1.Nuclear factor kappaB (NF-kappaB) pathway as a therapeutic target in rheumatoid arthritis.
Dae Myung JUE ; Kye Im JEON ; Jae Yeon JEONG
Journal of Korean Medical Science 1999;14(3):231-238
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint swelling and progressive destruction of cartilage and bone. Current RA treatments are largely empirical in origin and their precise mechanism of action is uncertain. Increasing evidence shows that chronic inflammatory diseases such as RA are caused by prolonged production of proinflammatory cytokines including tumor necrosis factor (TNF) and interleukin 1 (IL-1). The nuclear factor kappaB (NF-kappaB) plays an essential role in transcriptional activation of TNF and IL-1. NF-kappaB is induced by many stimuli including TNF and IL-1, forming a positive regulatory cycle that may amplify and maintain RA disease process. NF-kappaB and enzymes involved in its activation can be a target for anti-inflammatory treatment. Aspirin and sodium salicylate inhibit activation of NF-KB by blocking IkappaB kinase, a key enzyme in NF-kappaB activation. Glucocorticoids suppress expression of inflammatory genes by binding glucocorticoid receptor with NF-kappaB, and increasing expression of inhibitory protein of NF-kappaB, IkappaBalpha. Sulfasalazine and gold compounds also inhibit NF-kappaB activation. Continuing advances in our understanding of action mechanism of antirheumatic agents will benefit the future development of RA regimens with greater efficacy and less toxicity.
Animal
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Antirheumatic Agents/therapeutic use*
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Arthritis, Rheumatoid/therapy*
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Arthritis, Rheumatoid/metabolism
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Arthritis, Rheumatoid/immunology
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Cytokines/immunology
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Cytokines/genetics
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Gene Expression Regulation
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Human
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Macrophages/immunology
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NF-kappa B/metabolism*
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NF-kappa B/immunology
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NF-kappa B/biosynthesis
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Tumor Necrosis Factor/genetics
2.Expression of nuclear factor-kappaB in mouse uterus during peri-implantation.
Qingzhen, XIE ; Zhimin, XIN ; Lumin, CAO ; Wan, LI
Journal of Huazhong University of Science and Technology (Medical Sciences) 2004;24(4):361-4
To investigate the expression of the subunit p65 of NF-kappaB and inhibitor kappa B alpha (IkappaBalpha) in mouse uterus during peri-implantation, thereby investigating whether transient activation of nuclear factor-kappaB (NF-kappaB) takes place during embryo implantation in mice. Immunohistochemical technique was used to examine the expression and localization of p65 in endometrium or deciduas, and Western blot analysis was employed to detect the levels of IkappaBalpha protein in mouse endometrium or deciduas. P65 protein was detected in stromal cells, epithelial cells of endometrium as well as in myometrium. Staining was predominately seen in the cytoplasm of the cells. Staining intensity for p65 was stronger in the epithelial compartment than the stromal compartment and myometrium. Staining intensity increased slightly during pregnancy, and it reached a high level on pregnancy day 5 and day 8. In contrast to p65, the level of IkappaBalpha protein was lowest on pregnancy day 5 in all groups. Our results suggested that NF-kappaB may regulate embryo implantation by its transient activation in mice.
Decidua/metabolism
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Embryo Implantation/*physiology
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Endometrium/metabolism
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I-kappa B Proteins/*biosynthesis
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NF-kappa B/*biosynthesis
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Time Factors
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Uterus/*metabolism
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Uterus/physiology
3.The activation of nuclear factor kappa B and the expression of cyclooxygenase-2 in alcoholic liver disease in rats.
Hua-Li ZHOU ; Chao-Hui YU ; Shao-Hua CHEN ; Wei-Xing CHEN ; Li-Jun WANG ; Li-Xiong YING ; You-Ming LI
Chinese Journal of Hepatology 2004;12(9):568-569
Animals
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Cyclooxygenase 2
;
biosynthesis
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genetics
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Female
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Liver Diseases, Alcoholic
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metabolism
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Male
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NF-kappa B
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biosynthesis
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genetics
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Rats
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Rats, Sprague-Dawley
4.Suppression of NF-kappaB activation in normal T cells by supernatant fluid from human renal cell carcinomas.
Hyung Jin KIM ; Jong Kwan PARK ; Young Gon KIM
Journal of Korean Medical Science 1999;14(3):299-303
T lymphocytes from patients with renal cell carcinoma (RCC) show reduced immune function and impaired activation of the transcription factor, NF-kappaB. We determined the mechanism of NF-kappaB suppression in T cells of RCC patient and determined whether supernatant fluid from RCC explants (RCC-S) induced the same phenotype of NF-kappaB suppression in normal T cells that is observed in patient T cells. The pattern of kappaB-binding activity in T cells of RCC patient was altered as compared to that seen in T cells obtained from normal volunteers. In some patients, no activation of RelA/NFkappaB1-binding activity was detectable, while in others kappaB-binding activity was modestly induced but the duration was reduced. IkappaBalpha was degraded normally following stimulation in both normal controls and T cells from RCC patients. RCC-S did not alter the cytoplasmic levels of RelA and NF-kappaB1 but did suppress their nuclear localization and inhibited the activation of RelA/NF-kappaB1 binding complexes. These results show that RCC-S can induce in normal T cells the same phenotype of impaired NF-kappaB activation that is detected in T cells of RCC patient. It also appears that NF-kappaB suppression by RCC-S may contribute to the immunosuppression of host immunity.
Carcinoma, Renal Cell/metabolism*
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Culture Media, Conditioned/metabolism
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DNA-Binding Proteins/biosynthesis
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Human
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Kidney Neoplasms/metabolism*
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NF-kappa B/metabolism*
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NF-kappa B/biosynthesis
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Proto-Oncogene Proteins/biosynthesis
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Proto-Oncogene Proteins c-rel
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T-Lymphocytes/metabolism*
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Tissue Culture
6.Effects on the expression of lipopolysaccharide-induced inflammatory cytokines mediated by bovine bactericidal/permeability-increasing protein.
Nan YAO ; Jie BAI ; Xuemei ZHANG ; Ning ZHANG ; Weidong WU ; Wenrong LI
Chinese Journal of Biotechnology 2015;31(2):195-205
Bactericidal/permeability-increasing protein (BPI) can bind to and specifically neutralize lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria. In order to evaluate potent LPS-neutralizing activity of bovine BPI, the full-length coding sequence (1 449bp) or 714 bp N-terminal coding sequence (BPI714) of bovine BPI was transfected into mHEK293 cells and the expression of LPS-induced inflammatory cytokines was studied. First, we constructed the lentiviral expression vectors and generated mHEK293 cells stably expressing recombinant bovine BPI or BPI714. Then, we detected the expression of IL-8, IL-1β, TNF-α, NF-κB-1 and NF-κB-2 genes by real-time PCR at 0, 1, 3, 6, 12, 24, 36 and 48 h post of LPS induction in cells with or without recombinant bovine BPI or BPI714 ectopic expression, respectively. In response to LPS, the robust abundance of inflammatory cytokines including IL-8, IL-1β, TNF-α and NF-κB-2 was observed in wild type mHEK293 cells at eachtime point. On the contrary, mRNA abundance of IL-8, TNF-α and NF-κB-2 in transfected mHEK293 cells showed no significant changes at each indicated time point. Our results demonstrated that recombinant bovine full length BPI or BPI714 down-regulated the expression of inflammatory cytokines and revealed that either of bovine BPI or BPI714 was able to inhibit the immune respond stimulated by LPS. This study provides evidence for further investigating the mechanisms and application of BPI/LPS-neutralizing activity and also documents a reliable approach for analysis of the efficacy of antibacterial proteins.
Animals
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Antimicrobial Cationic Peptides
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chemistry
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Blood Proteins
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chemistry
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Cattle
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Cytokines
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biosynthesis
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HEK293 Cells
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Humans
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Interleukins
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biosynthesis
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Lipopolysaccharides
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chemistry
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NF-kappa B
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biosynthesis
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Transfection
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Tumor Necrosis Factor-alpha
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biosynthesis
7.Expression of nuclear factor-kappaB in mouse uterus during peri-implantation.
Qingzhen XIE ; Zhimin XIN ; Lumin CAO ; Wan LI
Journal of Huazhong University of Science and Technology (Medical Sciences) 2004;24(4):361-364
To investigate the expression of the subunit p65 of NF-kappaB and inhibitor kappa B alpha (IkappaBalpha) in mouse uterus during peri-implantation, thereby investigating whether transient activation of nuclear factor-kappaB (NF-kappaB) takes place during embryo implantation in mice. Immunohistochemical technique was used to examine the expression and localization of p65 in endometrium or deciduas, and Western blot analysis was employed to detect the levels of IkappaBalpha protein in mouse endometrium or deciduas. P65 protein was detected in stromal cells, epithelial cells of endometrium as well as in myometrium. Staining was predominately seen in the cytoplasm of the cells. Staining intensity for p65 was stronger in the epithelial compartment than the stromal compartment and myometrium. Staining intensity increased slightly during pregnancy, and it reached a high level on pregnancy day 5 and day 8. In contrast to p65, the level of IkappaBalpha protein was lowest on pregnancy day 5 in all groups. Our results suggested that NF-kappaB may regulate embryo implantation by its transient activation in mice.
Animals
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Decidua
;
metabolism
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Embryo Implantation
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physiology
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Endometrium
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metabolism
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Female
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I-kappa B Proteins
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biosynthesis
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Mice
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NF-KappaB Inhibitor alpha
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NF-kappa B
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biosynthesis
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Pregnancy
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Time Factors
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Uterus
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metabolism
;
physiology
8.Role of nuclear factor kappaB in intestine injury induced by hepatic ischemia reperfusion.
Journal of Huazhong University of Science and Technology (Medical Sciences) 2004;24(3):284-291
The role of nuclear factor kappaB in intestine injury induced by hepatic ischemia reperfusion was investigated. Eighteen male Wistar rats were divided into 3 groups randomly: sham operation group (group A), hepatic ischemia reperfusion group (group B) and hepatic ischemia reperfusion plus pyrrolidine dithiocarbamate (PDTC) group (group C). The rats in group A were only subjected to laparotomy, those in group B underwent partial hepatic ischemia reperfusion (ischemia for 1 h and reperfusion for 2 h) and those in group C underwent the same procedure as that of group B but received PDTC 200 mg/kg i.v. before and after ischemia. After reperfusion, tissues of jejunum and venous blood were obtained for measurement of TNF-alpha, MDA and MPO. The levels of TNF-alpha in jejunum and venous blood, the levels of MPO in jejunum in group B were significantly higher than those in group A and group C (P<0.05). There was no significant different in the levels of MDA between group B and group C. The severity of histological intestinal injury in group B and group C was similar. Hepatic ischemia reperfusion caused intestine injury, NF-kappaB may play an important role in this course and the targeting of upstream components of the inflammatory response, such as NF-kappaB, may have important therapeutic applications.
Animals
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Intestines
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pathology
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Liver
;
blood supply
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metabolism
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Male
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NF-kappa B
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biosynthesis
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Random Allocation
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Rats
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Rats, Wistar
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Reperfusion Injury
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metabolism
9.Role of nuclear factor kappaB in intestine injury induced by hepatic ischemia reperfusion.
Journal of Huazhong University of Science and Technology (Medical Sciences) 2004;24(3):284-5, 291
The role of nuclear factor kappaB in intestine injury induced by hepatic ischemia reperfusion was investigated. Eighteen male Wistar rats were divided into 3 groups randomly: sham operation group (group A), hepatic ischemia reperfusion group (group B) and hepatic ischemia reperfusion plus pyrrolidine dithiocarbamate (PDTC) group (group C). The rats in group A were only subjected to laparotomy, those in group B underwent partial hepatic ischemia reperfusion (ischemia for 1 h and reperfusion for 2 h) and those in group C underwent the same procedure as that of group B but received PDTC 200 mg/kg i.v. before and after ischemia. After reperfusion, tissues of jejunum and venous blood were obtained for measurement of TNF-alpha, MDA and MPO. The levels of TNF-alpha in jejunum and venous blood, the levels of MPO in jejunum in group B were significantly higher than those in group A and group C (P<0.05). There was no significant different in the levels of MDA between group B and group C. The severity of histological intestinal injury in group B and group C was similar. Hepatic ischemia reperfusion caused intestine injury, NF-kappaB may play an important role in this course and the targeting of upstream components of the inflammatory response, such as NF-kappaB, may have important therapeutic applications.
Intestines/*pathology
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Liver/*blood supply
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Liver/metabolism
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NF-kappa B/*biosynthesis
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Random Allocation
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Rats, Wistar
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Reperfusion Injury/*metabolism
10.Expression of nucleotide-binding oligomerization domain 1, nuclear factor-kappa B and human beta-defensins in candidal albicans leukoplakia.
Yajie QIAN ; Wenhui JIANG ; Xiang WANG ; Ning DUAN ; Xiaofeng HUANG ; Wenmei WANG
Chinese Journal of Stomatology 2014;49(8):464-469
<b>OBJECTIVEb>To examine the expression of nucleotide-binding oligomerization domain 1 (NOD1), nuclear factor-kappa B (NF-κB) and human beta-defensins in candidal albicans leukoplakia and to investigate the effect of candida albicans infection on key proteins in NOD1 signaling pathway and the expression of human beta-defensin.
<b>METHODSb>Forty cases of oral leukoplakia samples were collected and stained by hematoxylin-eosin staining, periodic acid-Schiff staining, silver staining and immunohistochemical methods. Nineteen samples were positive with these four methods and judged as candidal albicans leukoplakia, and the other twenty- one samples judged as leukoplakia without candidal albicans infection. Western blotting was used to detect the expressions of NOD1 and NF-κB in these forty samples. In addition, the immunohistochemical method was adopted to investigate the relationship between NOD1, NF-κB, human beta-defensin 1, 2, 3 expressions and candida albicans.
<b>RESULTSb>The positive rate of candida albicans in oral leukoplakia was 48% (19/40). The expressions of NOD1 and NF-κB in the candida albicans leukoplakia were lower than that in leukoplakia without candida albicans infection. The mean optical density value of NOD1, NF-κB, human beta-defensin 1, 2, 3 in candidal albicans leukoplakia were 0.25 ± 0.01, 0.30 ± 0.02, 0.35 ± 0.02, 0.42 ± 0.03, 0.36 ± 0.02 respectively, which were significantly lower than that in leukoplakia without candida albicans infection (0.31 ± 0.02, 0.47 ± 0.03, 0.42 ± 0.02, 0.53 ± 0.04, 0.47 ± 0.03) (P < 0.05).
<b>CONCLUSIONSb>By inhibiting the NOD1 signaling pathway, candida albicans infection may reduce the expression level of human beta-defensin 1, 2, 3 in oral leukoplakia.
Blotting, Western ; Candida albicans ; Candidiasis ; metabolism ; Humans ; Leukoplakia, Oral ; metabolism ; NF-kappa B ; biosynthesis ; Nod1 Signaling Adaptor Protein ; biosynthesis ; Nucleotides ; Signal Transduction ; beta-Defensins ; biosynthesis