The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)inductio...The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.展开更多
BACKGROUND The imbalance of Th17/Treg cells and the IL-23/IL-17 axis have been confirmed to be associated with sepsis and various inflammatory diseases. Early enteral nutrition (EEN) can modulate the inflammatory resp...BACKGROUND The imbalance of Th17/Treg cells and the IL-23/IL-17 axis have been confirmed to be associated with sepsis and various inflammatory diseases. Early enteral nutrition (EEN) can modulate the inflammatory response, improve immune dysfunction, and prevent enterogenic infection in critically ill patients;however, the precise mechanisms remain unclear. Considering the important roles of Th17 and Treg lymphocytes in the development of inflammatory and infectious diseases, we hypothesized that EEN could improve the immune dysfunction in sepsis by maintaining a balanced Th17/Treg cell ratio and by regulating the IL- 23/IL-17 axis. AIM To investigate the effects of EEN on the Th17/Treg cell ratios and the IL-23/IL-17 axis in septic patients. METHODS In this prospective clinical trial, patients were randomly divided into an EEN or delayed enteral nutrition (DEN) group. Enteral feeding was started within 48 h in the EEN group, whereas enteral feeding was started on the 4th day in the DEN group. The Th17 and Treg cell percentages and the interleukin levels were tested on days 1, 3, and 7 after admission. The clinical severity and outcome variables were also recorded. RESULTS Fifty-three patients were enrolled in this trial from October 2017 to June 2018. The Th17 cell percentages, Th17/Treg cell ratios, IL-17, IL-23, and IL-6 levels of the EEN group were lower than those of the DEN group on the 7th day after admission (P < 0.05). The duration of mechanical ventilation and of the intensive care unit stay of the EEN group were shorter than those of the DEN group (P <0.05). However, no difference in the 28-d mortality was found between the two groups (P = 0.728). CONCLUSION EEN could regulate the imbalance of Th17/Treg cell ratios and suppress the IL- 23/IL-17 axis during sepsis. Moreover, EEN could reduce the clinical severity of sepsis but did not reduce the 28-d mortality of septic patients.展开更多
Lung infections are usually caused by pathogenic microorganisms and are a disease with high morbidity and mortality. In clinical practice, the use of broad-spectrum antibiotics has become increasingly common, but this...Lung infections are usually caused by pathogenic microorganisms and are a disease with high morbidity and mortality. In clinical practice, the use of broad-spectrum antibiotics has become increasingly common, but this has also led to the problem of antibiotic abuse and irrational use, which in turn has spawned the emergence of multidrug-resistant bacteria, making the treatment of lung infections more complex and difficult. In the human immune system, γδ T cells play a crucial role in defense against foreign pathogens and regulation of autoimmune responses. These cells act as a bridge between innate and adaptive immunity and can be rapidly activated in the early stages of infection to produce inflammatory factors and chemokines that attract other immune cells to the site of infection. Recent advances have shown that γδ T cells not only play a direct role in the innate immunity of pathogen infection, but are also involved in regulating the subsequent adaptive immune response. The aim of this review is to explore the mechanism of γδ T cells in lung infections and to summarize the current progress of clinical research, with the aim of providing new scientific basis and therapeutic strategies for the treatment of lung infections.展开更多
Objective: To explore the expression of IL-27, Th17 cells and CD4+CD25+ regulatory T cells (Treg) as well as its associated cytokines in peripheral blood of patients with allergic rhinitis (AR). Method: From March 201...Objective: To explore the expression of IL-27, Th17 cells and CD4+CD25+ regulatory T cells (Treg) as well as its associated cytokines in peripheral blood of patients with allergic rhinitis (AR). Method: From March 2012 to May, the peripheral blood of 24 cases of AR patients (AR group) and 16 cases of healthy volunteers (control group) was collected, and the percentage of Th17 cells and Treg cells in the peripheral blood was detected by flow cytometry (FCM);the levels of IL-27, IL-17 and IL-10 in serum was detected by ELISA. Result: The percentage of Th17 cells in AR group and the control group was 1.76% ± 0.60% and 0.59% ± 0.17%, respectively. It was higher in AR group than in control group, and the difference between two groups was statistically significant (P 0.05). Conclusion: In the peripheral blood of AR patients there was a reduction of IL-27 level and imbalance of Th17/Treg cell function. IL-27 on Th17/Treg cells adjustment may play an important role on the pathogenesis of the AR.展开更多
γδT cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity.However,the metabolic requirements and regulation ofγδT-cell development and function remain poorly u...γδT cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity.However,the metabolic requirements and regulation ofγδT-cell development and function remain poorly understood.In this study,we investigated the role of liver kinase B1(Lkb1),a serine/threonine kinase that links cellular metabolism with cell growth and proliferation,inγδT-cell biology.Our findings demonstrate that Lkb1 is not only involved in regulatingγδT lineage commitment but also plays a critical role inγδT-cell effector function.Specifically,T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations inγδT-cell subsets in both the thymus and peripheral lymphoid tissues.Notably,loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4γδT cells,promoted the maturation of IL-17-producing Vγ6γδT cells,and led to the occurrence of fatal autoimmune hepatitis(AIH).Notably,clearance ofγδT cells or blockade of IL-17 significantly attenuated AIH.Mechanistically,Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity,accompanied by increased mTORC1 activation,thereby causing overactivation ofγδT cells and enhanced apoptosis.Interestingly,activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice.Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis ofγδT cells and preventing IL-17-mediated autoimmune diseases,providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymicγδT cells.展开更多
Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells(DCs)and T cells,ultimately leading to increased production of cytokines such as interleukin(IL)-23 and IL-17...Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells(DCs)and T cells,ultimately leading to increased production of cytokines such as interleukin(IL)-23 and IL-17A.It is established that the cGAS-STING pathway is essential for psoriatic inflammation,however,the specific role of cGAS-STING signaling in DCs within this context remains unclear.In this study,we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod(IMQ)-treated mice.Using a conditional Sting-knockout transgenic mouse model,we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17-and IFN-γ-producing T cells in psoriatic inflammation.Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells,and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model.Furthermore,we explored the therapeutic potential of the STING inhibitor C-176,which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response.Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.展开更多
CD4＋ helper T （TH） cells play crucial roles in immune responses. Recently a novel subset of TH cells, termed THIL-17, TH 17 or inflammatory TH （THi）, has been identified as critical mediators of tissue inflammati...CD4＋ helper T （TH） cells play crucial roles in immune responses. Recently a novel subset of TH cells, termed THIL-17, TH 17 or inflammatory TH （THi）, has been identified as critical mediators of tissue inflammation. These cells produce IL-17 （also called IL-17A） and IL-17F, two most homologous cytokines sharing similar regulations. Here we report that when overexpressed in 293T cells, IL-17 and IL-17F form not only homodimers but also heterodimers, which we name as IL-17A/F. Fully differentiated mouse THi cells also naturally secrete IL-17A/F as well as IL-17 and IL-17F homodimeric cytokines. Recombinant IL-17A/F protein exhibits intermediate levels of potency in inducing IL-6 and KC （CXCL 1） as compared to homodimeric cytokines. IL-17A/F regulation of IL-6 and KC expression is dependent on IL-17RA and TRAF6. Thus, IL-17A/F cytokine represents another mechanism whereby T cells regulate inflammatory responses and may serve as a novel target for treating various immune-mediated diseases.展开更多
基金National Natural Science Foundation of China(Grants Numbers 81902878 and 81971468).
文摘The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.
基金the National Natural Science Foundation of China,No.81701881the Nanjing Medical Science and Technology Development Foundation,No.YKK15098 and No.YKK17102
文摘BACKGROUND The imbalance of Th17/Treg cells and the IL-23/IL-17 axis have been confirmed to be associated with sepsis and various inflammatory diseases. Early enteral nutrition (EEN) can modulate the inflammatory response, improve immune dysfunction, and prevent enterogenic infection in critically ill patients;however, the precise mechanisms remain unclear. Considering the important roles of Th17 and Treg lymphocytes in the development of inflammatory and infectious diseases, we hypothesized that EEN could improve the immune dysfunction in sepsis by maintaining a balanced Th17/Treg cell ratio and by regulating the IL- 23/IL-17 axis. AIM To investigate the effects of EEN on the Th17/Treg cell ratios and the IL-23/IL-17 axis in septic patients. METHODS In this prospective clinical trial, patients were randomly divided into an EEN or delayed enteral nutrition (DEN) group. Enteral feeding was started within 48 h in the EEN group, whereas enteral feeding was started on the 4th day in the DEN group. The Th17 and Treg cell percentages and the interleukin levels were tested on days 1, 3, and 7 after admission. The clinical severity and outcome variables were also recorded. RESULTS Fifty-three patients were enrolled in this trial from October 2017 to June 2018. The Th17 cell percentages, Th17/Treg cell ratios, IL-17, IL-23, and IL-6 levels of the EEN group were lower than those of the DEN group on the 7th day after admission (P < 0.05). The duration of mechanical ventilation and of the intensive care unit stay of the EEN group were shorter than those of the DEN group (P <0.05). However, no difference in the 28-d mortality was found between the two groups (P = 0.728). CONCLUSION EEN could regulate the imbalance of Th17/Treg cell ratios and suppress the IL- 23/IL-17 axis during sepsis. Moreover, EEN could reduce the clinical severity of sepsis but did not reduce the 28-d mortality of septic patients.
文摘Lung infections are usually caused by pathogenic microorganisms and are a disease with high morbidity and mortality. In clinical practice, the use of broad-spectrum antibiotics has become increasingly common, but this has also led to the problem of antibiotic abuse and irrational use, which in turn has spawned the emergence of multidrug-resistant bacteria, making the treatment of lung infections more complex and difficult. In the human immune system, γδ T cells play a crucial role in defense against foreign pathogens and regulation of autoimmune responses. These cells act as a bridge between innate and adaptive immunity and can be rapidly activated in the early stages of infection to produce inflammatory factors and chemokines that attract other immune cells to the site of infection. Recent advances have shown that γδ T cells not only play a direct role in the innate immunity of pathogen infection, but are also involved in regulating the subsequent adaptive immune response. The aim of this review is to explore the mechanism of γδ T cells in lung infections and to summarize the current progress of clinical research, with the aim of providing new scientific basis and therapeutic strategies for the treatment of lung infections.
文摘Objective: To explore the expression of IL-27, Th17 cells and CD4+CD25+ regulatory T cells (Treg) as well as its associated cytokines in peripheral blood of patients with allergic rhinitis (AR). Method: From March 2012 to May, the peripheral blood of 24 cases of AR patients (AR group) and 16 cases of healthy volunteers (control group) was collected, and the percentage of Th17 cells and Treg cells in the peripheral blood was detected by flow cytometry (FCM);the levels of IL-27, IL-17 and IL-10 in serum was detected by ELISA. Result: The percentage of Th17 cells in AR group and the control group was 1.76% ± 0.60% and 0.59% ± 0.17%, respectively. It was higher in AR group than in control group, and the difference between two groups was statistically significant (P 0.05). Conclusion: In the peripheral blood of AR patients there was a reduction of IL-27 level and imbalance of Th17/Treg cell function. IL-27 on Th17/Treg cells adjustment may play an important role on the pathogenesis of the AR.
基金Natural Science Foundation of China(to M.Y.,82271754 and 82071737,to Z.Y.,32030036,to Q.Y.,32000615,and to P.F.,82301974)China Postdoctoral Science Foundation(to P.F.,2023M741377)+1 种基金Guangdong Basic and Applied Basic Research Fund(to Q.Y.,2023A1515012582,to P.F.,2022A1515110217,and to G.C.,2023B1515020018)111 Project(to Z.Y.,B16021).
文摘γδT cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity.However,the metabolic requirements and regulation ofγδT-cell development and function remain poorly understood.In this study,we investigated the role of liver kinase B1(Lkb1),a serine/threonine kinase that links cellular metabolism with cell growth and proliferation,inγδT-cell biology.Our findings demonstrate that Lkb1 is not only involved in regulatingγδT lineage commitment but also plays a critical role inγδT-cell effector function.Specifically,T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations inγδT-cell subsets in both the thymus and peripheral lymphoid tissues.Notably,loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4γδT cells,promoted the maturation of IL-17-producing Vγ6γδT cells,and led to the occurrence of fatal autoimmune hepatitis(AIH).Notably,clearance ofγδT cells or blockade of IL-17 significantly attenuated AIH.Mechanistically,Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity,accompanied by increased mTORC1 activation,thereby causing overactivation ofγδT cells and enhanced apoptosis.Interestingly,activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice.Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis ofγδT cells and preventing IL-17-mediated autoimmune diseases,providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymicγδT cells.
基金supported by China National Natural Science Foundation(grant nos.82374445,82303061,82305233 and 82373179)Shanghai Shuguang Scholar(grant no.22SG42)+3 种基金Scientific research project of Shanghai Municipal Health Commission(grant no.20224Z0019)Key Discipline Construction Project of Shanghai Three Year Action Plan for Strengthening the Construction of Public Health System(grant no.GWVI-11.1-24)High-level Chinese Medicine Key Discipline Construction Project(Integrative Chinese and Western Medicine Clinic)of National Administration of TCM(grant no.zyyzdxk-2023065)Evidence-based dermatology base sponsored by state Administration of Traditional Chinese medicine.
文摘Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells(DCs)and T cells,ultimately leading to increased production of cytokines such as interleukin(IL)-23 and IL-17A.It is established that the cGAS-STING pathway is essential for psoriatic inflammation,however,the specific role of cGAS-STING signaling in DCs within this context remains unclear.In this study,we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod(IMQ)-treated mice.Using a conditional Sting-knockout transgenic mouse model,we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17-and IFN-γ-producing T cells in psoriatic inflammation.Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells,and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model.Furthermore,we explored the therapeutic potential of the STING inhibitor C-176,which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response.Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.
文摘CD4＋ helper T （TH） cells play crucial roles in immune responses. Recently a novel subset of TH cells, termed THIL-17, TH 17 or inflammatory TH （THi）, has been identified as critical mediators of tissue inflammation. These cells produce IL-17 （also called IL-17A） and IL-17F, two most homologous cytokines sharing similar regulations. Here we report that when overexpressed in 293T cells, IL-17 and IL-17F form not only homodimers but also heterodimers, which we name as IL-17A/F. Fully differentiated mouse THi cells also naturally secrete IL-17A/F as well as IL-17 and IL-17F homodimeric cytokines. Recombinant IL-17A/F protein exhibits intermediate levels of potency in inducing IL-6 and KC （CXCL 1） as compared to homodimeric cytokines. IL-17A/F regulation of IL-6 and KC expression is dependent on IL-17RA and TRAF6. Thus, IL-17A/F cytokine represents another mechanism whereby T cells regulate inflammatory responses and may serve as a novel target for treating various immune-mediated diseases.
