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Tumor necrosis factor (TNF)-α-induced protein 8-like 2 (TIPE2) is a newly discovered negative immunoregulatory protein that is involved in various cellular immune responses to infections. However, the underlying mechanism by which TIPE2 affects the immune function of dendritic cells (DCs) is not yet understood. This study aimed to determine the correlations among DCs TIPE2 expression, autophagic activity and immune function in the context of sepsis. In addition, the signaling pathway by which TIPE2 regulates autophagy in DCs was investigated. We reported for the first time that TIPE2 overexpression (knock-in, KI) exerted an inhibitory effect on autophagy in DCs and markedly suppressed the immune function of DCs upon septic challenge both in vitro and in vivo. In addition, TIPE2 knockout (KO) in DCs significantly enhanced autophagy and improved the immune response of DCs in sepsis. Of note, we found that the transforming growth factor-β (TGF-β)-activated kinase-1 (TAK1)/c-Jun N-terminal kinase (JNK) pathway was inhibited by TIPE2 in DCs, resulting in downregulated autophagic activity. Collectively, these results suggest that TIPE2 can suppress the autophagic activity of DCs by inhibiting the TAK1/JNK signaling pathway and further negatively regulate the immune function of DCs in the development of septic complications.

BackgroundSepsis-induced coagulopathy (SIC) is defined as infection-induced organ dysfunction and coagulopathy. Although anticoagulation with heparin has been widely used in practice, its effectiveness for treating SIC remains controversial. This study aimed to investigate whether prophylactic heparin administration would provide a survival advantage for patients with SIC.Methods Patients with SIC were identified from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was ICU mortality, and the secondary outcomes were 7-day, 14-day, and 28-day mortality as well as hospital mortality. A Cox proportional hazards model and propensity score matching (PSM) were used to account for baseline differences in the probability of using prophylactic heparin. The marginal structural Cox model (MSCM) was employed to adjust for both baseline and time-varying confounding factors. E-value analysis was used for unmeasured confounding.Results A total of 6498 septic patients with SIC were enrolled in the study, with 1284 in the heparin group and 5124 in the nonheparin group. There was no significant effect on ICU mortality in the overall population (prematched, hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.77-1.14, P=0.517, postmatched, HR 0.89, 95% CI 0.70-1.12, P=0.323). Interestingly, the MSCM identified a significant effect on ICU mortality in the overall population (HR 0.77, 95% CI 0.60-0.98, P=0.032). Stratification analysis with the MSCM showed that prophylactic heparin administration was associated with decreased ICU mortality only among patients with a SIC score of 4 (HR 0.63, 95% CI 0.45-0.89, P=0.009). Similar results were replicated with PSM only for patients with a SIC score of 4 (ICU mortality HR 0.68, 95% CI 0.49-0.95, P=0.025; 7-day mortality HR 0.59, 95% CI 0.36-0.98, P=0.040; 14-day mortality HR 0.66, 95% CI 0.44-0.98, P=0.040; Hospital mortality HR 0.77, 95% CI 0.58-1.03, P=0.074; 28-day mortality HR 0.77, 95% CI 0.54-1.10, P=0.147). E-value analysis indicated robustness to unmeasured confounding.Conclusions: Prophylactic heparin administration to patients with a SIC score of 4 appears to be associated with improved survival outcomes, including ICU mortality and 7-day and 14-day mortality, but not with improvement in hospital or 28-day mortality. These results need to be verified in prospective randomized controlled trials.

Background Minimal data exist on anticoagulation use and timing and the dose of heparin in patients with sepsis, and whether heparin use improves sepsis survival remains largely unclear. This study was performed to assess whether heparin administration would provide a survival advantage in critically ill patients with sepsis. Methods A retrospective cohort study of patients with sepsis in the Medical Information Mart for Intensive Care (MIMIC)-IV database was conducted. Cox proportional hazards model and propensity score matching (PSM) were used to evaluate the outcomes of prophylactic anticoagulation with heparin administered by subcutaneous injection within 48 h of intensive care unit (ICU) admission. The primary outcome was in-hospital mortality. Secondary outcomes included 60-day mortality, length of ICU stay, length of hospital stay and incidence of acute kidney injury (AKI) on day 7. E-Value analysis were used for unmeasured confounding. Results A total of 6646 adult septic patients were included and divided into an early prophylactic heparin group (n = 3211) and a nonheparin group (n = 3435). In-hospital mortality in the heparin therapy group was significantly lower than that in the nonheparin group (prematched 14.7 vs 20.0%, hazard ratio (HR) 0.77, 95% confidence interval (CI) [0.68–0.87], p < 0.001, and postmatched 14.9 vs 18.3%, HR 0.78, 95% CI [0.68–0.89], p < 0.001). Secondary endpoints, including 60-day mortality and length of ICU stay, differed between the heparin and nonheparin groups (p < 0.01). Early prophylactic heparin administration was associated with in-hospital mortality among septic patients in different adjusted covariates (HR 0.71–0.78, p < 0.001), and only administration of five doses of heparin was associated with decreased in-hospital mortality after PSM (HR 0.70, 95% CI 0.56–0.87, p < 0.001). Subgroup analysis showed that heparin use was significantly associated with reduced in-hospital mortality in patients with sepsis-induced coagulopathy, septic shock, sequential organ failure assessment score ≥ 10, AKI, mechanical ventilation, gram-positive bacterial infection and gram-negative bacterial infection, with HRs of 0.74, 0.70, 0.58, 0.74, 0.73, 0.64 and 0.72, respectively (p Conclusions This study found an association between early administration prophylactic heparin provided to patients with sepsis and reduced risk-adjusted mortality. A prospective randomized-controlled study should be designed to further assess the relevant findings.

Ying-Yi Luan,1,&ast; Yan-Hong Chen,2,&ast; Xue Li,3 Zhi-Peng Zhou,2 Jia-Jia Huang,2,4 Zhen-Jia Yang,2,4 Jing-Jing Zhang,2,5 Ming Wu2,4,6 1Department of Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, People’s Republic of China; 2Department of Critical Care Medicine and Hospital Infection Prevention and Control, Shenzhen Second People`s Hospital & First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, 518035, People’s Republic of China; 3Department of Emergency, the Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, People’s Republic of China; 4Shantou University Medical College, Shantou, 515041, People’s Republic of China; 5Department of Critical Care Medicine, Pingshan District People’s Hospital of Shenzhen, Shenzhen, 518118, People’s Republic of China; 6Guangxi University of Chinese Medicine, Nanning, 530200, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming Wu Tel +86 755 83676149Email boshiyy@126.comBackground: Increasing evidence indicates carbapenem-resistant Klebsiella pneumoniae (CrKP) is increasingly prevalent in intensive care unit (ICU), but its clinical characteristics and risk factors remain unknown.Aim: The aim of the present study was to evaluate clinical characteristics, risk factors in critically ill patients with CrKP infection.Methods: A retrospective study was included in patients from January 2013 to October 2019. Clinical data were collected from CrKP patients on the day of specimen collection admitted to ICU. Multivariable logistic regression was used for risk factors. Receiver operating curve (ROC) and the area under the curve (AUC) with DeLong method of MedCalc software were used. Two-way repeated-measures ANOVA analysis was used to analyze the characteristics of independent risk factors over time.Findings: A total of 147 adult patients with CrKP were screened, among them, 89 (median age 64.0 years, 66 (74.15%) males) patients with CrKP were finally included, of which 38 patients (42.7%) were non-survival group. Multivariate logistic regression analysis indicated that lactic acid (OR3.04 95% CI 1.38– 6.68, P = 0.006), APACHE II score (OR 1.20, 95% CI 1.09– 1.33, P < 0.001), tigecycline combined with fosfomycin treatment (OR0.15, 95% CI 0.04– 0.65, P = 0.011) are independent risk factors for 28-day mortality in patients with CRKP infection (P< 0.05). Combined lactic acid with APACHE II score could predict 28-day mortality, of which AUC value was 0.916 (95% CI, 0.847– 0.985), with sensitivity 0.76 and specificity 0.98. ANOVA analysis showed that APACHE II score and lactic acid between the two groups at three-time points were statistically significant, which interactive with time and showed an upward and downward trend with time (P < 0.05).Conclusion: Therapeutic strategy based on improving lactic acid and APACHE II would contribute to the outcome in patients with CrKP infection. Tigecycline combined with fosfomycin could reduce the 28-day mortality in patients with CrKP infection in developing country.Keywords: carbapenem resistant Klebsiella pneumoniae, lactic acid, APACHE II score, tigecycline, fosfomycin, mortality

Background: Myoglobin released by rhabdomyolysis (RM) is considered to be involved in the pathogenesis of kidney disease caused by crush injury, but whether a high level of serum myoglobin predisposes patients to acute kidney injury (AKI) and increases mortality following exertional heatstroke (EHS) and its molecular mechanisms are still unclear. Methods: Serum myoglobin concentrations in patients with EHS were measured at admission, 24 h and 48 h after admission and discharge. The risk of AKI at 48 hours was the primary outcome, AKI at discharge and death at 90 days were the secondary outcome. In experimental studies, we further investigated the mechanisms of human kidney proximal tubular (HK-2) cells that were exposed to human myoglobin under heat stress conditions and the effect of baicalein.Results: The myoglobin levels were assessed in 187 patients who were undergoing EHS, 82 who were undergoing AKI. The highest myoglobin quartile (vs. the lowest) had an adjusted odds ratio (OR) of 18.95 (95% confidence interval [CI], 6.00 to 59.83) for the primary outcome and the OR (vs. quartile 2) was 7.92 (95% CI, 1.62 to 38.89) for the secondary outcome. The survival rate of HK-2 cells treated with myoglobin under heat stress was significantly decreased, and the production of Fe2+ and ROS was markedly increased, accompanied by changes in ferroptosis proteins, including increased p53, decreased SLC7A11 and GPX4, and alterations in ERS marker proteins. Treatment with baicalein attenuated HK-2 cell ferroptosis induced by myoglobin under heat stress through inhibition of ERS. Conclusions: High serum myoglobin levels were associated with AKI and mortality following EHS, which mechanisms involved ferroptosis and ERS. Baicalein-targeted ERS- ferroptosis may be a potential therapeutic drug for the treatment of AKI in patients with RM after EHS.

Dendritic cell (DC) dysfunction plays a pivotal role in sepsis-induced immunosuppression. Tumor necrosis factor α (TNF-α)–induced protein 8 like-1 (TIPE1), a new member of the tumor necrosis factor α–induced protein 8 family, may be related to cell death. The aim of the present study was to elucidate the effect of TIPE1 on the immune function of DCs and its regulatory mechanism via PD-L1/PD-1 signaling in mice. Sepsis was induced in adult C57BL/6 male mice via cecal ligation and puncture. In vitro, we found that expression of CD80, CD86, and major histocompatibility complex class II in DCs and levels of cytokines, including tumor necrosis factor α and interleukin 12p40, were elevated; similarly, T-cell proliferation and differentiation were promoted when the gene expressing TIPE1 was silenced. Next, we examined the in vivo role of TIPE1 in a cecal ligation and puncture animal model system. Flow cytometry of the immune functional status in DCs revealed negative regulation of TIPE1 on DC maturation, as well as activation. Moreover, changes in PD-L1/PD-1 levels confirmed the negative effect of TIPE1 in DCs. Collectively, we report that TIPE1 might exert negative regulation in sepsis, at least in part by inhibiting DC maturation and subsequent T-cell–mediated immunity via PD-L1/PD-1 signaling.

Regulated cell death profoundly affects on the progress of inflammatory and immune responses in various acute inflammatory diseases, as seen in sepsis and trauma. However, the mechanisms underlying CD4 T cells death have not yet been fully addressed. We demonstrated that interferon genes (STING) promoted excessive Poly (ADP-ribose) polymerase 1 (PARP-1) activity stimulated by endotoxin, which in turn induced apoptosis-inducing factor (AIF)-independent but PARP-1 dependent programmed cell death. Elevated PARP-1 activity triggered a cascade of molecular events, including PAR polymer release from the nucleus and the nicotinamide adenine dinucleotide (NAD

Objectives: To investigated the relationships between procalcitonin (PCT) and disseminated intravascular coagulation (DIC) during septic shock. Methods: A retrospective study was performed, which included septic shock patients admitted into intensive care unit (ICU) from January 1, 2015 to December 31, 2018. DIC was defined as international society of thrombosis and homeostasis criteria (ISTH≥5). PCT was based on the first value after admission into ICU and the routine biochemical coagulation data based on the worst value extracted from electronic medical records within 24 hours on admission into ICU.Results: Among 2156 patients screened, 164 patients with septic shock were included in the finally analysis and 35.4% (58/164) of whom developed DIC after admission. PCT level was significantly higher in septic shock patients who developed DIC than those who did not (54.6[13.6-200] vs12.6[2.4-53.3] ng/ml, P Conclusions: Our data suggest that PCT level over 42.1ng/ml on admission is associated with DIC during septic shock, and PCT is a potential predictive factor of DIC induced by septic shock at early stage.

Background: Early detection of suspected critical patients infected with coronavirus disease 2019 (COVID-19) is very important for the treatment of patients. This study aimed to investigate the role of COVID-19 associated coagulopathy (CAC) to preview and triage. Methods and Results: A cohort study was designed from government designated COVID-19 treatment center. CAC was defined as International Society on Thrombosis and Haemostasis (ISTH) score ≥2. Data from 117 patients COVID-19 were reviewed on admission. The primary and secondary outcomes were admission to Intensive Care Unit (ICU), the use of mechanical ventilation, vital organ dysfunction, discharges of days 14, 21 and 28 from admission and hospital mortality. Among them, admission to ICU was increased progressively from 16.1% in patients with non-CAC to 42.6% in patients with CAC (P, Highlights • COVID-19 patients with ISTH score ≥ 2 on admission need more admission to ICU and mechanical ventilation. • The incidence is high in acute hepatic injury and acute respiratory distress syndrome in COVID-19 patients with ISTH score ≥ 2. • The discharges of 14 days, 21 days and 28 days from admission were less in COVID-19 patients with ISTH score ≥ 2. • ISTH score ≥ 2 is an important indicator to preview and triage for COVID-19 patients on early admission.

Background Complication of disseminated intravascular coagulation (DIC) is a determinant of the prognosis in patients with sepsis shock. Procalcitonin (PCT) has been advocated as a marker of bacterial sepsis. The purpose of this study was to evaluate the relationship between serum PCT levels and DIC with sepsis shock Methods A cohort study was designed which included patients that admitted in intensive care unit (ICU) between January 1, 2015 and December 31, 2018 and the follow-up to discharge. 164 septic shock patients were divided into DIC and non-DIC groups according to international society of thrombosis and homeostasis (ISTH). PCT was measured at the admission to ICU, and all the participants received routine biochemical coagulation test subsequently. Results PCT levels were considerably higher in septic shock patients who developed DIC than those who did not (54.6[13.6–200]vs12.6[2.4–53.3]ng/ml), respectively, P

Objective: The objective of this study was to assess the relationship between serum procalcitonin (PCT) and acute kidney injury (AKI) induced by bacterial septic shock. Methods: A retrospective study was designed which included patients who were admitted to the ICU from January 2015 to October 2018. Multiple logistic regression and receiver operating characteristic (ROC) as well as smooth curve fitting analysis were used to assess the relationship between the PCT level and AKI. Results: Of the 1,631 patients screened, 157 patients were included in the primary analysis in which 84 (53.5%) patients were with AKI. Multiple logistic regression results showed that PCT (odds ratio [OR] = 1.017, 95% confidence interval [CI] 1.009–1.025, p < 0.001) was associated with AKI induced by septic shock. The ROC analysis showed that the cutoff point for PCT to predict AKI development was 14 ng/mL, with a sensitivity of 63% and specificity 67%. Specifically, in multivariate piecewise linear regression, the occurrence of AKI decreased with the elevation of PCT when PCT was between 25 ng/mL and 120 ng/mL (OR 0.963, 95% CI 0.929–0.999; p = 0.042). The AKI increased with the elevation of PCT when PCT was either p = 0.006) or >120 ng/mL (OR 1.042, 95% CI 1.009–1.076; p = 0.013). Moreover, the PCT level was significantly higher in the AKI group only in female patients aged ≤75 years (p = 0.001). Conclusions: Our data revealed a nonlinear relationship between PCT and AKI in septic shock patients, and PCT could be used as a potential biomarker of AKI in female patients younger than 75 years with bacterial septic shock.

Objective This study aims to assess the relationship between serum procalcitonin (PCT) and acute kidney injury (AKI) induced by sepsis shock.Methods A case-control study was designed which included patients that admitted in intensive care unit (ICU) between January 2015 and October 2018. The worst values of biochemical parameters in the first 48 hours from septic shock admission to ICU were evaluated. According to KDIGO guideline, these patients were divided into AKI and non-AKI groups.Results Of 1631 patients screened, 157 patients were included in the primary analysis in which 84 (53.5%) patients with AKI. Multiple logistic regression results showed that PCT (OR=1.017, 95% CI 1.009- 1.025, P

Tumor necrosis factor-α-induced protein-8 (TNFAIP8) is the earliest discovered component of TNFAIP8 family [tumor necrosis factor-α-induced protein-8 like (TIPE) family]. TNFAIP8 contains a putative death effector domain (DED) homologous to DED II in FLIP (Fas-associated death domain-like interleukin-1β-converting enzyme-inhibitory protein), which may affect cell survival/death process. Recently, it has been demonstrated that TNFAIP8 could inhibit apoptosis and autophagy in various types of cells. Moreover, TNFAIP8 level fluctuated evidently in patients with inflammatory, malignant, and autoimmune diseases, indicating that it might be an anti-apoptotic and oncogenetic protein. Herein we will review the discovery, gene/protein structure, pathophysiological functions, and clinical significance of TNFAIP8 together with its potential regulatory mechanism.

In the present study, we examined the activity of p53 protein in Jurkat cells treated with high mobility group box-1 protein (HMGB1), thereafter we investigated the mechanism of extracellular HMGB1 mediated p53 expression in immune dysfunction of T lymphocytes. mRNA expression of p53, mdm2, and p21 was determined by Real-time reverse transcription-polymerase chain reaction(RT-PCR). The apoptotic rate of Jurkat cells was analyzed by flow cytometry. Expressions of bcl-2, bax, caspase-3, phosphorylated (p) extracellular signal-regulated kinase (ERK)1/2, ERK1/2, p-p38 mitogen-activated protein kinase (MAPK), p38 MAPK, and p-c-jun amino-terminal kinase (JNK)1/2 and JNK1/2 were simultaneously determined by Western blotting. After treatment with HMGB1 (100 ng/ml or 1000 ng/ml), the proliferative activity of Jurkat cells was significantly decreased, and a low and medium concentration of HMGB1 induced an up-regulation of p53 mRNA, p-p53 and p53 protein expression. Meanwhile, levels of mdm2 and p21 were elevated by incubated with HMGB1 (100 ng/ml) for 24 or 48 hours. Moreover, the proliferation of Jurkat cells in response to HMGB1 (100 ng/ml) in the vector group was significantly depressed. The bax and caspase-3 levels in p53 shRNA-expressed cells treated with HMGB1 (100 ng/ml) was markedly decreased, whereas expression of bcl-2 was obviously enhanced. Among ERK1/2, p38 MAPK and JNK1/2 signaling, only p38 MAPK pathway could be significantly activated by treatment with HMGB1, and the specific inhibitor of p38 MAPK was used, p53 and p-p53 expression induced by HMGB1 were significantly down-regulated. Taken together, our data strongly indicated that HMGB1 might enhance p53 expression, which was associated with both the proliferative activity as well as apoptosis of T cells.

The aim of this study was to investigate the association between nadir platelet count and acute kidney injury (AKI) or 28-day all-cause mortality induced by hemorrhagic shock (HS), and to determine the cutoff value of nadir platelet count in HS clinical practice. This retrospective study included hospitalized patients enrolled in a tertiary-care teaching hospital from January 1, 2010 to December 31, 2015. Clinical data from HS admitted to the intensive care unit (ICU) were evaluated. Nadir platelet count was defined as the lowest values in the first 48 h. Multivariate logistic regression and Cox proportional hazards regression were used to assess the correlation between nadir platelet count and AKI or 28-day all-cause mortality induced by HS, respectively; the area under receiver operating characteristic (AU-ROC) and Youde's index were used to determine the optimal cutoff value of nadir platelet count. Kaplan-Meier's method and log-rank test were assessed for the 28-day all-cause mortality in AKI and non-AKI groups. Of 1589 patients screened, 84 patients (mean age,37.1 years; 58 males) were included in the primary analysis in which 30 patients with AKI. Multiple logistic results indicated that nadir platelet count was a risk factor of AKI (OR = 0.71,95% confidence interval [CI] 0.54-0.93, P < 0.05). Cox regression analysis revealed that nadir platelet count was independent risk factors for 28-day all-cause mortality (Hazard ratios [HR]0.89,95%CI 0.76-0.99, P < 0.05). Kaplan-Meier curve showed that 28-day all-cause mortality was significantly higher in patients with AKI than non-AKI (P < 0.001).These results suggest that nadir platelet count in the first 48 h is a new biomarker for AKI and 28-day all-cause mortality induced by HS. Moreover, the risk for AKI and 28-day all-cause mortality in HS patients decreased by 29% and 11%, respectively, for every 10 × 109/L increase in platelet count. Additional studies are needed to investigate whether elevation of nadir platelet count reduces the risk in different genders.

Tumor necrosis factor-α induced protein 8 like-2 (TNFAIP8L2, TIPE2) is a lately discovered negative regulator of innate immunity and cellular immunity. The present study was designed to investigate whether naturally occurring dendritic cells (DCs) could express TIPE2 mRNA/protein and its potential significance. Expressions of co-stimulatory molecules on DC surface and cytokines were analyzed to assess the functional role of TIPE2 in controlling DC maturation as well as activation. The activated DCs were assessed for their capacity to stimulate the proliferation and differentiation of T cells. It was found that TIPE2 was a cytoplasmic protein expressed in DCs, and the percentage of DCs which expressed co-stimulatory molecules and cytokines were obviously up-regulated when TIPE2 gene silenced by siRNA in vitro and in vivo. DCs undergone TIPE2 knockdown were found to promote the maturation of DCs, T-cell proliferation as well as differentiation, and they were significantly elevated IL-2 level and intranuclear NF-AT activation. Conversely, in over-expressing TIPE2 DC cells, it could inhibit T-cell proliferation and differentiation, and markedly down-regulate IL-2 expression and intranuclear NF-AT activation after scald injury. The results suggested that TIPE2 appeared to be a critical immunoregulatory molecule which affected DC maturation and subsequent T-cell mediated immunity.

Sepsis with subsequent multiple-organ dysfunction is a distinct systemic inflammatory response to concealed or obvious infection, and it is a leading cause of death in intensive care units. Thus, one of the key goals in critical care medicine is to develop novel therapeutic strategies that will affect favorably on outcome of septic patients. In addition to systemic response to infection, apoptosis is implicated to be an important mechanism of the death of immune cells, including neutrophils, macrophages, T lymphocytes, and dendritic cells, and it is usually followed by the development of multiple-organ failure in sepsis. The implication of apoptosis of immune cells is now highlighted by multiple studies that demonstrate that prevention of cell apoptosis can improve survival in relevant animal models of severe sepsis. In this review, we focus on major apoptotic death pathways and molecular mechanisms that regulate apoptosis of different immune cells, and advances in these areas that may be translated into more promising therapies for the prevention and treatment of severe sepsis.

With both in vivo and in vitro experiments, the present study was conducted to investigate the effect of regulatory T cell (Treg) on promoting T-lymphocyte apoptosis and its regulatory mechanism through transforming growth factor-beta (TGF-β1) signaling in mice. A murine model of polymicrobial sepsis was reproduced by cecal ligation and puncture (CLP); PC61 and anti-TGF-β antibodies were used to decrease counts of CD4(+)CD25(+) Tregs and inhibit TGF-β activity, respectively. Splenic CD4(+)CD25(+) Tregs and CD4(+)CD25(-) T cells were isolated. Phenotypes, including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), forkhead/winged helix transcription factor p3 (Foxp3), and TGFβ1(m+), as well as the apoptotic rate of CD4(+)CD25(-) T cell, were analyzed by flow cytometry. Real-time reverse transcription-polymerase chain reaction was performed to determine mRNA expression of TGF-β1, and the expressions of Smad2/Smad3, Bcl-2 superfamily members of Bcl-2/Bim, cytochrome C, the mitochondrial membrane potential, and caspases in CD4(+)CD25(-) T cells were simultaneously determined. After treatment with PC61 or anti-TGF-β antibody, CTLA-4, Foxp3, and TGFβ1(m+) expressions of CD4(+)CD25(+) Tregs were markedly decreased in comparison to that of the CLP group and the apoptosis rate of CD4(+)CD25(-) T cells was significantly positively correlated with the expression of TGF-β1. Meanwhile, levels of P-Smad2/P-Smad3, proapoptotic protein Bim, cytochrome C, and activity of caspase-3, -8, -9 were downregulated, whereas the mitochondrial membrane potential and antiapoptotic protein Bcl-2 expression were restored. Taken together, our data indicated that the TGF-β1 signal could be partly involved in the apoptosis of CD4(+)CD25(-) T cells promoted by CD4(+)CD25(+) Tregs, therefore inhibition of TGF-β1 expression may provide a novel strategy for the improvement of host immunosuppression following sepsis.

Sepsis is defined as severe systemic inflammation in response to invading pathogens, or an uncontrolled hyperinflammatory response, as mediated by the release of various proinflammatory mediators. Although some patients may die rapidly from septic shock accompanied by an overwhelming systemic inflammatory response syndrome (SIRS) triggered by a highly virulent pathogen, most patients survive the initial phase of sepsis, showing multiple organ damage days or weeks later. These patients often demonstrate signs of immune suppression accompanied by enhanced inflammation. Sepsis is a result of a complex process; there is interaction of various pathways, such as inflammation, immunity, coagulation, as well as the neuroendocrine system. This treatise is an attempt to provide a summary of several key regulatory mechanisms and to present the currently recognized molecular pathways that are involved in the pathogenesis of sepsis.

Sepsis with subsequent multiple organ dysfunction is a pronounced systemic inflammatory response to concealed or known infection and is a leading cause of death in intensive care units. The survival rate of severe sepsis and septic shock has not markedly improved in recent decades despite a great number of receptors and molecules involved in its pathogenesis have been found and taken as therapeutic targets. It is essential to thoroughly understand the host cell-mediated immunity involved in the development of sepsis and sepsis-related organ injury. Recent studies indicate that innate immune cells (such as neutrophils, macrophages, dendritic cells, T lymphocytes, regulatory T cells, and natural killer T cells) play pivotal roles in the maintenance of peripheral homeostasis and regulation of immune responses during sepsis. Therefore, an understanding of the biological significance and pathophysiological roles of different cell populations might gain novel insights into the immunoregulatory mechanisms of sepsis. In this review, we focus on major immune cells that may play potential roles in the contribution of new therapeutic approaches for sepsis.

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.

Sepsis with subsequent multiple organ dysfunction is a distinctly systemic inflammatory response to concealed or known infection and is a leading cause of death in intensive care units. In the initial stage of sepsis, a phase of immune activation can be evident, but a marked apoptosis-induced depletion of lymphocytes and a nonspecific anergy of immune function after severe trauma and burns might be responsible for the increased susceptibility of the host to subsequent septic complications. Recent studies indicated that negative regulation of immune function plays a pivotal role in the maintenance of peripheral homeostasis and regulation of immune responses; therefore, an understanding of the basic pathways might give rise to novel insights into the mechanisms of sepsis and immune homeostasis. This review is an attempt to provide a summary of the different pathways of negative regulation that are involved in the pathogenesis of sepsis, secondary to acute insults.

Tumor necrosis factor-α induced protein 8 like-2 (TNFAIP8L2, TIPE2), a lately discovered negative regulator of innate immunity and cellular immunity, shares considerable sequence homology with members of the tumor necrosis factor-α induced protein 8 (TNFAIP8) family. It is preferentially expressed in lymphoid-derived and marrow-derived cells. However, it is unclear whether TIPE2 is expressed in the regulatory T cells (Tregs) to contribute to its negative regulatory property in immune response. The present study was designed to examine whether naturally occurring CD4(+)CD25(+) Tregs isolated from murine spleens expressed TIPE2 by the use of Western blot and reverse transcription-polymerase chain reaction (RT-PCR). Based on the expression of cell surface molecules, including cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on CD4(+)CD25(+) Tregs, and cytokines including interleukin (IL)-10 as well as transforming growth factor (TGF)-β were analyzed to investigate the functional role of TIPE2 in controlling suppressive activity of CD4(+)CD25(+) Tregs. Meanwhile, IL-2, the ratio of interferon (IFN)-γ/IL-4 in CD4(+)CD25(+)Treg/CD4(+)CD25(-) T cell coculture supernatant and nuclear factor of activated T cells (NF-AT) activation in T lymphocytes were determined to examine the effects of TIPE2 on the T-cell proliferation and differentiation induced by CD4(+)CD25(+) Tregs. It was found that TIPE2 was a cytoplasmic protein expressed in CD4(+)CD25(+) Tregs, and cell surface molecules as well as cytokines (IL-10, TGF-β) expressions were significantly down-regulated when TIPE2 gene silenced by siRNA. On the other hand, CD4(+)CD25(+) Tregs treated with TIPE2 knock-down promoted T-cell proliferation as well as differentiation, and markedly upregulated IL-2 expression and intranuclear NF-AT activation. The results suggested that TIPE2 appeared to be a critical immunoregulatory molecule involved in immunosuppressive function of CD4(+)CD25(+) Tregs.