Repression of TNF-α-induced IL-8 expression by the glucocorticoid receptor-β involves inhibition of histone H4 acetylation

김상훈,Doh-Hyung Kim,Paul Lavender,Ji-Hee Seo,Yun-Seop Kim,Jae-Suk Park,Sahng-June Kwak,Young-Koo Jee 생화학분자생물학회 2009 Experimental and molecular medicine Vol.41 No.5

Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)β, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRα. However, recent data suggest that GRβ is not a dominant negative inhibitor of GRα in the transrepressive process and has its own functional role. We investigated the functional role of GRβ expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-α-induced IL-8 release in an airway epithelial cell line. GRβ expression was induced by treatment of epithelial cells with either dexamethasone or TNF-α. GRβ was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-α-induced IL-8 transcription was not affected by GRβ overexpression, rather GRβ had its own weak suppressive activity on TNF-α-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRβ overexpression, but TNF-α-induced histone H4 acetylation at the IL-8 promoter was decreased with GRβ overexpression. This study suggests that GRβ overexpression does not affect glucocorticoid- induced suppression of IL-8 expression in airway epithelial cells and GRβ induces its own histone deacetylase activity around IL-8 promoter site. Increased expression of a number of proinflammatory genes, including IL-8, is associated with inflammatory conditions such as asthma. Glucocorticoid receptor (GR)β, one of the GR isoforms, has been suggested to be upregulated in asthma associated with glucocorticoid insensitivity and to work as a dominant negative inhibitor of wild type GRα. However, recent data suggest that GRβ is not a dominant negative inhibitor of GRα in the transrepressive process and has its own functional role. We investigated the functional role of GRβ expression in the suppressive effect of glucocorticoids on tumor necrosis factor (TNF)-α-induced IL-8 release in an airway epithelial cell line. GRβ expression was induced by treatment of epithelial cells with either dexamethasone or TNF-α. GRβ was able to inhibit glucocorticoid-induced transcriptional activation mediated by binding to glucocorticoid response elements (GREs). The suppressive effect of dexamethasone on TNF-α-induced IL-8 transcription was not affected by GRβ overexpression, rather GRβ had its own weak suppressive activity on TNF-α-induced IL-8 expression. Overall histone deacetylase activity and histone acetyltransferase activity were not changed by GRβ overexpression, but TNF-α-induced histone H4 acetylation at the IL-8 promoter was decreased with GRβ overexpression. This study suggests that GRβ overexpression does not affect glucocorticoid- induced suppression of IL-8 expression in airway epithelial cells and GRβ induces its own histone deacetylase activity around IL-8 promoter site.

지속성 급성호흡곤란증후군 환자에서 "저용량" 글루코코르티코이드 치료 효과에 대한 예비연구

남해성,박소영,김수아,송재욱,전경만,김호중,권오정,서지영,박맹렬,임소연 대한중환자의학회 2009 Acute and Critical Care Vol.24 No.2

Background: The role of glucocorticoids for treating persistent acute respiratory distress syndrome (ARDS) is matter of debate. In the previous studies, the side effects of moderate doses of glucocorticoids might have negated positive effects of glucocorticoids. This study aimed at determining the feasibility of administering "low-dose" glucocorticoid to treat the patients who suffer with persistent ARDS. Methods: We retrospectively reviewed the medical records of twelve patients with ARDS of at least seven days` duration and who were treated with "low-dose" glucocorticoid (starting dose of 1 mg/kg) between June 2007 to December 2008. The patients were divided by whether or not they were successfully weaned from the ventilator after glucocorticoid therapy. The baseline characteristics and physiologic parameters were recorded for up to 7 days after starting glucocorticoid therapy. Results: Five patients (42%) were included in the weaned group. There was no significant difference in the clinical characteristics and the physiologic parameters between the two groups on the day of ARDS. Yet the weaned group had a significantly lower Sequential Organ Failure Assessment (SOFA) score, as compared to that of the failed group [3 (3-6) vs 8 (5-12), p = 0.009)] at start of glucocorticoid treatment. After 3 days of glucocorticoid therapy, there was significant improvement in the PEEP, the PaO2/FIO2 ratio, the PCO2, the SOFA score and the Murray Lung Injury Score of the weaned group, as compared to that of the failed group. There were no major neuromuscular side effects from the therapy. Conclusions: This study suggests that the "low-dose" glucocorticoid therapy is feasible and that the SOFA score and the physiologic parameters may assist in determining whether or not to initiate and to continue glucocorticoid therapy for the patients who are suffering with persistent ARDS.

Association between perioperative glucocorticoids and cancer metastasis and survival in patients undergoing radical cystectomy for urothelial carcinoma of the bladder: A single-center retrospective study

Shiyu Mao,Yuan Wu,Ruiliang Wang,Yadong Guo,Jing Yuan,Wentao Zhang,Junfeng Zhang,Yang Yan,Xudong Yao 대한비뇨의학회 2020 Investigative and Clinical Urology Vol.61 No.4

Purpose: Perioperative glucocorticoids have the potential to increase the risk of tumor metastasis. However, the relationship between perioperative glucocorticoids and oncologic outcomes remains controversial. The present study was undertaken to evaluate the association of perioperative glucocorticoids with clinicopathologic outcomes following radical cystectomy (RC). Materials and Methods: We screened and included 185 patients who underwent radical surgery for bladder cancer in our center between 2009 and 2018. The Kaplan–Meier method was applied, and a log-rank test was used to estimate differences in metastasis-free survival (MFS) and overall survival (OS) between the groups. Multivariate Cox proportional hazards regression models were used to analyze any association of glucocorticoids with clinical outcomes. Results: A total of 76 (41.1%) patients received perioperative glucocorticoids. Median postoperative follow-up was 2.0 years. Kaplan–Meier survival curve indicated that the glucocorticoids group was significantly associated with increased distant MFS (p=0.008) but not with OS. In the multivariate analysis, no significant differences were observed for MFS between the groups. Interestingly, when the variable of blood transfusion was excluded from the multivariate analysis model, we found that patients receiving glucocorticoids were independently associated with worse MFS (hazard ratio, 1.790; p=0.030). Furthermore, the partial correlation analysis showed a significant positive correlation between perioperative glucocorticoids and blood transfusion (r=0.604, p<0.001). In the nontransfusion subgroup, propensity score matching showed that patients receiving glucocorticoids had a higher risk of distant metastasis. Conclusions: Perioperative glucocorticoids were associated with a higher rate of distant metastasis in patients undergoing RC for bladder cancer.

자발적인 저항성운동이 글루코코르티코이드를 투여한 쥐의 체조성 및 골 칼슘 농도에 미치는 영향

강형숙 한국운동과학회 2003 운동과학 Vol.12 No.2

강형숙. 자발적인 저항성운동이 글루코코르티코이드를 투여한 쥐의 체조성 및 골 칼슘 농도에 미치는 영향. 운동과학, 제12권 제2호, 307-318, 2003. 본 연구는 글루코코르티코이드(Glucocorticoid ; GC)를 투여한 노화 모델 쥐에게 자발적인 저항성운동인 승강(Climbing)운동을 일상화시켜 체조성 및 골 칼슘농도에 미치는 영향을 알아보는 것이다. 실험동물로서는 10주령 Wistar계 숫컷 쥐 29마리를 이용하였다. 2주간 예비사육 후, 대조군(Saline+Sedentary: SS), GC투여·안정군(glucocorticoid+sedentary ; GS), GC투여·운동군(glucocorticoid+exercise : GE)으로 분류하여 8주간 사육하였다. GC투여는 매일 아침 2mg/kg/q를 복강투여하였으며, 자발적인 저항성운동으로는 철망타워(Ø20cm×200cm)내를 자발적으로 오르내리는 승강운동을 실시하였다. 실험기간 중 체중증가량은 GC투여군(GS, GE)이 대조군(SS)에 비하여 통계적으로 유의하게(p<.05) 낮게 나타났다. 조직중량은 GC투여군(GS, GE)이 대조군(SS)에 비하여 낮게 나타났으나 체중 kg당 조직중량에서는 심장, 간, 신장에서 GC투여군(GS, GE)이 유의하게(p<.05) 높은 것으로 나타났다. 골 칼슘 농도는 대퇴골과 경골에서 GC투여·안정군(GS)이 다른 군에 비해 유의하게 낮게 나타났으며(p<.01, p<.001), 척골에서도 대조군(SS)에 비해 유의하게 낮은 것으로 나타났다(p<.001). Kang, H.S. Effect of voluntary resistance exercise on body composition, bone calcium concentration in glucocorticoid-injected rats. Exercise Science, 12(2): 307-318, 2003. The purpose of the study is to investigates effect of voluntary resistance exercise on body composition, bone calcium concentration in glucocorticoid-injected rats. To determine the effects of tower climbing exercise on hematological status in glucocorticoid injected rats as an aging model, 29 male Sprague-Dawley rats, 10 weeks of age, were assigned to three groups : a saline control group(SS, n=9), a glucocorticoid-sedentary group(GS, n=10) and a glucocorticoid-exercise group(GE, n=10). The GS and GE groups were given 2 mg/kg/day of prednisolone. The GE group voluntarily climbed the 200-cm tower to drink water from the bottle set at the top of it. Weight gain during the 8-week experimental period was greater in the SS group than in the GS and GE groups. And bone calcium concentration was greater in the GS and GE groups than in the SS group. The hematological parameters were not influenced by glucocorticoid administration with or without climbing exercise.

Update on Glucocorticoid Induced Osteoporosis

조수경,성윤경 대한내분비학회 2021 Endocrinology and metabolism Vol.36 No.3

Glucocorticoids are used to treat many autoimmune and inflammatory diseases. However, an adverse systemic effect is a deleterious effect on bone, which may lead to glucocorticoid-induced osteoporosis, characterized by a rapid and transient increase in bone resorption and fracture risk, which may increase rapidly within 3 months of commencing oral glucocorticoids. Therefore, early risk assessment and intervention are crucial for preventing fractures in patients receiving glucocorticoids. Recent practice guidelines recommend an assessment for fracture risk in patients beginning or receiving glucocorticoids for more than 3 months, and they have suggested fracture risk assessment tool values for identifying patients who need preventive treatment. Bisphosphonates are currently the recommended first-line therapy for the prevention and treatment of glucocorticoid-induced osteoporosis. These have been shown to increase the bone mineral density in the spine and hip and to decrease the incidence of vertebral fractures. Recently, a more potent antiresorptive agent, denosumab, has been shown to increase the bone density in patients receiving glucocorticoids. Teriparatide has been shown to have a preventive effect on vertebral fractures, but not on nonvertebral fractures. In this article we aimed to providean update on glucocorticoid-induced osteoporosis by focusing on the assessment of its risk and treatment options.

스테로이드 유발성 골다공증

정주양 ( Ju-yang Jung ),서창희 ( Chang-hee Suh ) 대한내과학회 2017 대한내과학회지 Vol.92 No.2

Osteoporosis is a common adverse event among patients on glucocorticoid therapy. Glucocorticoids reduce bone formation and increase cortical porosity in proportion to the dose and duration of glucocorticoid use. While the epidemiology of glucocorticoid-induced osteoporosis has been well characterized, its pathophysiology and effective management remain unclear. Several recommendations for glucocorticoid-induced osteoporosis are used to determine which patients on long-term glucocorticoid treatment to treat and when. The fracture risk can be assessed using dual-energy X-ray absorptiometry and the Fracture Risk Assessment Tool algorithm, along with other clinical factors. The management of glucocorticoid-induced osteoporosis includes anti-osteoporotic therapy and measures to prevent bone loss. Bisphosphonates are currently the first choice treatment, with teriparatide and denosumab being alternatives. (Korean J Med 2017;92:142-149)

부신피질 호르몬이 사람골수기질세포의 Apoptosis에 미치는 영향

김하영,김덕재,이시열,홍정수,김동관,김기수 대한내분비학회 2002 Endocrinology and metabolism Vol.17 No.1

Background: Osteoporosis is one of the most serious side effects of long-term glucocorticoid therapy, but the mechanism of glucocorticoid-induced bone loss remains poorly defined. Glucocorticoid induces decreased bone formation and death of isolated segments of bone (osteonecrosis) suggesting that glucocorticoid excess may affect the birth or death rate of bone cells and thereby reduce their numbers. It has been known that reduction in bone formation is due to reduced proliferation in osteoblast precursor cells and reduced matrix synthesis in mature osteoblast. Here, we present evidence for dexamethasone-induced apoptosis on human bone marrow stromal cells (hBMSC). To understand the mechanism of glucocorticoid-induced osteoporosis, we investigated the effects of glucocorticoid on primary cultured hBMSC. Methods: Treatment with dexamethasone at the concentration of 10^-9 M for 3∼5 days significantly decreased cleavage tetrazolium salt WST-1 level/concentration by mitochondrial dehydrogenase in viable cells. Greater decrease was observed with higher concentration of dexamethasone (10^-7 M, and 10^-5 M). Apoptosis was measured by annexin V binding/propidium iodide using fluorescence-activated cell sorter (FACS) analysis and nuclear morphology stained with the fluorescence dye, Hoechst 33342. Results: The level/concentration of apoptotic hBMSC (annexin V positive / PI negative) was increased with 10^-9 M dexamethasone (1.2% to 5.3%) and further increased with 10^-7 M, and 10^-5 M concentration (11.7% and 12.5%, respectively). The same result was observed with Hoechst 33342 staining. Conclusion: These results indicate that glucocorticoid induces apoptosis on osteoblast precursor cell, hBMSC, and may contribute to decrease bone formation

Dexamethasone downregulates caveolin-1 causing muscle atrophy via inhibited insulin signaling

Son, Young Hoon,Lee, Seok-Jin,Lee, Ki-Baek,Lee, Jin-Haeng,Jeong, Eui Man,Chung, Sun Gun,Park, Sang-Chul,Kim, In-Gyu Journal of Endocrinology, Ltd. [etc.] 2015 The Journal of endocrinology Vol.225 No.1

<P>Glucocorticoids play a major role in the development of muscle atrophy in various medical conditions, such as cancer, burn injury, and sepsis, by inhibiting insulin signaling. In this study, we report a new pathway in which glucocorticoids reduce the levels of upstream insulin signaling components by downregulating the transcription of the gene encoding caveolin-1 (CAV1), a scaffolding protein present in the caveolar membrane. Treatment with the glucocorticoid dexamethasone (DEX) decreased CAV1 protein and <I>Cav1</I> mRNA expression, with a concomitant reduction in insulin receptor alpha (IRα) and IR substrate 1 (IRS1) levels in C2C12 myotubes. On the basis of the results of promoter analysis using deletion mutants and site-directed mutagenesis a negative glucocorticoid-response element in the regulatory region of the <I>Cav1</I> gene was identified, confirming that <I>Cav1</I> is a glucocorticoid-target gene. <I>Cav1</I> knockdown using siRNA decreased the protein levels of IRα and IRS1, and overexpression of <I>Cav1</I> prevented the DEX-induced decrease in IRα and IRS1 proteins, demonstrating a causal role of <I>Cav1</I> in the inhibition of insulin signaling. Moreover, injection of adenovirus expressing <I>Cav1</I> into the gastrocnemius muscle of mice prevented DEX-induced atrophy. These results indicate that CAV1 is a critical regulator of muscle homeostasis, linking glucocorticoid signaling to the insulin signaling pathway, thereby providing a novel target for the prevention of glucocorticoid-induced muscle atrophy.</P>

Glucocorticoid-Induced Hyperglycemia: A Neglected Problem

조정환,서성환 대한내분비학회 2024 Endocrinology and metabolism Vol.39 No.2

Glucocorticoids provide a potent therapeutic response and are widely used to treat a variety of diseases, including coronavirus disease 2019 (COVID-19) infection. However, the issue of glucocorticoid-induced hyperglycemia (GIH), which is observed in over one-third of patients treated with glucocorticoids, is often neglected. To improve the clinical course and prognosis of diseases that necessitate glucocorticoid therapy, proper management of GIH is essential. The key pathophysiology of GIH includes systemic insulin resistance, which exacerbates hepatic steatosis and visceral obesity, as well as proteolysis and lipolysis of muscle and adipose tissue, coupled with β-cell dysfunction. For patients on glucocorticoid therapy, risk stratification should be conducted through a detailed baseline evaluation, and frequent glucose monitoring is recommended to detect the onset of GIH, particularly in high-risk individuals. Patients with confirmed GIH who require treatment should follow an insulin-centered regimen that varies depending on whether they are inpatients or outpatients, as well as the type and dosage of glucocorticoid used. The ideal strategy to maintain normoglycemia while preventing hypoglycemia is to combine basal-bolus insulin and correction doses with a continuous glucose monitoring system. This review focuses on the current understanding and latest evidence concerning GIH, incorporating insights gained from the COVID-19 pandemic.

Lentivirus System을 이용한 Glucocorticoid 유도 Reporter 유전자 발현의 분석

이미숙,김지연,허송욱,Lee, Mi-Sook,Kim, Ji-Yeon,Her, Song 한국해양바이오학회 2007 한국해양바이오학회지 Vol.2 No.2

글루코코르티코이드의 다양한 생리학적 과정은 이 호르몬에 의해 활성화된 수용체가 표적 유전자의 전사를 촉진 혹은 억제시킴으로써 일어나게 된다. 본 논문은 렌티바이러스 리포터 시스템을 이용하여 글루코코르티코이드 호르몬에 의한 GR 활성을 핵내에서 GRE에 의해 유도된 리포터 단백질인 mRFP 또는 루시퍼라아제의 발현을 통해 정성, 정량화 하였다. 그 결과 GR이 endogenous 하게 발현되는 HeLa 세포에서 코티졸을 처리하였을 때 활성화된 GR에 의해 GRE-inducible한 RFP와 루시퍼라아제의 발현이 각각 공초점 형광 현미경과 IVIS-200을 이용하여 형광 또는 BLI을 통해 증가함을 확인하였다. 이러한 결과를 통해 렌티바이러스 리포터 시스템을 이용한 연구는 세포 내에서 뿐 만 아니라 향후 생체내에서의 GR signaling을 모니터링하는데 유용하게 사용되어질 수 있을 것이다. Glucocorticoid hormone regulates numerous physiological processes, such as regulation of metabolism, and anti-inflammatory and immunosuppressive actions via the activation and repression of gene expression. Here we described a lentivirus-based reporter vector system expressing red fluorescent protein (mRFP) or firefly luciferase (Luc) under the control of a glucocorticoid-responsive element that allows observation of the temporospatial pattern of glucocorticoid induced GR-mediated signaling on a cellular level. Moreover, usage of the chromatin insulator of the chicken ${\beta}$-globin locus induced a marked increase of sensitivity of glucocorticoid inducible promoter of a reporter gene. Use of this method will be applicable of screening for agonist and antagonist of GR in vitro, and also a reporter gene assay for the in vivo determination of the GR-mediated gene activation.