Yeon LEE ; Soo Young LEE ; Gwang Cheon JANG ; Dong In SUH ; Hyeon Jong YANG ; Bong Sung KIM ; Suk Joo CHOI ; Soo Young OH ; Ja Young KWON ; Kyung Ju LEE ; Hee Jin PARK ; Pil Ryang LEE ; Hye Sung WON ; Soo Jong HONG
Korean Journal of Pediatrics 2013;56(10):439-445
		                        		
		                        			
		                        			PURPOSE: Previous studies suggest that the concentration of 25-hydroxyvitamin D [25(OH)D] in cord blood may show an inverse association with respiratory tract infections (RTI) during childhood. The aim of the present study was to examine the influence of 25(OH)D concentrations in cord blood on infant RTI in a Korean birth cohort. METHODS: The levels of 25(OH)D in cord blood obtained from 525 Korean newborns in the prospective COhort for Childhood Origin of Asthma and allergic diseases were examined. The primary outcome variable of interest was the prevalence of RTI at 6-month follow-up, as diagnosed by pediatricians and pediatric allergy and pulmonology specialists. RTI included acute nasopharyngitis, rhinosinusitis, otitis media, croup, tracheobronchitis, bronchiolitis, and pneumonia. RESULTS: The median concentration of 25(OH)D in cord blood was 32.0 nmol/L (interquartile range, 21.4 to 53.2). One hundred and eighty neonates (34.3%) showed 25(OH)D concentrations less than 25.0 nmol/L, 292 (55.6%) showed 25(OH)D concentrations of 25.0-74.9 nmol/L, and 53 (10.1%) showed concentrations of > or =75.0 nmol/L. Adjusting for the season of birth, multivitamin intake during pregnancy, and exposure to passive smoking during pregnancy, 25(OH)D concentrations showed an inverse association with the risk of acquiring acute nasopharyngitis by 6 months of age (P for trend=0.0004). CONCLUSION: The results show that 89.9% of healthy newborns in Korea are born with vitamin D insufficiency or deficiency (55.6% and 34.3%, respectively). Cord blood vitamin D insufficiency or deficiency in healthy neonates is associated with an increased risk of acute nasopharyngitis by 6 months of age. More time spent outdoors and more intensified vitamin D supplementation for pregnant women may be needed to prevent the onset of acute nasopharyngitis in infants.
		                        		
		                        		
		                        		
		                        			Asthma
		                        			;
		                        		
		                        			Bronchiolitis
		                        			;
		                        		
		                        			Cohort Studies*
		                        			;
		                        		
		                        			Croup
		                        			;
		                        		
		                        			Fetal Blood*
		                        			;
		                        		
		                        			Follow-Up Studies
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Hypersensitivity
		                        			;
		                        		
		                        			Infant
		                        			;
		                        		
		                        			Infant, Newborn
		                        			;
		                        		
		                        			Korea
		                        			;
		                        		
		                        			Nasopharyngitis
		                        			;
		                        		
		                        			Otitis Media
		                        			;
		                        		
		                        			Parturition
		                        			;
		                        		
		                        			Pregnancy
		                        			;
		                        		
		                        			Pregnant Women
		                        			;
		                        		
		                        			Prevalence
		                        			;
		                        		
		                        			Prospective Studies
		                        			;
		                        		
		                        			Respiratory System Abnormalities*
		                        			;
		                        		
		                        			Respiratory Tract Infections*
		                        			;
		                        		
		                        			Seasons
		                        			;
		                        		
		                        			Specialization
		                        			;
		                        		
		                        			Tobacco Smoke Pollution
		                        			;
		                        		
		                        			Vitamin D
		                        			
		                        		
		                        	
7.Risk Factors for Acute Hepatitis A Infection in Korea in 2007 and 2009: A Case-Control Study.
Joo Youn SEO ; Bo Youl CHOI ; Moran KI ; Hye Lim JANG ; Hee Suk PARK ; Hyun Jin SON ; Si Hyun BAE ; Jin Han KANG ; Dae Won JUN ; Jin Woo LEE ; Young Jin HONG ; Young Seok KIM ; Chang Hwi KIM ; U Im CHANG ; Jong Hyun KIM ; Hyeon Woong YANG ; Hong Soo KIM ; Kyeong Bae PARK ; Jae Seok HWANG ; Jeong HEO ; In Hee KIM ; Jung Soo KIM ; Gab Jin CHEON
Journal of Korean Medical Science 2013;28(6):908-914
		                        		
		                        			
		                        			This study aimed to identify the risk factors associated with acute hepatitis A virus (HAV) infection in the Korean population. Participants were recruited from five referral hospitals across the country in 2007 and from 11 hospitals in 2009. Patients with positive anti-HAV IgM antibody tests became the case group, while patients treated for non-contagious diseases at the same hospitals were recruited as controls. A total of 222 and 548 case-control pairs were studied in the 2007 and 2009 surveys, respectively. Data from the surveys were analyzed jointly. In a multivariate analysis, sharing the household with HAV-infected family members (OR, 6.32; 95% CI, 1.4-29.6), contact with other HAV-infected individuals (OR, 4.73; 95% CI, 2.4-9.4), overseas travel in 2007 (OR, 19.93; 95% CI, 2.3-174.4), consumption of raw shellfish (OR, 2.51; 95% CI, 1.8-3.5), drinking bottled water (OR, 1.64; 95% CI, 1.3-8.4), and occupation that involve handling food (OR, 3.30; 95% CI, 1.3-8.4) increased the risk of HAV infection. Avoiding contact with HAV-infected individuals and avoiding raw foods eating could help minimize the risk of hepatitis A infection. Immunization must be beneficial to individuals who handle food ingredients occupationally or travel overseas to HAV-endemic areas.
		                        		
		                        		
		                        		
		                        			Acute Disease
		                        			;
		                        		
		                        			Adolescent
		                        			;
		                        		
		                        			Adult
		                        			;
		                        		
		                        			Case-Control Studies
		                        			;
		                        		
		                        			Child
		                        			;
		                        		
		                        			Child, Preschool
		                        			;
		                        		
		                        			Female
		                        			;
		                        		
		                        			Food Handling
		                        			;
		                        		
		                        			Hepatitis A/*diagnosis/etiology/prevention & control
		                        			;
		                        		
		                        			Hepatitis A Antibodies/blood
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Immunoglobulin M/blood
		                        			;
		                        		
		                        			Infant
		                        			;
		                        		
		                        			Infant, Newborn
		                        			;
		                        		
		                        			Interviews as Topic
		                        			;
		                        		
		                        			Male
		                        			;
		                        		
		                        			Middle Aged
		                        			;
		                        		
		                        			Multivariate Analysis
		                        			;
		                        		
		                        			Odds Ratio
		                        			;
		                        		
		                        			Referral and Consultation
		                        			;
		                        		
		                        			Risk Factors
		                        			;
		                        		
		                        			Seafood
		                        			;
		                        		
		                        			Travel
		                        			;
		                        		
		                        			Vaccination
		                        			;
		                        		
		                        			Young Adult
		                        			
		                        		
		                        	
8.Clinical Characteristics and Surgical Outcomes in Adolescents and Adults with Varicocele.
Hun Joo LEE ; Sang Hyeon CHEON ; Young Hwan JI ; Kyung Hyun MOON ; Kun Suk KIM ; Seonghun PARK ; Sungchan PARK
Korean Journal of Urology 2011;52(7):489-493
		                        		
		                        			
		                        			PURPOSE: To compare clinical characteristics and surgical results in adolescents and adults with varicocele. MATERIALS AND METHODS: We retrospectively analyzed the characteristics of 93 patients, 34 adolescents (mean age, 14.4+/-2.1 years) and 59 adults (mean age, 30.4+/-12.4 years), who underwent surgical repair of varicocele between 2006 and 2009. Median follow-up time in all patients was 18.7 months. The most bothersome symptoms, bilaterality, grades, surgical methods, artery-sparing rates, operation times, semen analysis, success rates, and recurrence-free period were compared between the two groups. RESULTS: The overall success rate of surgical repair was 92.5%. The most bothersome symptoms were scrotal mass, pain, and hypotrophy in adolescents and pain, scrotal mass, infertility, and hypotrophy in adults (p=0.008). There were no significant between-group differences in bilaterality, grades, surgical methods, operation times, pre- or postoperative semen analyses, success rates, or recurrence-free periods. Patients who underwent artery-sparing surgery had higher recurrence rates than did those who underwent surgery that did not spare arteries. In adults, semen density increased significantly after surgery, from 35.6 million/ml to 49.6 million/ml (p=0.046). CONCLUSIONS: There were no significant differences in clinical characteristics or surgical results between adolescents and adults with varicocele, except for the most bothersome symptoms. Semen density increased after surgery in both groups.
		                        		
		                        		
		                        		
		                        			Adolescent
		                        			;
		                        		
		                        			Adult
		                        			;
		                        		
		                        			Arteries
		                        			;
		                        		
		                        			Follow-Up Studies
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Infertility
		                        			;
		                        		
		                        			Recurrence
		                        			;
		                        		
		                        			Retrospective Studies
		                        			;
		                        		
		                        			Semen
		                        			;
		                        		
		                        			Semen Analysis
		                        			;
		                        		
		                        			Spermatic Cord
		                        			;
		                        		
		                        			Treatment Outcome
		                        			;
		                        		
		                        			Varicocele
		                        			
		                        		
		                        	
9.Diagnosis of Systemic Lupus Erythematosus During Medical Follow-up After Urinary Screening.
So Jin YOON ; Ji Eun SONG ; Jae Il SHIN ; Il Cheon JEONG ; Jae Seung LEE ; Hyo Sup SHIM ; Hyeon Joo JEONG
Journal of the Korean Society of Pediatric Nephrology 2008;12(2):227-232
		                        		
		                        			
		                        			A 16-year-old girl presented with proteinuria and microscopic hematuria detected through mass urinary screening and was diagnosed as having suspected postinfectious glomerulonephritis by renal biopsy. However, heavy proteinuria did not respond to angiotensin converting enzyme inhibitor therapy. After 6 months, cervical lymphadenitis developed and a neck node biopsy showed subacute necrotizing lymphadenitis. After an additional 2 months, she developed facial erythema and thrombocytopenia. A repeat renal biopsy demonstrated lupus nephritis class IV. She was treated with pulse methylprednisolone(500 mg/day intravenously for 3 consecutive days) followed by oral deflazacort and monthly intravenous cyclophosphamide pulse(1 g/m2) for 6 months. We report a case diagnosed as systemic lupus erythematosus(SLE) during medical follow-up after urinary screening.
		                        		
		                        		
		                        		
		                        			Adolescent
		                        			;
		                        		
		                        			Biopsy
		                        			;
		                        		
		                        			Cyclophosphamide
		                        			;
		                        		
		                        			Erythema
		                        			;
		                        		
		                        			Follow-Up Studies
		                        			;
		                        		
		                        			Glomerulonephritis
		                        			;
		                        		
		                        			Hematuria
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			Lupus Erythematosus, Systemic
		                        			;
		                        		
		                        			Lupus Nephritis
		                        			;
		                        		
		                        			Lymphadenitis
		                        			;
		                        		
		                        			Mass Screening
		                        			;
		                        		
		                        			Neck
		                        			;
		                        		
		                        			Peptidyl-Dipeptidase A
		                        			;
		                        		
		                        			Pregnenediones
		                        			;
		                        		
		                        			Proteinuria
		                        			;
		                        		
		                        			Thrombocytopenia
		                        			
		                        		
		                        	
10.Signaling pathway for 2,3,7,8-tetrachlorodibenzo- p-dioxin-induced TNF-alpha production in differentiated THP-1 human macrophages.
Hyeon Joo CHEON ; Young Seok WOO ; Ji Young LEE ; Hee Sook KIM ; Hyun Jin KIM ; Sungwon CHO ; Nam Hee WON ; Jeongwon SOHN
Experimental & Molecular Medicine 2007;39(4):524-534
		                        		
		                        			
		                        			2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototypic halogenated aromatic hydrocarbon (HAH), is known as one of the most potent toxicants. At least a part of its toxic effects appears to be derived from its ability to induce TNF-alpha production. However, the signaling pathway of TCDD that leads to TNF-alpha expression has not been elucidated. In this study, we investigated the signaling mechanism of TCDD-induced TNF-alpha expression in PMA-differentiated THP-1 macrophages. TCDD induced both mRNA and protein expression of TNF-alpha in a dose- and time-dependent manner. Alpha-Naphthoflavone (NF), an aryl hydrocarbon receptor (AhR) inhibitor, prevented the TCDD-induced expression of TNF-alpha at both mRNA and protein levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, and PD153035, an EGFR inhibitor, also blocked the increase of TNF-alpha expression by TCDD, indicating the role of EGFR in TCDD-induced TNF-alpha expression. On the other hand, PP2, a c-Src specific inhibitor, did not affect TCDD-induced TNF-alpha expression. EGFR phosphorylation was detected as early as 5 min after TCDD treatment. TCDD-induced EGFR activation was AhR-dependent since co-treatment with alpha-NF prevented it. ERK was found to be a downstream effector of EGFR activation in the signaling pathway leading to TNF-alpha production after TCDD stimulation. Activation of ERK was observed from 30 min after TCDD treatment. PD98059, an inhibitor of the MEK-ERK pathway, completely prevented the TNF-alpha mRNA and protein expression induced by TCDD, whereas inhibitors of JNK and p38 MAPK had no effect. PD153035, an EGFR inhibitor, as well as alpha-NF significantly reduced ERK phosphorylation, suggesting that ERK activation by TCDD was mediated by both EGFR and AhR. These results indicate that TNF-alpha production by TCDD in differentiated THP-1 macrophages is AhR-dependent and involves activation of EGFR and ERK, but not c-Src, JNK, nor p38 MAPK. A signaling pathway is proposed where TCDD induces sequential activation of AhR, EGFR and ERK, leading to the increased expression of TNF-alpha.
		                        		
		                        		
		                        		
		                        			Animals
		                        			;
		                        		
		                        			Benzoflavones/pharmacology
		                        			;
		                        		
		                        			Cell Differentiation
		                        			;
		                        		
		                        			Cell Line, Tumor
		                        			;
		                        		
		                        			Enzyme Activation
		                        			;
		                        		
		                        			Genistein/pharmacology
		                        			;
		                        		
		                        			Hazardous Substances/*toxicity
		                        			;
		                        		
		                        			Humans
		                        			;
		                        		
		                        			MAP Kinase Signaling System/drug effects/physiology
		                        			;
		                        		
		                        			Macrophages/*metabolism
		                        			;
		                        		
		                        			Mice
		                        			;
		                        		
		                        			Phosphorylation
		                        			;
		                        		
		                        			Pyrimidines/pharmacology
		                        			;
		                        		
		                        			Quinazolines/pharmacology
		                        			;
		                        		
		                        			RNA, Messenger/metabolism
		                        			;
		                        		
		                        			Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism
		                        			;
		                        		
		                        			Receptors, Aryl Hydrocarbon/antagonists & inhibitors
		                        			;
		                        		
		                        			Signal Transduction
		                        			;
		                        		
		                        			Tetrachlorodibenzodioxin/*toxicity
		                        			;
		                        		
		                        			Tumor Necrosis Factor-alpha/*biosynthesis
		                        			;
		                        		
		                        			src-Family Kinases/antagonists & inhibitors/metabolism
		                        			
		                        		
		                        	
            
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