NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells

BACKGROUND: NKX2-3 is associated with inflammatory bowel disease (IBD). NKX2-3 is expressed in microvascular endothelial cells and the muscularis mucosa of the gastrointestinal tract. Human intestinal microvascular endothelial cells (HIMECs) are actively involved in the pathogenesis of IBD and IBD-associated microvascular dysfunction. To understand the cellular function of NKX2-3 and its potential role underlying IBD pathogenesis, we investigated the genes regulated by NKX2-3 in HIMEC using cDNA microarray. METHODOLOGY/PRINCIPAL FINDINGS: NKX2-3 expression was suppressed by shRNA in two HIMEC lines and gene expression was profiled by cDNA microarray. Pathway Analysis was used to identify gene networks according to biological functions and associated pathways. Validation of microarray and genes expression in intestinal tissues was assessed by RT-PCR. NKX2-3 regulated genes are involved in immune and inflammatory response, cell proliferation and growth, metabolic process, and angiogenesis. Several inflammation and angiogenesis related signaling pathways that play important roles in IBD were regulated by NKX2-3, including endothelin-1 and VEGF-PI3K/AKT-eNOS. Expression levels of NKX2-3, VEGFA, PI3K, AKT, and eNOS are increased in intestinal tissues from IBD patients and expression levels of EDN1 are decreased in intestinal tissues from IBD patients. These results demonstrated the important roles of NKX2-3, VEGF, PI3K, AKT, eNOS, and EDN1 in IBD pathogenesis. Correlation analysis showed a positive correlation between mRNA expression of NKX2-3 and VEGFA and a negative correlation between mRNA expression of NKX2-3 and EDN1 in intestinal tissues from IBD patients. CONCLUSION/RELEVANCE: NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs.     

ERM蛋白在微血管内皮细胞通透性调控中的研究进展

埃兹蛋白(Ezrin)/根蛋白(Radixin)/膜突蛋白(Moesin)(ERM)是细胞膜与胞内骨架的连接蛋白,具有高度同源性。细胞外刺激因子可通过多种信号通路磷酸化ERM蛋白,使细胞骨架重构,从而调控微血管内皮细胞通透性,在感染、炎症、代谢异常等病理过程中发挥作用。ERM功能调节的一个重要环节就是其羧基末端苏氨酸残基磷酸化后引起ERM构象的改变,暴露的羧基末端尾部的肌动蛋白(actin)-细胞骨架结合位点;故通过ERM的桥接作用,可将肌动蛋白微丝与细胞膜相连,使血管内皮细胞屏障功能发生变化。目前已知能使ERM磷酸化的激酶有蛋白激酶C(PKC)、促分裂原活化蛋白激酶(MAPK)、Rho相关激酶(ROCK),分别通过p38-MAPK、Rho/ROCK、PKC信号通路参与微血管内皮屏障功能的调控。本文旨在阐述ERM及其相关信号通路在微血管内皮细胞通透性调控中发挥的作用。     

Dietary quercetin ameliorates experimental colitis in mouse by remodeling the function of colonic macrophages via a heme oxygenase-1-dependent pathway

Inflammatory bowel disease (IBD) results from a chronic intestinal inflammation and tissue destruction via an aberrant immune-driven inflammatory response towards an altered gut microbiota. Dietary intervention is becoming an attractive avenue for the therapy of colitis because diet is a key determinant of the mucosal immune response. Quercetin (QCN) is the most common in nature and the major representative of dietary antioxidant flavonoids, which has been demonstrated to influence the progression of colitis. However, the underlying mechanism of QCN on intestinal immunomodulation remains unclear. Here, our study demonstrated dietary QCN could ameliorate experimental colitis in part by modulating the anti-inflammatory effects and bactericidal capacity of macrophages via Heme oxygenase-1 (Hmox1, HO-1) dependent pathway. It suggested that QCN might restore the proper intestinal host-microbe relationship to ameliorate the colitis via rebalancing the pro-inflammatory, anti-inflammatory and bactericidal function of enteric macrophages. Hence, modulating the function of intestinal macrophages with dietary administration of QCN to restore the immunological hemostasis and rebalance the enteric commensal flora is a potential and promising strategy for IBD therapy.     

Deficient iNOS in inflammatory bowel disease intestinal microvascular endothelial cells results in increased leukocyte adhesion

Microvascular endothelial cells play a key role in inflammation by undergoing activation and recruiting circulating immune cells into tissues and foci of inflammation, an early and rate-limiting step in the inflammatory process. We have previously [Binion et al., Gastroenterology112:1898-1907, 1997] shown that human intestinal microvascular endothelial cells (HIMEC) isolated from surgically resected inflammatory bowel disease (IBD) patient tissue demonstrate significantly increased leukocyte binding in vitro compared to normal HIMEC. Our studies [Binion et al., Am. J. Physiol.275 (Gastrointest. Liver Physiol. 38):G592-G603, 1998] have also demonstrated that nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) normally plays a key role in downregulating HIMEC activation and leukocyte adhesion. Using primary cultures of HIMEC derived from normal and IBD patient tissues, we sought to determine whether alterations in iNOS-derived NO production underlies leukocyte hyperadhesion in IBD. Both nonselective (N(G)-monomethyl-L-arginine) and specific (N-Iminoethyl-L-lysine) inhibitors of iNOS significantly increased leukocyte binding by normal HIMEC activated with cytokines and lipopolysaccharide (LPS), but had no effect on leukocyte adhesion by similarly activated IBD HIMEC. When compared to normal HIMEC, IBD endothelial cells had significantly decreased levels of iNOS mRNA, protein, and NO production following activation. Addition of exogenous NO by co-culture with normal HIMEC or by pharmacologic delivery with the long-acting NO donor detaNONOate restored a normal leukocyte binding pattern in the IBD HIMEC. These data suggest that loss of iNOS expression is a feature of chronically inflamed microvascular endothelial cells, which leads to enhanced leukocyte binding, potentially contributing to chronic, destructive inflammation in IBD.     

The role of heme oxygenase and carbon monoxide in inflammatory bowel disease

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease, is a chronic and recurrent inflammatory disorder of the intestinal tract. Since the precise pathogenesis of IBD remains unclear, it is important to investigate the pathogenesis of IBD and to evaluate new anti-inflammatory strategies. Recent evidence suggests that heme oxygenase-1 (HO-1) plays a critical protective role during the development of intestinal inflammation. In fact, it has been demonstrated that the activation of HO-1 may act as an endogenous defensive mechanism to reduce inflammation and tissue injury in various animal intestinal injury models induced by ischemia-reperfusion, indomethacin, lipopolysaccharide-associated sepsis, trinitrobenzene sulfonic acid or dextran sulfate sodium. In addition, carbon monoxide (CO) derived from HO-1 has been shown to be involved in the regulation of intestinal inflammation. Furthermore, administration of a low concentration of exogenous CO has a protective effect against intestinal inflammation. These data suggest that HO-1 and CO may be novel therapeutic molecules for patients with gastrointestinal inflammatory diseases. In this review, we present what is currently known regarding the role of HO-1 and CO in intestinal inflammation.     

Role of sphingosine-1-phosphate receptors in vascular injury of inflammatory bowel disease

Sphingosine-1-phosphate receptors (S1PRs) have an impact on the intestinal inflammation of inflammatory bowel disease (IBD) by regulating lymphocyte migration and differentiation. S1PR modulators as an emerging therapeutic approach are being investigated for the treatment of IBD. However, the role of S1PRs in intestinal vessels has not drawn much attention. Intestinal vascular damage is one of the major pathophysiological features of IBD, characterized by increased vascular density and impaired barrier function. S1PRs have pleiotropic effects on vascular endothelial cells, including proliferation, migration, angiogenesis and barrier homeostasis. Mounting evidence shows that S1PRs are abnormally expressed on intestinal vascular endothelial cells in IBD. Unexpectedly, S1PR modulators may damage intestinal vasculature, for example increase intestinal bleeding; therefore, S1PRs are thought to be involved in the regulation of intestinal vascular function in IBD. However, little is understood about how S1PRs regulate intestinal vascular function and participate in the initiation and progression of IBD. In this review, we summarize the pathogenic role of S1PRs in and the underlying mechanisms behind the intestinal vascular injury in IBD in order for improving IBD practice including S1PR-targeted therapies.     

Protective signaling by activated protein C is mechanistically linked to protein C activation on endothelial cells

Activated protein C (APC) has endothelial barrier protective effects that require binding to endothelial protein C receptor (EPCR) and cleavage of protease activated receptor-1 (PAR1) and that may play a role in the anti-inflammatory action of APC. In this study we investigated whether protein C (PC) activation by thrombin on the endothelial cell surface may be linked to efficient protective signaling. To minimize direct thrombin effects on endothelial permeability we used the anticoagulant double mutant thrombin W215A/E217A (WE). Activation of PC by WE on the endothelial cell surface generated APC with high barrier protective activity. Comparable barrier protective effects by exogenous APC required a 4-fold higher concentration of APC. To demonstrate conclusively that protective effects in the presence of WE are mediated by APC generation and not direct signaling by WE, we used a PC variant with a substitution of the active site serine with alanine (PC S360A). Barrier protective effects of a low concentration of exogenous APC were blocked by both wildtype PC and PC S360A, consistent with their expected role as competitive inhibitors for APC binding to EPCR. WE induced protective signaling only in the presence of wild type PC but not PC S360A and PAR1 cleavage was required for these protective effects. These data demonstrate that the endogenous PC activation pathway on the endothelial cell surface is mechanistically linked to PAR1-dependent autocrine barrier protective signaling by the generated APC. WE may have powerful protective effects in systemic inflammation through signaling by the endogenously generated APC.     

Intestinal epithelial cell signalling and chronic inflammation: From the proteome to specific molecular mechanisms

Advancing knowledge regarding the cellular mechanisms of intestinal inflammation has led to a better understanding of the disease pathology in patients with inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis. It has become clear from numerous studies that enteric bacteria are a critical component in the development and prevention/treatment of chronic intestinal inflammation. An emerging new paradigm suggests that changes in the homeostasis of bacteria- and host-derived signal transduction at the intestinal epithelial cell (IEC) level may lead to a break in barrier function and the development of adaptive immune disturbances. The functional loss of anti-inflammatory host-derived signals in the gut including the immunosuppressive cytokines Interleukin 10 (IL-10) and transforming growth factor (TGF)-beta are of high relevance to the pathogenesis of IBD. The development of analytical tools including two-dimensional (2D) high-resolution protein separation techniques and peptide mass fingerprinting via high-sensitivity mass-spectrometers (MS) allows the quantitative assessment of protein expression changes in disease-relevant cell types. By using these advanced methods, the characterization of the epithelial cell proteome from murine models of experimental colitis and human IBD patients identified novel disease-related mechanisms with respect to the regulation of the glucose-regulated endoplasmic reticulum stress response protein 78 (grp-78). In conclusion, the identification and functional analysis of differentially expressed proteins in purified intestinal target cell types will help to add important insights to the understanding of the molecular pathogenesis of these immune-mediated chronic intestinal disorders.     

Inhibition of RICK/nuclear factor-kappaB and p38 signaling attenuates the inflammatory response in a murine model of Crohn disease

Nuclear factor-kappaB (NF-kappaB) is the main target of anti-inflammatory therapies in human chronic inflammatory bowel diseases (IBD), Crohn disease, and ulcerative colitis. This study investigates the molecular anti-inflammatory mechanisms of SB203580, an inhibitor of the mitogen-activated protein kinase p38. The murine trinitrobenzene sulfonic acid (TNBS)-induced colitis was used as an established model of human Crohn disease. Here we show that SB203580 improved the clinical condition, reduced intestinal inflammation, and suppressed mRNA levels of pro-inflammatory cytokines elevated upon induction of colitis. Besides p38 kinase activity, the "classical" IkappaB-dependent NF-kappaB pathway was strongly up-regulated during colitis induction, whereas the "alternative" was not. SB203580 treatment resulted in a drastic down-regulation of p38 and NF-kappaB activity. The molecular analysis of NF-kappaB activation revealed that Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK), a key component of a pathway leading to NF-kappaB induction, is also strongly inhibited by SB203580. In contrast, SB203580 had no effect on the colitis-induced activation of other potential NF-kappaB-activating kinases such as protein kinase C (PKC), mixed lineage kinase 3, and the oncogene product Cot/TPL2. Thus, the inhibitory effect of SB203580 on NF-kappaB activation is to a large extent mediated by RICK inhibition. RICK is the effector kinase of the intracellular receptor of bacterial peptidoglycan NOD. Because bacterial products are suggested to be the key pathogenic agents triggering IBD, inhibition of the NOD/RICK pathway may serve as a novel target of future therapies in human IBD.     

The endothelial cell protein C receptor (EPCR) functions as a primary receptor for protein C activation on endothelial cells in arteries, veins, and capillaries.

Plasma protein C functions as an anticoagulant when it is converted to the active form of serine protease. Protein C activation has been found to be mediated by the endothelial cell surface thrombin/thrombomodulin (TM) complex. In addition, we recently identified the endothelial cell protein C/activated protein C receptor (EPCR) which is capable of high-affinity binding for protein C. In this study, we established monoclonal antibodies (mAbs) against EPCR including several function blocking antibodies. Immunohistochemical analysis using these mAbs demonstrated that EPCR is widely expressed in the endothelial cells of arteries, veins, and capillaries in the lung, heart, and skin. Function blocking anti-EPCR mAbs strongly inhibited protein C activation mediated by primary cultured arterial endothelial cells which express abundant EPCR. Anti-EPCR mAbs also prevent protein C activation mediated by microvascular endothelial cells. These results indicate that EPCR functions as an important regulator for the protein C pathway in various types of vessels.     

Protein C is an autocrine growth factor for human skin keratinocytes

The protein C (PC) pathway plays an important role in coagulation and inflammation. Many components of the PC pathway have been identified in epidermal keratinocytes, including endothelial protein C receptor (EPCR), which is the specific receptor for PC/activated PC (APC), but the core member of this pathway, PC, and its function in keratinocytes has not been defined. In this study, we reveal that PC is strongly expressed by human keratinocytes at both gene and protein levels. When endogenous PC was blocked by siRNA the proliferation of keratinocytes was significantly decreased. This inhibitory effect was restored by the addition of recombinant APC. PC siRNA treatment also increased cell apoptosis by 3-fold and inhibited cell migration by more than 20%. When keratinocytes were pretreated with RCR252, an EPCR-blocking antibody, or PD153035, an epidermal growth factor receptor (EGFR) inhibitor, cell proliferation was hindered by more than 30%. These inhibitors also completely abolished recombinant APC (10 mug/ml)-stimulated proliferation. Blocking PC expression or inhibiting its binding to EPCR/EGFR decreased the phosphorylation of ERK1/2 but increased p38 activation. Furthermore, inhibition of ERK decreased cell proliferation by approximately 30% and completely abolished the stimulatory effect of APC on proliferation. Taken together, these results indicate that keratinocyte-derived PC promotes cell survival, growth, and migration in an autocrine manner via EPCR, EGFR, and activation of ERK1/2. Our results highlight a novel role for the PC pathway in normal skin physiology and wound healing.     

Up-regulation and cytoprotective role of epithelial multidrug resistance-associated protein 1 in inflammatory bowel disease

MRP1 (multidrug resistance-associated protein 1) is well known for its role in providing multidrug resistance to cancer cells. In addition, MRP1 has been associated with both pro- and anti-inflammatory functions in nonmalignant cells. The pro-inflammatory function is evident from the fact that MRP1 is a high affinity transporter for cysteinyl-leukotriene C4 (LTC4), a lipid mediator of inflammation. It remains unexplained, however, why the absence of Mrp1 leads to increased intestinal epithelial damage in mice treated with dextran-sodium sulfate, a model for inflammatory bowel disease (IBD). We found that MRP1 expression is induced in the inflamed intestine of IBD patients, e.g. Crohn disease and ulcerative colitis. Increased MRP1 expression was detected at the basolateral membrane of intestinal epithelial cells. To study a putative role for MRP1 in protecting epithelial cells against inflammatory cues, we manipulated MRP1 levels in human epithelial DLD-1 cells and exposed these cells to cytokines and anti-Fas. Inhibition of MRP1 (by MK571 or RNA interference) resulted in increased cytokine- and anti-Fas-induced apoptosis of DLD-1 cells. Opposite effects, e.g. protection of DLD-1 cells against cytokine- and anti-Fas-induced apoptosis, were observed after recombinant MRP1 overexpression. Inhibition of LTC4 synthesis reduced anti-Fas-induced apoptosis when MRP1 function was blocked, suggesting that LTC4 is the pro-apoptotic compound exported by epithelial MRP1 during inflammation. These data show that MRP1 protects intestinal epithelial cells against inflammation-induced apoptotic cell death and provides a functional role for MRP1 in the inflamed intestinal epithelium of IBD patients.     

Phosphatidylcholine regulates NF-κB activation in attenuation of LPS-induced inflammation: evidence from in vitro study

Phosphatidylcholine (PC) has been demonstrated as anti-inflammatory and antioxidant/pro-oxidant molecules. In this study, we investigated the protective effects of PC on inflammatory bowel disease (IBD) caused by lipopolysaccharide (LPS)-induced injury in intestinal epithelia cells. The IEC-6 cells (intestinal epithelia cells) were stimulated with LPS (1 μg/mL) for 24 h with or without PC pretreatment, in the next steps: (1) the level of the inflammatory cytokine tumor necrosis factor (TNF)-α was measured with ELISA; (2) the nuclear translocation and phosphorylation of NF-κB was investigated with Western blot, EMSA, immunofluorence assay; (3) the protein phosporylation levels in MAPK signaling pathway were detected with Western blot method. The results showed: (1) compared with the normal group, 10 and 20?μg/mL of PC significantly inhibited the production and activation of TNF-α, (P < 0.01); (2) pretreatment with PC inhibited LPS-induced nuclear translocation and phosphorylation of p65 in IEC-6 cells; (3) pretreatment with PC inhibited the protein phosphorylation levels in MAPK signaling pathway. Our findings indicated that PC had the effect to protect IEC-6 cells from LPS-induced injury and this effect was exerted possibly through inhibiting the TNF-ɑ secretion, down-regulating nuclear translocation and phosphorylation of p65 and inhibiting MAPK signaling pathways.     

IL-6 induces NF-kappa B activation in the intestinal epithelia

IL-6 is a potent proinflammatory cytokine that has been shown to play an important role in the pathogenesis of inflammatory bowel disease (IBD). It is classically known to activate gene expression via the STAT-3 pathway. Given the crucial role of IL-6 in the pathogenesis of chronic intestinal inflammation, it is not known whether IL-6 activates NF-kappaB, a central mediator of intestinal inflammation. The model intestinal epithelial cell line, Caco2-BBE, was used to study IL-6 signaling and to analyze whether suppressor of cytokine signaling 3 (SOCS-3) proteins play a role in the negative regulation of IL-6 signaling. We show that IL-6 receptors are present in intestinal epithelia in a polarized fashion. Basolateral IL-6 and, to a lesser extent, apical IL-6 induces the activation of the NF-kappaB pathway. Basolateral IL-6 stimulation results in a maximal induction of NF-kappaB activation and NF-kappaB nuclear translocation at 2 h. IL-6 induces polarized expression of ICAM-1, an adhesion molecule shown to be important in the neutrophil-epithelial interactions in IBD. Using various deletion constructs of ICAM-1 promoter, we show that ICAM-1 induction by IL-6 requires the activation of NF-kappaB. We also demonstrate that overexpression of SOCS-3, a protein known to inhibit STAT activation in response to IL-6, down-regulates IL-6-induced NF-kappaB activation and ICAM-1 expression. In summary, we demonstrate the activation of NF-kappaB by IL-6 in intestinal epithelia and the down-regulation of NF-kappaB induction by SOCS-3. These data may have mechanistic and therapeutic implications in diseases such as IBD and rheumatoid arthritis in which IL-6 plays an important role in the pathogenesis.     

Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease

Nitric oxide (.NO) generation from conversion of l-arginine to citrulline by nitric oxide synthase isoforms plays a critical role in vascular homeostasis. Loss of .NO is linked to vascular pathophysiology and is decreased in chronically inflamed gut blood vessels in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). Mechanisms underlying decreased .NO production in IBD gut microvessels are not fully characterized. Loss of .NO generation may result from increased arginase (AR) activity, which enzymatically competes with nitric oxide synthase for the common substrate l-arginine. We characterized AR expression in IBD microvessels and endothelial cells and its contribution to decreased .NO production. AR expression was assessed in resected gut tissues and human intestinal microvascular endothelial cells (HIMEC). AR expression significantly increased in both ulcerative colitis and Crohn's disease microvessels and submucosal tissues compared with normal. TNF-alpha/lipopolysaccharide increased AR activity, mRNA and protein expression in HIMEC in a time-dependent fashion. RhoA/ROCK pathway, a negative regulator of .NO generation in endothelial cells, was examined. The RhoA inhibitor C3 exoenzyme and the ROCK inhibitor Y-27632 both attenuated TNF-alpha/lipopolysaccharide-induced MAPK activation and blocked AR expression in HIMEC. A significantly higher AR activity and increased RhoA activity were observed in IBD submucosal tissues surrounding microvessels compared with normal control gut tissue. Functionally, inhibition of AR activity decreased leukocyte binding to HIMEC in an adhesion assay. Loss of .NO production in IBD microvessels is linked to enhanced levels of AR in intestinal endothelial cells exposed to chronic inflammation in vivo.     

MicroRNA-193a-3p Reduces Intestinal Inflammation in Response to Microbiota via Down-regulation of Colonic PepT1

Intestinal inflammation is characterized by epithelial disruption, leading to the loss of barrier function, recruitment of immune cells, and host immune responses to gut microbiota. PepT1, a di/tripeptide transporter that uptakes bacterial products, is up-regulated in inflamed colon tissue, which implies its role in bacterium-associated intestinal inflammation. Although microRNA (miRNA)-mediated gene regulation has been found to be involved in various processes of inflammatory bowel disease (IBD), the biological function of miRNAs in the pathogenesis of IBD remains to be explored. In this study we detected miRNA expression patterns in colon tissues during colitis and investigated the mechanism underlying the regulation of colonic PepT1 by miRNAs. We observed an inverse correlation between PepT1 and miR-193a-3p in inflamed colon tissues with active ulcerative colitis, and we further demonstrated that miR-193a-3p reduced PepT1 expression and activity as a target gene and subsequently suppressed the NF-κB pathway. Intracolonic delivery of miR-193a-3p significantly ameliorated dextran sodium sulfate-induced colitis, whereas the overexpression of colonic PepT1 via PepT1 3′-untranslated region mutant lentivirus vector abolished the anti-inflammatory effect of miR-193a-3p. Furthermore, antibiotic treatment eliminated the difference in the dextran sodium sulfate-induced inflammation between the presence and absence of miR-193a-3p. These findings suggest that miR-193a-3p regulation of PepT1 mediates the uptake of bacterial products and is a potent mechanism during the colonic inflammation process. Overall, we believe miR-193a-3p may be a potent regulator of colonic PepT1 for maintaining intestinal homeostasis.     

Molecular signaling blockade as a new approach to inhibit leukocyte-endothelial interactions for Inflammatory bowel disease treatment

Mitogen-activated protein kinases (MAPK) are among the major widespread transduction pathways in humans. They are involved in several inflammatory disorders, including the pathogenesis of inflammatory bowel disease (IBD). A recent paper showed that activated MAPK are up-regulated on endothelium and fibroblasts from intestinal biopsies of active IBD patients. In vitro experiments demonstrated that MAPK activation on intestinal endothelial cells and fibroblasts are responsible for the production of certain chemokines, increased leukocyte adhesion and transmigration. Specific local inhibition of MAPK activity on endothelial cells and fibroblasts may provide a new mechanism to control mucosal inflammation and leukocyte recruitment into the intestine of active IBD patients.     

蛋白激酶在微血管通透性中的作用

微血管内皮细胞层是一层半选择通透性屏障,可以调节血液中的液体、溶质和血浆蛋白进入组织间隙。在炎症刺激作用下,可通过旁细胞途径和跨细胞途径引起内皮通透性上升。旁细胞通路主要由内皮细胞间的紧密连接、黏附连接和细胞与外基质的黏着斑组成。炎症介质,如脂多糖和肿瘤坏死因子α可激活多种蛋白激酶。活化的蛋白激酶主要包括Rho相关的卷曲蛋白激酶、肌球蛋白轻链激酶、蛋白激酶C、酪氨酸激酶和丝裂原活化蛋白激酶等,参与引发内皮屏障生化和结构改变,旁细胞通路开放,导致通透性上升。该文对上述蛋白激酶在微血管通透性中作用机制的研究进展进行综述。     

The unfolded protein response and its role in intestinal homeostasis and inflammation

The unfolded protein response (UPR) is a signaling pathway from the endoplasmic reticulum (ER) to the nucleus that protects cells from the stress caused by misfolded or unfolded proteins [1, 2]. As such, ER stress is an ongoing challenge for all cells given the central biologic importance of secretion as part of normal physiologic functions. This is especially the case for cells that are highly dependent upon secretory function as part of their major duties. Within mucosal tissues, the intestinal epithelium is especially dependent upon an intact UPR for its normal activities [3]. This review will discuss the UPR and the special role that it provides in the functioning of the intestinal epithelium and, when dysfunctional, its implications for understanding mucosal homeostasis and intestinal inflammation, as occurs in inflammatory bowel disease (IBD).