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Article in English | WPRIM | ID: wpr-358700


High mobility group box-1 protein (HMGB1), which is a nuclear protein, participates in chromatin architecture and transcriptional regulation. When released from cells, HMGB1 also plays a well-established role as a pro-inflammatory mediator during innate immune responses to injury. In the initial stage of injury, there is a release of large quantities of early pro-inflammatory mediators to initiate or perpetuate immune responses against pathogens, but this pro-inflammatory period is transient, and it is followed by a prolonged period of immune suppression. At present, several lines of evidences have suggested that HMGB1 is a late cytokine provoking delayed endotoxin morbidity, which may enhance the production of early proinflammatory mediators, and it can contribute potently to the activation of different immune cells and play a role in the development of host cell-mediated immunity. The biology of HMGB1 has been extensively studied as a pro-inflammatory cytokine of systemic inflammation, however, this review will attempt to provide a summary of the effects of HMGB1 on different immune cells and its regulatory mechanism in acute insults.

Cytokines , Allergy and Immunology , HMGB1 Protein , Allergy and Immunology , Humans , Immunity, Cellular , Inflammation , Allergy and Immunology
Chinese Journal of Burns ; (6): 104-108, 2010.
Article in Chinese | WPRIM | ID: wpr-305617


<p><b>OBJECTIVE</b>To observe the influence of high mobility group box-1 protein (HMGB1) derived from spleen on the phenotype of regulatory T lymphocytes (Treg) and HMGB1-mediated immune function in severely scalded rats after delayed resuscitation.</p><p><b>METHODS</b>One hundred and four Wistar rats were divided into normal control group (NC, n = 8), sham scald group (SS, n = 32), scald group (S, n = 32), and ethyl pyruvate (EP) treatment group (EPT, n = 32) according to the random comparison table. Rats in the latter 2 groups were subjected to 30%TBSA full-thickness scald, which were intraperitoneally injected with Ringer solution or EP solution at post scald hour (PSH) 6 (delayed antishock treatment) and administered with 4 mL Ringer solution or EP solution per 12 hours after PSH 12 till PSH 48. Rats in SS group were treated the same as that of S group except for sham scald with 37 degrees C water. Injured rats were sacrificed at post scald day (PSD) 1, 3, 5, 7 (rats in NC group were also sacrificed), and CD4(+)CD25(+)Treg were isolated from spleen with magnetic-activated cell sorting method. The content of HMGB1 in spleen and IL-2 level in supernatant were determined with ELISA. The expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on Treg was determined with flow cytometry, and the proliferation activity of T lymphocytes was also detected (recorded as absorbance value). Data were processed with analysis of variance among groups and independent samples t test.</p><p><b>RESULTS</b>(1) Compared with that of rats in SS group and EPT group, the expression of splenic HMGB1 in S group increased significantly on PSD 1 through PSD 7 [peaked on PSD 1: (46.7 +/- 8.3) ng/mg protein]. (2) Compared with that in SS group, the expression of CTLA-4 in S group was enhanced significantly on PSD 1 through PSD 5 (with t value respectively 10.459, 12.051, 4.029, P < 0.05 or P < 0.01); while that in EPT group decreased significantly on PSD 1 through PSD 7 as compared with that from S group (with t value respectively 2.796, 9.913, 9.581, 10.022, P < 0.05 or P < 0.01). (3) Compared with that of rats in SS group, the proliferation activity of T lymphocytes in S group was markedly suppressed on PSD 1 through PSD 7 (nadir on PSD1: 0.167 +/- 0.059), and release of IL-2 was decreased significantly [nadir on PSD 5: (44 +/- 24) pg/mL]. T lymphocytes proliferation activity was restored and excretion of IL-2 increased in EPT group as compared respectively with that of S group at each time point.</p><p><b>CONCLUSIONS</b>The release of HMGB1 may stimulate splenic Treg to mature, thereby induce suppression of proliferation activity of T lymphocytes and immune function. EP can ameliorate immune dysfunction in animals with delayed resuscitation through inhibiting the synthesis and release of HMGB1.</p>

Animals , Antigens, CD , Metabolism , Burns , Allergy and Immunology , CTLA-4 Antigen , Cell Proliferation , HMGB1 Protein , Metabolism , Interleukin-2 , Metabolism , Male , Pyruvates , Pharmacology , Rats , Rats, Wistar , Spleen , Cell Biology , Allergy and Immunology , T-Lymphocytes, Regulatory , Cell Biology , Allergy and Immunology
Chinese Journal of Burns ; (6): 405-410, 2006.
Article in Chinese | WPRIM | ID: wpr-331558


<p><b>OBJECTIVE</b>To investigate the pattern of nuclear factor-kappaB (NF-kappaB) activation in rats with lipopolysaccharide( LPS) shock, and to explore the mechanism of NF-kappaB signal pathway in the biopterin-mediated nitric oxide(NO) induction, as well as its role in the development of multiple organ dysfunction syndrome ( MODS) secondary to endotoxin challenge.</p><p><b>METHODS</b>Fourty-seven male Wistar rats were randomly divided into control group ( C, n = 8) , LPS group ( n = 24, with 8 rats at each time-points, and shock model was made by injection of same dosage of LPS) , and pyrrolidine dithiocarbamate (PDTC) treatment group ( PDTC, n = 15, with 5 rats at each time-points, and the rats were injected with LPS and PDTC). The rats were sacrificed at 2,6,12 post-injection hour( PIH) , and the blood and tissue samples from liver, lungs and kidneys were harvested for the determination of NF-KB activity, GTP cyclohydrolase I (GTP-CH I ) , and inducible nitric oxide synthase (iNOS) mRNA expression in the liver, lungs and kidneys, plasma and tissue content of biopterin and NO, as well as hepatic and renal function, and pulmonary myeloperoxidase activity.</p><p><b>RESULTS</b>NF-kappaB DNA binding activity in LPS group was rapidly enhanced in liver, lungs and kidneys after endotoxin challenge when compared with that in controls (e. g. in pulmonary tissue it was 26+/-6) , and it reached the peak at 2 PIH, which was 291 +/-44 in pulmonary tissue( P <0. 01). GTP-CH I mRNA expression and biopterin levels in the liver, lung and kidney of each group were obviously higher than those in control group( P <0.05 or 0.01) , and it maintained at high levels at 12 PIH. Additionally, different degrees of dysfunction of the above mentioned organs was observed. Treatment with PDTC, an inhibitor of NF-KB signal transduction pathway, could reduce NF-kappaB DNA binding activity, inhibit GTP-CH I and iNOS/NO mRNA expression, as well as BH4, and NO levels in various tissues. Meanwhile the multiple organ damage was significantly ameliorated by PDTC pretreatment.</p><p><b>CONCLUSION</b>Endotoxin challenge can rapidly lead to activation of NF-kappaB in various tissues, and NF-KB pathway might markedly up-regulate the production of biopterin/NO following endotoxic shock. Inhibition of NF-kappaB pathway attenuates inflammatory response and ameliorates multiple organ dysfunction, which might be associated with its down-regulation of the excessive activation of iNOS mediated by biopterin.</p>

Animals , Biopterin , Metabolism , Endotoxins , Pharmacology , Male , NF-kappa B , Metabolism , Nitric Oxide , Metabolism , Nitric Oxide Synthase Type II , Metabolism , Pyrrolidines , Pharmacology , Rats , Rats, Wistar , Shock, Septic , Metabolism , Signal Transduction , Thiocarbamates , Pharmacology
Chinese Journal of Surgery ; (12): 1127-1131, 2005.
Article in Chinese | WPRIM | ID: wpr-306173


<p><b>OBJECTIVE</b>To observe the influence of treatment with the inhibitor of extracellular-signal regulated protein kinase (ERK) signal transduction pathway on the expression of biopterin/nitric oxide (NO) as well as the activation of nuclear factor-kappaB (NF-kappaB), and to clarify the potential cross-talk regulation mechanisms between ERK and NF-kappaB pathway in biopterin-mediated NO induction in rats with endotoxic shock.</p><p><b>METHODS</b>Using an endotoxic shock model, 60 male Wistar rats were randomly divided into normal controls (n = 8), endotoxic shock group (n = 32) and PD98059 treatment group (n = 20). At serial time points animals in each group were sacrificed, and tissue samples from liver, lungs as well as kidneys were harvested to detect NF-kappaB activity, guanosine triphosphate-cyclohydrolase (GTP-CHI) and inducible nitric oxide synthase (iNOS) mRNA expression. Biopterin and NO levels in plasma and tissues were also assayed.</p><p><b>RESULTS</b>It was found that after lipopolysaccharide (LPS) challenge, GTP-CHI mRNA expression and biopterin levels significantly elevated in liver, lungs and kidneys, keeping at high values up to 24 h, so did the values of iNOS mRNA expression and NO levels. NF-kappaB DNA binding activity was enhanced rapidly in various tissues, peaking at 2 h after LPS challenge. Treatment with PD98059, an inhibitor of ERK signal transduction pathway, could significantly inhibit GTP-CHI mRNA expression in kidneys, and GTP-CHI mRNA expression in liver and lungs showed certain down-regulation tendency. At the same time, biopterin level was significantly decreased in plasma, liver and kidneys at 12 h. Similarly, iNOS/NO induction at early stage markedly decreased in various tissues. In addition, treatment with PD98059 reduced NF-kappaB DNA binding activity in liver, lungs, as well as kidneys at 2-6 h, 2 h, 24 h and 24 h after LPS challenge, respectively.</p><p><b>CONCLUSIONS</b>Inhibition of ERK pathway could partially inhibit the production of biopterin/NO as well as the activation of NF-kappaB pathway, which indicated that cross-talk regulation seems to be existed between ERK and NF-kappaB pathway, and they might be involved in the regulatory process of biopterin-mediated nitric oxide induction in rats with endotoxic shock.</p>

Animals , Biopterin , Metabolism , Physiology , Disease Models, Animal , Extracellular Signal-Regulated MAP Kinases , Physiology , GTP Cyclohydrolase , Genetics , Male , NF-kappa B , Metabolism , Nitric Oxide , Nitric Oxide Synthase Type II , Genetics , Random Allocation , Rats , Rats, Wistar , Shock, Septic , Signal Transduction