TNF,p38 MAPK与细胞凋亡

丝裂素活化的蛋白激酶(MAPK)是细胞内主要的信号转导系统之一.细胞运用这一系统将胞外信号传递给胞核,参与和影响细胞的多种生理病理过程.近年来发现一类新的MAPK通路--p38 MAPK信号通路,它不仅在炎症、应激反应中具有重要作用,还参与细胞的存活、分化和凋亡等过程.p38 MAPK信号通路与TNF共同参与了对细胞凋亡的调控.p38 MAPK可以上调TNF的表达,进而诱导细胞凋亡;同时TNF可以激活p38 MAPK通路,但活化后的p38 MAPK在细胞凋亡中的作用还不明确.此通路为临床治疗疾病提供了新思路.     

MAPK信号转导在成骨细胞分化中的作用

MAPK信号转导途径是细胞外信号引起细胞核内反应的通道之一 ,通过三级酶促级联反应 ,最终磷酸化靶蛋白 ,激活转录因子 ,调节特定的基因表达。近年研究表明 ERK、P38和 JNK通路参与了成骨细胞分化增殖的信号转导过程。本文介绍了这三种 MAPK通路的基本概况 ,并着重阐述其在成骨细胞分化中的作用     

ERK5 MAPK信号转导通路研究进展

MAPK信号转导通路是一条关键的调节细胞增生和凋亡的通路。MAPK信号转导通路的异常与多种肿瘤或增殖性疾病关系密切。因此,MAPK是潜在的治疗分子靶。目前已鉴定了4条MAPK信号转导通路：ERK1／2、JNK、P38和ERK5。其中ERK5信号途径是相对较新的一条通路。本文拟从ERK5信号转导通路的性质特点、功能以及与人类疾病关系各方面分别加以综述。     

神经病理性疼痛中星形胶质细胞被激活后的p38丝裂原活化蛋白激酶信号转导通路

目的:探索神经性病理痛中星形胶质细胞被激活后的p38丝裂原活化蛋白激酶(p38MAPK)信号转导通路.方法:SD大鼠分为坐骨神经慢性结扎模型组(CCI组)和假手术组(Sham组),并于术前ld和术后1、3、7、14d取第4～5腰段脊髓做石蜡切片,免疫荧光组织化学标记p38MAPK的表达,免疫荧光双标技术检测其与脊髓神经细胞之间的关系.结果:CCI组术后术侧脊髓背角p38MAPK免疫阳性细胞数量增多;p38MAPK平均荧光强度明显增高并在术后第7天显示为最高.p38MAPK和小胶质细胞在CCI组脊髓背角术侧的分布有较好的一致性.结论:在神经病理性疼痛巾,p38MAPK信号转导通路被激活但未参与星形胶质细胞的痛觉信号转导.     

p38 MAPK信号通路参与受体介导的细胞内吞的调控

目的：观察p38 MAPK信号转导通路在受体介导的细胞内吞中的作用。方法：利用Alexa 594标记的转铁蛋白作为受体介导的内吞作用的观察指标，来研究p38特异性抑制剂SB203580或ERK通路特异性抑制剂PD98059预处理以及p38基因敲除对该过程的影响。 结果：在受体介导的细胞内吞中，p38被磷酸化激活。SB203580的预处理或p38基因的敲除都能阻断受体介导的细胞内吞，而PD98059的预处理对该过程没有影响。 结论：p38 MAPK信号转导通路参与了受体介导的细胞内吞的调控。     

c-Jun氨基末端激酶与caspase在细胞凋亡中的作用及相互关系

丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)是信号从细胞表面转导到细胞核内部的重要传递者.在真核细胞中,已确定出4条MAPK信号转导通路[1],即细胞外调节蛋白激酶(extracellular regulated protein kinases,ERK) 通路、c-Jun 氨基末端激酶(c-Jun N-terminal kinase,JNK)通路、P38通路及ERK5通路.JNK也称为应激蛋白激酶,参与应激反应和细胞死亡[2].     

MAPK信号转导通路与肿瘤细胞分化

丝裂素活化蛋白激酶 (MAPK)信号转导通路是近年来细胞信号转导方面最活跃的研究领域。该通路具有调控肿瘤细胞分化的功能 ,已确定出 4条MAPK信号转导通路 ,其中ERK(P42 /P44MAPK) ,SAPK/JNK ,p38MAPK三条通路与肿瘤细胞分化关系密切。     

p38 MAPK与内毒素性肺损伤

MAPK是信号由细胞表面转导到细胞内部的重要传递者,参与了LPS激活效应细胞产生活性物质的细胞内信号转导过程.p38 MAPK通过磷酸化转录因子引起多种相关基因转录,调控活性物质的表达,参与炎症反应过程.在信号通路水平阻断和调控p38 MAPK的表达将成为治疗急性肺损伤的新途径.     

c-Jun氨基末端激酶在脑缺血再灌注损伤中的作用

在生物体内,丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)是信号从细胞表面转导至细胞核内部的重要传递者,是一类丝/苏氨酸残基的蛋白激酶。目前在真核生物细胞中,已明确了4条MAPK信号转导通路,即细胞外信号调节蛋白激酶(extracellular signal-regulated protein kinases,ERK)通路、c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)通路、p38通路及ERK5通路。JNK信号通路作为MAPK信号通路中重要的通路之一,参与了多种生理、病理过程,目前诸多研究表明其在脑缺血/再灌注损伤过程中尤其是程序性细胞死亡过程中起着重要的调控作用,本文就近年来对JNK通路的研究及JNK在脑缺血再灌注诱导的细胞凋亡中的作用及机制作一综述。     

阻断4-1BB/4-1BBL通路在系统性红斑狼疮患者T淋巴细胞活化中的作用

目的 探讨协同刺激分子4-1BB/4-1BBL在系统性红斑狼疮(systemic lupus erythematosus,SLE)T淋巴细胞活化中的作用机制.方法 应用RT-PCR和Western blot方法检测体外培养20例SLE患者和20例正常对照者T淋巴细胞活化前后及应用抗4-1BB单抗阻断后p38 MAPK和NF-kB表达的变化.结果 SLE患者T淋巴细胞NF-kB mRNA和p38 MAPK mRNA表达及其蛋白水平明显高于正常对照组(P均＜0.01),活化后的表达进一步升高(P均＜0.01).阻断4-1BB/4-1BBL通路后SLE患者T淋巴细胞p38 MAPK mRNA及蛋白水平的表达均明显下降(P均＜0.01),但是NF-kB mRNA及蛋白水平的表达无明显变化(P＞0.05).结论 协同刺激分子4-1BB可能通过p38MAPK信号转导通路促使SLE患者T淋巴细胞的活化与增殖.     

内毒素诱导p38MAPK信号转导作用的研究进展

The diseases caused by endotoxin have seriously affected human health. Previous studies have shown that p38 MAPK pathway is involved in the intracellular signal transduction induced by lipopolysaccharide (LPS), which plays an important role in the activation of inflammation-related cells to release inflammation mediator. Recently there have been some progresses in the isoforms distribution, substrate, molecular mechanism of regulating the release of inflammatory mediators, cellular specific activation and levels of p38 MAPK.     

p38 mitogen-activated protein kinase (p38 MAPK)-mediated autoimmunity: Lessons to learn from ANCA vasculitis and pemphigus vulgaris

Evidence is beginning to accumulate that p38 mitogen activated protein kinase (p38 MAPK) signaling pathway plays an important role in the regulation of cellular and humoral autoimmune responses. The exact mechanisms and the degree by which the p38 MAPK pathway participates in the immune-mediated induction of diseases have started to emerge. This review discusses the recent advances in the molecular dissection of the p38 MAPK pathway and the findings generated by reports investigating its role in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and autoimmune hepatitis. Application of newly-developed protocols based on sensitive flow cytometric detection has proven to be a useful tool in the investigation of the phosphorylation of p38 MAPK within different peripheral blood mononuclear cell populations and may help us to better understand the enigmatic role of this signaling cascade in the induction of autoimmunity as well as its role in immunosuppressive-induced remission. Special attention is paid to reported data proposing a specific role for autoantibody-induced activation of p38 MAPK-mediated immunopathology in the pathogenesis of autoimmune blistering diseases and anti-neutrophilic antibody-mediated vasculitides.     

Autoantibodies in the autoimmune disease pemphigus foliaceus induce blistering via p38 mitogen-activated protein kinase-dependent signaling in the skin

Pemphigus foliaceus (PF) is a human autoimmune blistering disease in which a humoral immune response targeting the skin results in a loss of keratinocyte cell-cell adhesion in the superficial layers of the epidermal epithelium. In PF, desmoglein-1-specific autoantibodies induce blistering. Evidence is beginning to accumulate that activation of signaling may have an important role in the ability of pathogenic pemphigus IgGs to induce blistering and that both p38 mitogen-activated protein kinase (MAPK) and heat shock protein (HSP) 27 are part of this signaling pathway. This study was undertaken to investigate the ability of PF IgGs to activate signaling as well as the contribution of this signaling pathway to blister induction in an in vivo model of PF. Phosphorylation of both p38 MAPK and HSP25, the murine HSP27 homolog, was observed in the skin of PF IgG-treated mice. Furthermore, inhibition of p38 MAPK blocked the ability of PF IgGs to induce blistering in vivo. These results indicate that PF IgG-induced blistering is dependent on activation of p38 MAPK in the target keratinocyte. Rather than influencing the immune system, limiting the autoantibody-induced intracellular signaling response that leads to target end-organ damage may be a more viable therapeutic strategy for the treatment of autoimmune diseases. Inhibition of p38 MAPK may be an effective strategy for the treatment of PF.     

Down-regulation of p38 mitogen-activated protein kinase activation and proinflammatory cytokine production by mitogen-activated protein kinase inhibitors in inflammatory bowel disease

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD) characterized by chronic relapsing mucosal inflammation. Tumour necrosis factor (TNF)‐α, a known agonist of the mitogen‐activated protein kinase (MAPK) pathway, is a key cytokine in this process. We aimed first to determine whether p38 MAPK is activated in IBD inflamed mucosa, and then studied the effect of four different p38α inhibitory compounds on MAPK phosphorylation and secretion of proinflammatory cytokines by IBD lamina propria mononuclear cells (LPMCs) and organ culture biopsies. In vivo phospho‐p38α and p38α expression was evaluated by immunoblotting on intestinal biopsies from inflamed areas of patients affected by Crohn's disease and ulcerative colitis, and from normal mucosa of sex‐ and age‐matched control subjects. Both mucosal biopsies and isolated LPMCs were incubated with four different p38α selective inhibitory drugs. TNF‐α, interleukin (IL)‐1β and IL‐6 were measured in the organ and cell culture supernatants by enzyme‐linked immunosorbent assay. We found higher levels of phospho‐p38α in the inflamed mucosa of IBD patients in comparison to controls. All the p38α inhibitory drugs inhibited p38α phosphorylation and secretion of TNF‐α, IL‐1β and IL‐6 from IBD LPMCs and biopsies. Activated p38α MAPK is up‐regulated in the inflamed mucosa of patients with IBD. Additionally, all the p38α selective inhibitory drugs significantly down‐regulated the activation of the MAPK pathway and the secretion of proinflammatory cytokines.     

Involvement of the mannose receptor and p38 mitogen-activated protein kinase signaling pathway of the microdomain of the integral membrane protein after enteropathogenic Escherichia coli infection

The microdomain of the integral membrane protein (MIMP) has been shown to adhere to mucin and to antagonize the adhesion of enteropathogenic Escherichia coli (EPEC) to epithelial cells; however, the mechanism has not been fully elucidated. In this study, we further identified the receptor of MIMP on NCM460 cells and investigated the mechanism (the p38 mitogen-activated protein kinase [MAPK] pathway) following the interaction of MIMP and its corresponding receptor, mannose receptor. We first identified the target receptor of MIMP on the surfaces of NCM460 cells using immunoprecipitation-mass spectrometry technology. We also verified the mannose receptor and examined the degradation and activation of the p38 MAPK signaling pathway. The results indicated that MIMP adhered to NCM460 cells by binding to the mannose receptor and inhibited the phosphorylation of p38 MAPK stimulated after EPEC infection via inhibition of the Toll-like receptor 5 pathway. These findings indicated that MIMPs relieve the injury of NCM460 cells after enteropathogenic E. coli infection through the mannose receptor and inhibition of the p38 MAPK signaling pathway, both of which may therefore be potential therapeutic targets for intestinal diseases, such as inflammatory bowel disease.     

Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers

Sepsis resulting in multiorgan failure and death is still a major problem in intensive care medicine, despite extensive attempts to interfere in the supposed underlying mechanism of a deranged immune system. This is not only due to the persistent lacunae in knowledge about the immune system in sepsis but also due to the lack of sufficient instruments for intervention. Inhibitors of the p38 mitogen-activated protein kinase (p38MAPK) have been used to study the signalling pathway of the immune response. In vitro and animal studies have demonstrated that blocking p38MAPK could mitigate the pro-inflammatory response and improve survival after endotoxaemia. Using an endotoxaemia model in healthy human volunteers we evaluated the attenuation of clinical and cytokine response to endotoxin after inhibition of p38MAPK by an oral dose of RWJ-67657, a pyrindinyl imidazole. We measured the clinical parameters temperature, blood pressure and heart rate. The proinflammatory cytokines tumour necrosis factor-alpha, interleukin-6 and interleukin-8 were measured by ELISA at various points during a 24-h period. Drug toxicity was evaluated by routine clinical and laboratory examinations. After a single dose dose of RWJ-67657 the temperature and blood pressure response remained at the basal level. The inhibition of TNF-alpha, IL-6 and IL-8 response was a dose dependent. With the maximum dosage, reduction in peak serum levels of the proinflammatory cytokines was greater than 90%. There was no drug-related toxicity. Interpretation: We conclude that inhibition of p38MAPK by RWJ-67657 might be a tool to intervene in the deranged immune response in sepsis and other inflammatory diseases.     

Inhibition of p38 MAPK Reduces Expression of Vascular Endothelial Growth Factor in Allergic Airway Disease

Background

The p38 mitogen-activated protein kinase (MAPK) appears to play an important role in various pathophysiological responses and has been suggested to be involved in many processes considered critical to the inflammatory response and tissue remodeling. Bronchial asthma is a chronic inflammatory disorder of the airway accompanied by increased vascular permeability. Vascular endothelial growth factor (VEGF) is a potent stimulator of bronchial inflammation, airway remodeling, and physiologic dysregulation that augments antigen sensitization and T-helper type 2 cell (Th2)-mediated inflammation in allergic airway diseases. However, there are little data on the relationship between p38 MAPK signaling and VEGF expression in allergic airway disease.

Objective

This study aimed to investigate the role of p38 MAPK on the pathogenesis of allergic airway disease, more specifically in VEGF expression.

Methods

Using ovalbumin (OVA)-inhaled mice and a selective p38 MAPK inhibitor, SB 239063, the involvement of p38 MAPK in allergen-induced VEGF expression in the airway was evaluated.

Results

The increases of phosphorylation of p38 MAPK, VEGF protein expression, and vascular permeability in the lung after OVA inhalation were decreased substantially by the administration of SB 239063. In addition, SB 239063 significantly reduced the increase of Th2 cytokines and OVA-specific IgE. The inhibition of p38 MAPK or VEGF signaling prevented and also decreased the increases in the number of inflammatory cells and airway hyperresponsiveness in OVA-induced allergic airway disease.

Conclusions

These results indicate that inhibition of p38 MAPK may attenuate allergen-induced airway inflammation and vascular leakage through modulation of VEGF expression in mice.     

Suppression of cytokine production by glucocorticoids is mediated by MKP-1 in human lung epithelial cells

Mitogen-activated protein kinase phosphatase 1 (MKP-1) expression is induced by inflammatory factors and serves as an endogenous p38 MAPK suppressor to limit inflammatory response. Glucocorticoids are very effective anti-inflammatory drugs and they are used for the treatment of many inflammatory diseases, such as asthma and COPD. We investigated the role of MKP-1 in the inhibition of cytokine production by dexamethasone in human A549 bronchial epithelial cells. We found that dexamethasone increased MKP-1 expression, inhibited p38 MAPK phosphorylation, and suppressed TNF and MIP-3α production in A549 cells. Interestingly, the suppression of p38 MAPK phosphorylation and the inhibition of TNF expression by dexamethasone were attenuated in cells, where MKP-1 expression was silenced by siRNA. In conclusion, these data suggest that dexamethasone increases MKP-1 expression and this results in the suppression of p38 MAPK signaling leading to the inhibition of cytokine production in human bronchial epithelial cells. These results point to the role of MKP-1 as an important factor in the therapeutic effects of glucocorticoids in the treatment of inflammatory lung diseases.     

The selective cyclooxygenase-2 inhibitor rofecoxib suppresses brain inflammation and protects cholinergic neurons from excitotoxic degeneration in vivo

Brain inflammatory processes underlie the pathogenesis of Alzheimer's disease, and non-steroidal anti-inflammatory drugs have a protective effect in the disease. The aim of this work was to study in vivo whether attenuation of brain inflammatory response to excitotoxic insult by the selective cyclooxygenase-2 inhibitor, rofecoxib, may prevent neurodegeneration, as a contribution to a better understanding of the role inflammation plays in the pathology of Alzheimer's disease. We investigated, by immunohistochemical methods, glia reaction, the activation of p38 mitogen-activated protein kinase (p38MAPK) pathway with an antibody selective for the phosphorylated form of the enzyme and the number of choline acetyltransferase-positive neurons and, by in vivo microdialysis, cortical extracellular levels of acetylcholine following the injection of quisqualic acid into the right nucleus basalis of adult rats. Seven days after injection, a marked reduction in the number of choline acetyltransferase-positive neurons was found, along with an intense glia reaction, selective activation of p38MAPK at the injection site and a significant decrease in the extracellular levels of acetylcholine in the cortex ipsilateral to the injection site. The loss of cholinergic neurons persisted for at least up to 28 days. Rofecoxib (3 mg/kg/day, starting 1 h prior to injection of quisqualic acid) treatment for 7 days significantly attenuated glia activation and prevented the loss of choline acetyltransferase-positive cells and a decrease in cortical acetylcholine release. The prevention of cholinergic cell loss by rofecoxib occurred concomitantly with the inhibition of p38MAPK phosphorylation. Our findings suggest an important role of brain inflammatory reaction in cholinergic degeneration and demonstrate a neuroprotective effect of rofecoxib, presumably mediated through the inhibition of p38MAPK phosphorylation.     

p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation

Dendritic cells (DC) play a role in the regulation of immune responses to haptens, which in turn impact DC maturation. Whether beryllium (Be) is able to induce DC maturation and if this occurs via the MAPK pathway is not known. Primary monocyte-derived DCs (moDCs) models were generated from Be non-exposed healthy volunteers as a non-sensitized cell model, while PBMCs from BeS (Be sensitized) and CBD (chronic beryllium disease) were used as disease models. The response of these cells to Be was evaluated. The expression of CD40 was increased significantly (p < 0.05) on HLA-DP Glu69+ moDCs after 100 μM BeSO₄-stimulation. BeSO₄ induced p38MAPK phosphorylation, while IκB-α was degraded in Be-stimulated moDCs. The p38 MAPK inhibitor SB203580 blocked Be-induced NF-κB activation in moDCs, suggesting that p38MAPK and NF-κB are dependently activated by BeSO₄. Furthermore, in BeS and CBD subjects, SB203580 downregulated Be-stimulated proliferation in a dose-dependent manner, and decreased Be-stimulated TNF-α and IFNγ cytokine production. Taken together, this study suggests that Be-induces non-sensitized Glu69+ DCs maturation, and that p38MAPK signaling is important in the Be-stimulated DCs activation as well as subsequent T cell proliferation and cytokine production in BeS and CBD. In total, the MAPK pathway may serve as a potential therapeutic target for human granulomatous lung diseases.