Differential effects of caspase-1/interleukin-1beta-converting enzyme on acinar cell necrosis and apoptosis in severe acute experimental pancreatitis.

There is recent experimental evidence that inhibition of caspase-1/interleukin-1beta converting enzyme (ICE) significantly ameliorates overall severity and survival in severe acute experimental pancreatitis. However, little is known about the effects of this approach on the dynamics and mechanisms of local acinar cell damage, which we aimed to investigate in the present study. Severe acute pancreatitis (SAP) was induced by retrograde infusion of 4% sodium taurocholate in rats treated with isotonic saline or a highly selective, irreversible inhibitor of ICE. After 3, 6, and 24 hours, 3 and 7 days, acinar cell death by necrosis and apoptosis, as well as intrapancreatic and systemic interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) expression, was assessed. Treatment with the ICE inhibitor significantly reduced the extent of acinar cell necrosis accounting for major parenchymal destruction. In contrast, apoptosis was confined to the postacute course of the disease and was closely related to tubular complex formation, both remaining unchanged. Whereas intrapancreatic IL-1beta mRNA expression was highly up-regulated in both treated and untreated animals, active IL-1beta protein expression and subsequent neutrophil tissue infiltration was dramatically decreased in the ICE-inhibited group. Parallel to the onset of enhanced apoptotic acinar cell death and tubular complex formation, TNF-alpha mRNA and protein expression was up-regulated, with levels being lower in ICE inhibitor-treated rats. We conclude that activation of caspase-1/ICE plays a central role in the progression of acinar cell death by necrosis in SAP. Herein, IL-1beta-mediated neutrophil infiltration seems to be a crucial step in enhanced cellular destruction. In contrast, acinar cell apoptosis contributes to ductal transformation and is independent of this mechanism, but may be influenced by TNF-alpha.     

Fas/FasL介导的caspase-3活化与急性胰腺炎腺泡细胞凋亡的关系

目的： 研究凋亡调控基因及蛋白Fas、FasL和caspase-3在大鼠急性胰腺炎（AP）组织中的表达及其相互关系。方法：经胰胆管逆行注射不同浓度的牛磺胆酸钠建立不同炎症程度的AP模型,采用RT-PCR、Western blotting技术检测大鼠胰腺炎组织Fas、FasL和caspase-3蛋白及mRNA的表达, TUNEL法检测胰腺炎组织腺泡细胞凋亡。结果：在正常胰腺组织内即可见Fas、FasL、caspase-3蛋白和mRNA的表达;建立AP模型后,随胰腺炎症程度的加重,Fas、FasL、caspase-3蛋白和mRNA的表达逐渐下降,腺泡细胞凋亡率亦逐渐下降,且caspase-3 表达水平在各个组间的变化趋势与Fas/FasL系统的变化趋势相一致。结论：Fas/FasL系统介导的凋亡途径参与了急性胰腺炎腺泡细胞凋亡的调节。     

Induction of salivary gland epithelial cell injury in Sjogren's syndrome: in vitro assessment of T cell-derived cytokines and Fas protein expression

Sjogren's syndrome (SS) is an exocrinopathy characterized by T cell infiltrates, salivary gland epithelial cell (SGEC) apoptosis and high Fas and FasL expression. To address the participation of T cell-derived cytokines and of Fas apoptotic pathway in SS glandular lesions, we utilized non-neoplastic SGEC lines established from SS patients and controls. Possibly attesting to their intrinsic activation, cell lines derived from SS patients displayed significantly higher constitutive Fas and FasL than controls. Surface co-expression of Fas and FasL was not associated with spontaneous fratricide apoptosis. SGEC were resistant to anti-Fas-mediated apoptosis (possibly owing to the constitutive expression of anti-apoptotic proteins cFLIP and Bcl-2), but became sensitive after protein or RNA synthesis inhibition. IFN-gamma and TNF-alpha were able to upregulate surface Fas and FasL, whereas IL-1beta downregulated surface FasL. IFN-gamma (but not several other cytokines) reduced the survival of SGEC in a dose- and time-dependent manner and induced Fas/FasL-mediated apoptosis, directly and via anoikia. Dexamethasone inhibited the upregulation of Fas and FasL by IFN-gamma and the induction of SGEC apoptosis and detachment by anti-Fas mAb or IFN-gamma. Our findings indicate the injurious role of IFN-gamma for the salivary epithelia of SS patients through the induction of Fas-mediated apoptosis and anoikia.     

Fas pulls the trigger on psoriasis

Fas/FasL signaling is best known for induction of apoptosis. However, there is an alternate pathway of Fas signaling that induces inflammatory cytokines, particularly tumor necrosis factor (TNF)-alpha and interleukin (IL)-8. This pathway is prominent in cells that express high levels of anti-apoptotic molecules such as Bcl-xL. Because TNF-alpha is central to the pathogenesis of psoriasis and psoriatic epidermis has a low apoptotic index with high expression of Bcl-xL, we hypothesized that inflammatory Fas signaling mediates induction of psoriasis by activated lymphocytes. Noninvolved skin from psoriasis patients was grafted to beige-severe combined immunodeficiency mice, and psoriasis was induced by injection of FasL-positive autologous natural killer cells that were activated by IL-2. Induction of psoriasis was inhibited by injection of a blocking anti-Fas (ZB4) or anti-FasL (4A5) antibody on days 3 and 10 after natural killer cell injection. Anti-Fas monoclonal antibody significantly reduced cell proliferation (Ki-67) and epidermal thickness, with inhibition of epidermal expression of TNF-alpha, IL-15, HLA-DR, and ICAM-1. Fas/FasL signaling is an essential early event in the induction of psoriasis by activated lymphocytes and is necessary for induction of key inflammatory cytokines including TNF-alpha and IL-15.     

Immunohistochemical analysis of cytokines and apoptosis in tuberculous lymphadenitis

Relatively little is known about the effector mechanisms whereby the human immune system controls Mycobacterium tuberculosis infection. In this study we elaborate on the immune response and mechanisms of persistence of mycobacteria in lesions by analysing, using immunohistochemistry, the expression of cytokines [tumour necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta) and interferon-gamma (IFN-gamma)], apoptotic cells and apoptosis-related proteins [Bcl2, Bax, Fas ligand (FasL) and Fas] in the human tuberculous lymphadenitis lesions. The expression of apoptosis-related proteins has been shown to be exploited by mycobacteria to evade the immune response and persist in the host. Foreign body (FB) granulomas were used as controls. In tuberculosis (TB) granulomas, epithelioid cells and multinucleated giant cells expressed cytokines differently. In epithelioid cells, the numbers of TNF-alpha-, IL-10- and TGF-beta-stained cells were higher than IFN-gamma-stained cells (P < 0.01). TGF-beta and FasL were strongly expressed in the necrotic centres as compared with other cytokines. More giant cells expressed IL-10 and TGF-beta than expressed TNF-alpha and IFN-gamma (P < 0.01). Staining of consecutive sections revealed that some giant cells expressed IL-10 but not TNF-alpha. Apoptotic TB giant cells correlated positively with the expression of TNF-alpha, IFN-gamma and TGF-beta, but not with the expression of IL-10. The percentage of giant cells expressing Bax was lower than those expressing Fas, unlike the epithelioid cells, suggesting that TB giant cells are less susceptible to apoptosis. Compared with FB giant cells, there were fewer TB giant cells showing TNF-alpha, IFN-gamma, FasL, Fas expression or undergoing apoptosis (P < 0.05). Taken together, these observations show that the cellular microenvironment of TB granulomas down-regulates microbicidal functions, favouring bacillary survival and persistence. TGF-beta and FasL may be responsible for tissue destruction. The giant cells, being less susceptible to apoptosis, may remain a continuous source of pro-inflammatory cytokines, causing immune pathology.     

HDV/HBV感染树鼩肝组织中的肝细胞凋亡

目的探讨 HDV/ HBV感染树鼠句肝组织中 Fas/ Fas L、Bcl2 / Bax和 ICE表达与 HDV感染之间的关系 ,以及Fas/ Fas L、Bcl2 / Bax和 ICE在丁型肝炎肝细胞凋亡中的作用。方法采用免疫组化技术对 HDV/ HBV感染树鼠句肝组织中 Fas/Fas L、Bcl2 / Bax和 ICE的表达进行检测 ;应用原位末端标记技术对肝细胞凋亡进行检测。结果 HDAg表达与 Fas/ Fas L、Bcl2 /Bax和 ICE表达之间关系密切 ( P<0 .0 5 ) ,HDAg表达越强 ,Fas、Fas L、Bax和 ICE表达也越强 ,而 Bcl2 表达则越弱。 Fas/Fas L、Bcl2 / Bax和 ICE表达与肝细胞凋亡之间关系密切 ( P<0 .0 5 ) ,Fas、Fas L、Bax和 ICE表达越强 ,凋亡细胞越多 ;相反 ,Bcl2 表达越强 ,凋亡细胞越少。结论肝细胞内 HDAg表达可诱导 Fas、Fas L、Bax和 ICE表达 ,但对 Bcl2 表达无明显诱导作用 ;Fas/ Fas L、Bcl2 / Bax和 ICE在肝细胞凋亡中起重要作用。     

In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-gamma/TNF-alpha

Immunization with mycobacterial preparation such as Bacille Calmette-Guerin (BCG) or complete Freund's adjuvant (CFA) prevents the onset and recurrence of type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we explored the mechanism underlying the down-regulation of diabetogenic T cells by BCG treatment. We found that the potential of splenocytes from BCG-immunized diabetic NOD mice to adoptively transfer diabetes was significantly impaired. BCG immunization sequentially induced the production of TNF-alpha, IFN-gamma and IL-4 by splenocytes, increased the expression of Fas(high) (Apo-1/CD95), Fas ligand (FasL, CD95L) and TNF receptor (TNFR) on T cells leading to T cell apoptosis. The primary role of IFN-gamma and TNF-alpha in BCG-immunotherapy was demonstrated by (i) reversing the immune regulatory effect of BCG by in vivo treatment with neutralizing anti-cytokine antibodies, (ii) inducing effect similar to BCG by treatment with these cytokines. We show that Fas and TNF are two pathways in BCG-induced apoptosis of diabetogenic T cells, since in vitro blocking FasL or TNFR1 with antibody reduced T cell apoptosis and increased T cell proliferative response. In addition, TNF-alpha and agonistic anti-Fas antibody had a synergistic effect on the in vitro apoptosis of diabetogenic T cells. Our results suggest that BCG down-regulates destructive autoimmunity by TNF-alpha/IFN-gamma-induced apoptosis of diabetogenic T cells through both Fas and TNF pathways. These studies provide a novel mechanism for blocking disease recurrence and immune modulating effect of BCG immunization in type 1 diabetes.     

转基因小鼠高表达的FasL对Sertoli细胞免疫调节功能的影响

目的 :研究转基因小鼠高表达的FasL对Sertoli细胞在睾丸局部感染时的免疫调节作用的影响。方法 :将溶脲脲原体 (UU)分别注入FasL转基因及野生型小鼠膀胱 ,模拟上行性感染的途径。分别在感染后 1、2和 3wk处死小鼠 ,分离睾丸组织观察其病理变化 ,并用免疫组化染色法比较UU感染前后 ,Ser toli细胞上FasL和TGF β、IL 1α、IL 6的表达及分泌格局的差异。从野生型小鼠睾丸组织中分离高纯度的Sertoli细胞 ,与未感染UU的对照组相比 ,观察UU感染后FasL Sertoli细胞介导Fas Jurkat细胞的凋亡能力的变化。结果 :UU感染组的转基因小鼠 ,睾丸组织发生的病理改变比野生型更为明显 ;两种小鼠感染后Sertoli细胞分泌的调节因子变化格局不同 ;感染后Sertoli细胞对Jurkat细胞的杀伤能力增强。结论 :在抗感染免疫中 ,转基因表达的FasL可影响Sertoli细胞分泌细胞因子的格局 ,进而影响睾丸局部的免疫平衡。过高表达的FasL对机体的抗感染应答并非一定有利。     

雷公藤红素诱导CEM-6T细胞凋亡的机制研究

在已经证明雷公藤红素能诱导人T淋巴细胞株CEM 6T细胞凋亡的基础上 ,进一步探讨此凋亡过程的机制。本项目研究雷公藤红素诱导CEM 6T细胞凋亡过程中Fas/FasL、ICEmRNA的变化以及ICE抑制剂、磷酸酶抑制剂对凋亡的影响。结果发现 ( 1)CEM 6T细胞表达Fas,不表达FasL ,雷公藤红素处理不能改变这一情况 ;( 2 )雷公藤红素不能改变ICEmRNA的表达水平 ,但ICE抑制剂Ac YVAD CHO能使雷公藤红素诱导CEM 6T的凋亡率下降 ;( 3) 1 5 μmol/L磷酸酶抑制剂okadaicacid能使凋亡率下降。提示雷公藤红素诱导CEM 6T细胞凋亡不依赖Fas/FasL ,而与细胞内原已存在的ICE有关 ,蛋白去磷酸化参与了此凋亡过程     

Induction of interleukin-8 secretion and apoptosis in bronchiolar epithelial cells by Fas ligation.

Epithelial cell injury is the common manifestation of lung injury. Contributing to such injury of epithelial cells is apoptosis. Although apoptosis is part of the normal process of epithelial renewal, in excess it is pathologic. We previously demonstrated the excessive apoptosis of lung epithelial cells and the upregulation of Fas and Fas ligand (FasL) in fibrosing lung diseases. We also showed that inhalation of anti-Fas antibody induced lung injury and fibrosis in mice. Interleukin (IL)-8 is one of the most important cytokines in the pathophysiology of acute lung injury and pulmonary fibrosis. In this study we investigated whether Fas ligation induces IL-8 secretion in addition to apoptosis in bronchiolar epithelial cells in vitro. Bronchiolar epithelial cells underwent apoptosis and also secreted IL-8 in response to tumor necrosis factor (TNF)-alpha or Fas ligation. New gene expression and protein synthesis were not necessary for Fas ligation- and TNF-alpha- mediated apoptosis, but were necessary for IL-8 secretion. We further found that Fas ligation induced activation of nuclear factor-kappa B. We conclude that the Fas/FasL pathway not only mediates apoptosis but also plays a proinflammatory role, and that stimulation of the Fas/FasL pathway in bronchiolar epithelial cells leads to IL-8 production, which may amplify the inflammatory cascade in lung injury and pulmonary fibrosis.     

Participation of the Fas and Fas ligand systems in apoptosis during atrophy of the rat submandibular glands

Most acinar cells and some duct cells undergo apoptosis during atrophy of the submandibular gland. The present study was designed to elucidate whether Fas and its receptor ligand (FasL) are involved during apoptotic atrophy of the gland. The excretory duct of the right submandibular gland of rats was doubly ligated with metal clips from 1 to 14 days for induction of gland atrophy. Control rats were untreated. Fas and FasL expression in the atrophied submandibular gland was detected using immunohistochemistry (IHC) and Western immunoblot. Expression of activated caspase 8 and activated caspase 3 was also detected with IHC. Fas-positive acinar and duct cells and FasL-positive duct cells increased in the atrophic glands at 3 and 5 days after duct ligation when apoptotic cells were commonly observed. Thereafter, Fas- and FasL-positive cells declined in number. Patterns of expression of Fas and FasL using Western immunoblots concurred with the IHC results. Activated caspase 8-positive cells were present at every time interval but peaked at 3 and 5 days following duct ligation. The cells showing immunoreaction for activated caspase 3 first appeared on day 3, with the peak in apoptosis, after which they decreased. The results indicate that the Fas/FasL systems likely play an important role in apoptotic pathways during atrophy of the submandibular gland.     

The role of apoptosis in the pathophysiology of Acute Respiratory Distress Syndrome (ARDS): An up-to-date cell-specific review

ARDS pathophysiology is characterized by complex mechanisms that involve cells of inflammation, lung tissue cells, cytokines, chemokines, as well as apoptosis activators and inhibitors. There are two important theories that link apoptosis with ARDS and suggest that epithelial cell apoptosis, as well as the accumulation of neutrophils in the lung, may contribute to a cascade of events and, finally, ARDS. The activation of the Fas/FasL pathway is an important mechanism of alveolar epithelial injury in the lungs of patients with ALI. In addition, neutrophilic inflammation in the alveolar spaces is characteristic of ALI in humans and in most animal models of ALI. The enhanced phagocytosis of apoptotic neutrophils could lead to resolution of inflammation and repair during ARDS. In this review, we will focus on elucidating the role of apoptosis in the pathophysiology of ARDS and the contribution of Fas-mediated inflammation in ARDS. Furthermore, we will give evidence that TNF-alpha, IL-1beta and IL-13 attenuate the pro-cell death effects of Fas/CD95 on A549 epithelial cells, at least partially, by the NF-kB and PI3-K pathways, suggesting that induction of the expression of antiapoptotic genes protects the epithelial cells from cell death.     

Molecular mechanism of ultraviolet-induced keratinocyte apoptosis.

This article reviews advances in the study of the molecular mechanisms for ultraviolet (UV)-induced keratinocyte apoptosis, with particular reference to the cytokines tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL). TNF-alpha and FasL induce their respective receptors and then activate caspase enzymes that are critically involved in the apoptotic process. This activation is further amplified by intracellular mitochondria-associated mechanisms. Using gene-targeted knockout mice lacking either the TNF-Rp55 or the TNF-Rp75, we have shown that TNF-alpha plays an important role in UV-induced keratinocyte apoptosis via TNF-Rp55. TNF-Rp55 shares homology with Fas and contains an intracellular death domain. UV seems to directly stimulate cross-linking of Fas, resulting in the engagement of the death machinery. Fas-associated death domain protein (FADD) acts as an adapter protein in both the TNF-Rp55 and Fas death-inducing cascades and is responsible for downstream signal transduction by recruiting caspases. Moreover, signaling of p53 contributes to the induction of apoptosis by regulating Bcl-2 family expression and increasing surface Fas expression. In addition to induction mechanisms of apoptosis, there are numerous inhibitory molecules that play a role in restricting the apoptotic pathway. Thus, the ultimate determination of whether or not a cell undergoes apoptosis after UV radiation is based on the balance between agonist and antagonist pathways.     

Roles of apoptosis in airway epithelia

The airway epithelium functions primarily as a barrier to foreign particles and as a modulator of inflammation. Apoptosis is induced in airway epithelial cells (AECs) by viral and bacterial infections, destruction of the cytoskeleton, or by exposure to toxins such as high oxygen and polycyclic hydrocarbons. Various growth factors and cytokines including TGF-beta, IFN-gamma, or the activators of the death receptors, TNF-alpha and FasL, also induce apoptosis in AECs. However, cell death is observed in maximally 15% of AECs after 24 h of treatment. Preincubation with IFN-gamma or a zinc deficiency increases the percentage of apoptotic AECs in response to TNF-alpha or FasL, suggesting that AECs have mechanisms to protect them from cell death. Apoptosis of AECs is a major mechanism in reducing cell numbers after hyperplastic changes in airway epithelia that may arise due to major injuries in response to LPS or allergen exposures. Resolution of hyperplastic changes or changes during prolonged exposure to an allergen is primarily regulated by the Bcl-2 family of proteins. Fas and FasL are both expressed in AECs, and their main function may be to control inflammation by inducing Fas-induced death in inflammatory cells without inducing apoptosis in neighboring cells. Furthermore, AECs engulf dying eosinophils to clear them by phagocytosis. Therefore, in the airway epithelium apoptosis serves three main roles: (1) to eliminate damaged cells; (2) to restore homeostasis following hyperplastic changes; and (3) to control inflammation, and thereby support the barrier and anti-inflammatory functions.     

Apoptosis in labial salivary glands from Sjögren's syndrome (SS) patients: comparison with human T lymphotropic virus-I (HTLV-I)-seronegative and -seropositive SS patients

Apoptosis is a type of cell death that occurs during morphogenesis and development of the immune system. One of the mechanisms is mediated through the Fas and Fas ligand (FasL) pathway. To determine the possible involvement of Fas and its ligand in salivary gland destruction, we analysed the appearance of nuclei with DNA fragmentation by using nick end labelling (TUNEL) and the expression of Fas and FasL by immunohistochemistry in labial salivary glands. Furthermore, we compared the features of apoptosis in labial salivary glands between HTLV-I^? and HTLV-I⁺ SS. When the frozen sections of 10 primary SS patients in the absence of anti-HTLV-I antibody were examined, several apoptotic cells were found in the acinar and ductal epithelial cells as well as infiltrated mononuclear cells. Both Fas and FasL were detected in the infiltrated mononuclear cells. Acinar epithelial cells, which are surrounded by FasL⁺ mononuclear cells, were also double-positive with Fas and FasL, although the expression of FasL was localized at their apical border, suggesting that apoptosis of mononuclear cells was achieved by activation-induced mechanisms through Fas/FasL pathways, and that of acinar epithelial cells was mediated by FasL derived from either acinar epithelial cells themselves or infiltrated mononuclear cells. Interestingly, Fas expression in ductal epithelial cells was localized around the lumen side of the ducts, indicating that FasL secreted from acinar epithelial cells may induce Fas-mediated apoptosis of ductal epithelial cells. We also studied the labial salivary glands from nine SS patients with anti-HTLV-I antibodies. There was no significant difference in the occurrence of apoptotic cells or in the expression of Fas and FasL between HTLV-I⁺ and HTLV-I^? SS patients. It was of note that neither the expression of Fas and FasL nor the presence of apoptotic cells were determined in labial salivary glands from subjects without SS. These findings indicate that Fas-mediated apoptosis in salivary glands could be involved in the pathological manifestations of SS, irrespective of HTLV-I seropositivity.     

Increased serum IL-10 in lupus patients promotes apoptosis of T cell subsets via the caspase 8 pathway initiated by Fas signaling

We sought to investigate the expression of Fas and FasL on T cell surface and caspase 8 involvement in T cell apoptosis promoted by serum IL-10 in systemic lupus erythematosus(SLE) patients.Cells and sera were obtained from 35 SLE patients.Apoptosis of T cells in patients with SLE was increased and associated with the SLE disease activity index(SLEDAI).Elevated expression of Fas and FasL on T cell surface contributed to increased apoptosis of T cells.Increased IL-10 in the sera of SLE patients was capable of inducing Fas and FasL expression on CD4~+T cell surface,promoting apoptosis of this cell subset.Decreased IL-10 serum levels and low expression of Fas were found in 5 patients of the first follow-up group after 2-month treatment.In another group with one-year treatment,the SLEDAI declined to inactive scores.Serum IL-10 was decreased significantly,and expression of Fas and FasL on T cells was also reduced.Declined apoptosis was predominant only in CD4~+T cell subset.When sera with high level of IL-10 were used to culture PBMCs from healthy controls,activated caspase 8 was elevated in CD3~+T,CD4~+T and CD8~+T cells.The study showed that serum IL-10 induced apoptosis of T cell subsets via the caspase8 pathway initiated by Fas signaling.Increased apoptosis of T cells contributes to autoantigen burden,which is pathogenic in the development of SLE.     

Interferon-gamma induces Fas trafficking and sensitization to apoptosis in vascular smooth muscle cells via a PI3K- and Akt-dependent mechanism

Vascular smooth muscle cell (VSMC) apoptosis occurs in advanced atherosclerotic plaques where it may contribute to plaque instability. VSMCs express the death receptor Fas but are relatively resistant to Fas-induced apoptosis due in part to the intracellular sequestration of Fas. Although inflammatory cytokines such as interferon (IFN)-gamma present in plaques can prime VSMCs to FasL-induced death, the mechanism of this effect is unclear. We examined Fas expression and FasL-induced apoptosis in human VSMCs in response to IFN-gamma. IFN-gamma induced Fas trafficking to the cell surface within 24 hours, an effect that required Jak2/Stat1 activity. IFN-gamma also stimulated Akt activity, and both Fas trafficking and Stat1 activation were inhibited by blocking PI3K, Akt, or Jak-2. IFN-gamma increased Fas-induced apoptosis in vitro by 46 +/- 8% (mean +/- SEM, P = 0.04), an event that could be abrogated by inhibition of PI3K, Akt, or Jak-2. IFN-gamma also increased Fas-induced apoptosis in vivo 7.5- to 15-fold (P < 0.05) in human arteries transplanted into immunodeficient mice, accompanied by increased Fas and phospho-Ser727-Stat1. We conclude that IFN-gamma primes VSMCs to Fas-induced apoptosis, in part by relocation of Fas to the cell surface, a process that involves PI3K, Akt, and Jak-2/Stat1. IFN-gamma present in plaques may co-operate with FasL to induce VSMC apoptosis in atherosclerosis.     

pSS患者唇腺组织中Fas介导的凋亡信号蛋白的表达

目的:研究原发性干燥综合症( primary Sjgren’s syndrome，pSS)唇腺组织细胞中Fas 介导的细胞凋亡信号蛋白的表达，探讨导致干燥综合征的细胞信号转导的可能途径。 方法:采用Western blotting法检测唇腺组织中Fas、FasL、FADD蛋白的表达;免疫组织化学法检测caspase-3蛋白表达;RT-PCR半定量检测CAD mRNA表达。 结果:pSS患者唇腺组织细胞中Fas 介导的细胞凋亡信号转导相关蛋白Fas、FasL、FADD、caspase-3及CAD mRNA表达都有不同程度高于对照组(P＜0.05)。 结论:导致干燥综合征患者唇腺组织凋亡的信号转导途径可能是：FasL与其受体Fas结合后，通过FADD激活caspase-8，级联激活ICE家族成员，最后通过caspase-3裂解ICAD释放CAD催化DNA降解导致细胞凋亡。