Bcl-2 inhibits gut epithelial apoptosis induced by acute lung injury in mice but has no effect on survival

Gut epithelial apoptosis is increased in human studies and animal models of noninfectious inflammation and sepsis. Elevated intestinal cell death appears to be physiologically significant in sepsis. Previous studies demonstrate that overexpression of the antiapoptotic protein Bcl-2 in the gut epithelium of transgenic mice is associated with improved survival from Pseudomonas aeruginosa pneumonia and cecal ligation and puncture. The functional significance of elevated gut apoptosis in noninfectious inflammation has not been examined. We hypothesized that intestinal apoptosis would be detrimental to survival in noninfectious critical illness. To address this issue, acute lung injury (ALI) was induced with intratracheal injection of lipopolysaccharide (LPS, 800 microg) in wild-type (WT) FVB/N mice and transgenic mice that overexpress Bcl-2 in their intestinal epithelium. Guts were harvested at 12, 24, 48, and 72 h and assessed for apoptosis by both hematoxylin and eosin and active caspase-3 staining in 100 contiguous crypts. ALI increased gut epithelial apoptosis 12 h after LPS instillation compared with shams (P < 0.01), whereas overexpression of Bcl-2 decreased intestinal apoptosis compared with WT animals with ALI when assayed by active caspase-3 (P < 0.05). Plasma levels of tumor necrosis factor alpha, interleukin (IL)-6, and IL-10 were similar between WT and transgenic animals with ALI, both of which had elevated IL-10 levels at 12 h and elevated IL-6 levels at 24 h compared with sham animals. In a separate experiment, transgenic and WT animals with ALI were followed for mortality to determine whether gut overexpression of Bcl-2 conferred a survival advantage. Survival at 10 days was 73% in WT animals (n = 33) and 65% in Bcl-2 animals (n = 23, P = ns). These results indicate that while gut epithelial apoptosis is elevated in multiple models of critical illness, prevention of intestinal cell death by overexpression of Bcl-2 is associated with a disparate survival effect between sepsis and noninfectious inflammation.     

Maturational differences in lung NF-kappaB activation and their role in tolerance to hyperoxia

Neonatal rodents are more tolerant to hyperoxia than adults. We determined whether maturational differences in lung NF-kappaB activation could account for the differences. After hyperoxic exposure (O2 > 95%), neonatal (<12 hours old) lung NF-kappaB binding was increased and reached a maximum between 8 and 16 hours, whereas in adults no changes were observed. Additionally, neonatal NF-kappaB/luciferase transgenic mice (incorporating 2 NF-kappaB consensus sequences driving luciferase gene expression) demonstrated enhanced in vivo NF-kappaB activation after hyperoxia in real time. In the lungs of neonates, there was a propensity toward NF-kappaB activation as evidenced by increased lung I-kappaB kinase protein levels, I-kappaBalpha phosphorylation, beta-transducin repeat-containing protein levels, and total I-kappaBalpha degradation. Increased lung p-JNK immunoreactive protein was observed only in the adult lung. Inhibition of pI-kappaBalpha by BAY 11-7085 resulted in decreased Bcl-2 protein levels in neonatal lung homogenates and decreased cell viability in lung primary cultures after hyperoxic exposure. Furthermore, neonatal p50-null mutant (p50(-/-)) mice showed increased lung DNA degradation and decreased survival in hyperoxia compared with WT mice. These data demonstrate that there are maturational differences in lung NF-kappaB activation and that enhanced NF-kappaB may serve to protect the neonatal lung from acute hyperoxic injury via inhibition of apoptosis.     

Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction

The physiological role of B cell lymphoma 2 (Bcl-2) homology 3-only proteins has been investigated in mice lacking the individual genes identifying rate-limiting roles for Bim (Bcl-2-interacting mediator of cell death) and Puma (p53-up-regulated modulator of apoptosis) in apoptosis induction. The loss of Bim protects lymphocytes from apoptosis induced by cytokine deprivation and deregulated Ca++ flux and interferes with the deletion of autoreactive lymphocytes and the shutdown of immune responses. In contrast, Puma is considered the key mediator of p53-induced apoptosis. To investigate the hypothesis that Bim and Puma have overlapping functions, we generated mice lacking both genes and found that bim-/-/puma-/- animals develop multiple postnatal defects that are not observed in the single knockout mice. Most strikingly, hyperplasia of lymphatic organs is comparable with that observed in mice overexpressing Bcl-2 in all hemopoietic cells exceeding the hyperplasia observed in bim-/- mice. Bim and Puma also have clearly overlapping functions in p53-dependent and -independent apoptosis. Their combined loss promotes spontaneous tumorigenesis, causing the malignancies observed in Bcl-2 transgenic mice, but does not exacerbate the autoimmunity observed in the absence of Bim.     

Anti-inflammatory effect of MAPK phosphatase-1 local gene transfer in inflammatory bone loss

Alveolar bone loss associated with periodontal diseases is the result of osteoclastogenesis induced by bacterial pathogens. The mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is a critical negative regulator of immune response as a key phosphatase capable of dephosphorylating activated MAPKs. In this study, rat macrophages transduced with recombinant adenovirus (Ad.)MKP-1 specifically dephosphorylated activated MAPKs induced by lipopolysaccharide (LPS) compared with control cells. Bone marrow macrophages from MKP-1 knockout (KO) mice exhibited higher interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and select chemokine compared with wild-type (WT) mice when stimulated by LPS. In addition, bone marrow cultures from MKP-1 KO mice exhibited significantly more osteoclastogenesis induced by LPS than when compared with WT mice. Importantly, MKP-1 gene transfer in bone marrow cells of MKP-1 KO mice significantly decreased IL-6, IL-10, TNF-α and chemokine levels, and formed fewer osteoclasts induced by LPS than compared with control group of cells. Furthermore, MKP-1 gene transfer in an experimental periodontal disease model attenuated bone resorption induced by LPS. Histological analysis confirmed that periodontal tissues transduced with Ad. MKP-1 exhibited less infiltrated inflammatory cells, less osteoclasts and less IL-6 than compared with rats of control groups. These studies indicate that MKP-1 is a key therapeutic target to control of inflammation-induced bone loss.     

Cytokine Response Modifier A (CrmA) Inhibits Ceramide Formation in Response to Tumor Necrosis Factor (TNF)-α: CrmA and Bcl-2 Target Distinct Components in the Apoptotic Pathway

Proteases are now firmly established as major regulators of the “execution” phase of apoptosis. Here, we examine the role of proteases and their relationship to ceramide, a proposed mediator of apoptosis, in the tumor necrosis factor-α (TNF-α)–induced pathway of cell death. Ceramide induced activation of prICE, the protease that cleaves the death substrate poly(ADP-ribose) polymerase. Bcl-2 inhibited ceramide-induced death, but not ceramide generation. In contrast, Cytokine response modifier A (CrmA), a potent inhibitor of Interleukin-1β converting enzyme and related proteases, inhibited ceramide generation and prevented TNF-α–induced death. Exogenous ceramide could overcome the CrmA block to cell death, but not the Bcl-2 block. CrmA, however, did not inhibit the activation of nuclear factor (NF)-κB by TNF-α, demonstrating that other signaling functions of TNF-α remain intact and that ceramide does not play a role in the activation of NF-κB. These studies support a distinct role for proteases in the signaling/activation phase of apoptosis acting upstream of ceramide formation.     

miR-499-5p上调对动脉粥样硬化大鼠心肌细胞凋亡的影响及作用机制

目的研究微小核糖核酸(micoroRNA,miR)-499-5p上调对动脉粥样硬化大鼠心肌细胞凋亡影响及作用机制。方法选取30只健康Wistar大鼠,经腹腔注射维生素D3和高脂饲料喂养方法建立动脉粥样硬化模型,分为模型组、竞争性短核糖核苷酸阴性对照序列(scramble-NC)组和miR-499-5p上调组各10只,另选10只健康Wistar大鼠为正常组。构建miR-499-5p表达载体,检测血清氧化应激指标[丙二醛(MDA)、超氧化物歧化酶(SOD)、肌酸激酶(CK)、髓过氧化物酶(MPO)]、炎症因子[白细胞介素(IL)-1β、肿瘤坏死因子(TNF)-α、IL-10]水平。HE染色观察心肌细胞凋亡,Western blot法检测心肌细胞凋亡相关蛋白[B细胞淋巴瘤/白血病-xl(Bcl-xl)和Bcl-2相关X蛋白(Bax)]的表达。结果模型组、scramble-NC组、miR-499-5p上调组较正常组血清CK、MDA、MPO、IL-1β、TNF-α水平和心肌细胞凋亡率、Bax蛋白表达升高,SOD、IL-10水平和Bcl-xl蛋白表达降低(P均<0.05);miR-499-5p上调组较模型组及scramble-NC组血清CK、MDA、MPO、IL-1β、TNF-α水平和心肌细胞凋亡率、Bax蛋白表达降低,SOD、IL-10水平和Bcl-xl蛋白表达升高(P均<0.05)。结论miR-499-5p上调可逆转动脉粥样硬化所致氧化应激、血管炎症反应,抑制大鼠动脉粥样硬化发展,可能通过调控Bax、Bcl-xl蛋白表达,抑制心肌细胞凋亡。     

A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection

Stimulation of the Fas (APO-1, CD95) receptor, which is present on a variety of cells, usually triggers a process of programmed cell death. Systemic injection of anti-Fas antibody into mice leads to fulminant liver destruction resulting from massive hepatocyte apoptosis, and to rapid death. Hepatocytes bear Fas but do not express Bcl-2, a protein that plays, in a number of conditions, a protective role against apoptosis. We have generated mice whose liver expresses Bcl-2 as the result of bcl-2 transgene placed under the control of the hepatocyte- specific alpha1-anti-trypsin gene promoter, but is otherwise not distinguishable from that of normal mice. These mice display a marked to almost total resistance to liver damage induced by anti-Fas antibody injection. This protective effect of Bcl-2 occurs in the absence of significant variations, in the stimulated livers, in the level of expression of other proteins also involved in resistance or sensitivity to apoptosis, namely Bcl-x, Bax, Bad, Bak, and p53. Mice with protected livers, however, die almost as rapidly as normal mice, which indicates that acute lethality results from stimulation of Fas receptors present on other target organs or cells.     

破壁灵芝孢子粉对裸鼠移植性淋巴瘤生长的抑制作用

本研究通过N-甲基亚硝基脲诱导小鼠胸腺T细胞淋巴瘤模型,研究灵芝孢子粉对裸鼠移植性淋巴瘤生长的抑制作用,并初步探讨其抑瘤机制。应用透射电子显微镜观察淋巴瘤组织细胞的凋亡,用RT-PCR检测肿瘤组织中Bax、Bcl-2、Bcl-xl mRNA表达水平。结果表明,灵芝孢子粉4 g/kg(ig,每日1次,连续21 d)组肿瘤抑制率为45.8%。透射电子显微镜检结果显示,灵芝孢子粉可诱导淋巴瘤细胞凋亡。RT-PCR显示,灵芝孢子粉4 g/kg组BaxmRNA表达明显上调,Bcl-2、Bcl-xl mRNA表达稍下调。结论:灵芝孢子粉具有抑制肿瘤细胞生长的作用,并可诱导淋巴瘤细胞凋亡,其机制可能与上调Bax mRNA,下调Bcl-2、Bcl-xl mRNA表达有关。     

Altered cutaneous immune parameters in transgenic mice overexpressing viral IL-10 in the epidermis

IL-10 is a pleiotropic cytokine that inhibits several immune parameters, including Th1 cell-mediated immune responses, antigen presentation, and antigen-specific T cell proliferation. Recent data implicate IL-10 as a mediator of suppression of cell-mediated immunity induced by exposure to UVB radiation (280-320 nm). To investigate the effects of IL-10 on the cutaneous immune system, we engineered transgenic mice that overexpress viral IL-10 (vIL-10) in the epidermis. vIL-10 transgenic mice demonstrated a reduced number of I-A(+) epidermal and dermal cells and fewer I-A(+) hapten-bearing cells in regional lymph nodes after hapten painting of the skin. Reduced CD80 and CD86 expression by I-A(+) epidermal cells was also observed. vIL-10 transgenic mice demonstrated a smaller delayed-type hypersensitivity response to allogeneic cells upon challenge but had normal contact hypersensitivity to an epicutaneously applied hapten. Fresh epidermal cells from vIL-10 transgenic mice showed a decreased ability to stimulate allogeneic T cell proliferation, as did splenocytes. Additionally, chronic exposure of mice to UVB radiation led to the development of fewer skin tumors in vIL-10 mice than in WT controls, and vIL-10 transgenic mice had increased splenic NK cell activity against YAC-1targets. These findings support the concept that IL-10 is an important regulator of cutaneous immune function.     

To live or die: a critical decision for the lung

Every cell in the body expresses a set of proteins designed to trigger permeabilization of the mitochondria and cell death. Inactivation or inappropriate triggering of these pathways is increasingly recognized as a contributor to human disease. A study in this issue of the JCI demonstrates that IL-6 exerts its protective effect against the development of lung injury following exposure of mice to 95% O(2) by increasing the expression of a Bcl-2-related protein, A1. This protein acts to prevent mitochondrial membrane permeabilization and cell death following exposure to hyperoxia. The data in this study lend support to the hypothesis that inappropriate triggering of cell-death pathways may contribute to the development of hyperoxic pulmonary edema, lung injury, and respiratory failure.     

Apoptotic protease activating factor 1 (Apaf-1)-independent cell death suppression by Bcl-2

Reportedly, antiapoptotic Bcl-2 family proteins suppress apoptosis by binding to and inhibiting members of the CED-4 family of caspase activators. To explore this question, we used embryonic stem (ES) cells in which one (-/+) or both (-/-) copies of the gene encoding apoptotic protease activating factor 1 (Apaf-1), a CED-4 homologue, were disrupted by homologous recombination. Stable clones of heterozygous (-/+) and homozygous (-/-) Apaf-1 knockout ES cells that overexpressed Bcl-2 were generated. Withdrawal of serum growth factors or stimulation of heterozygous ES cells with staurosporine (STS), ultraviolet (UV)B irradiation, etoposide (VP16), or cisplatin induced apoptosis followed by cell death (determined by failure to exclude propidium iodide dye). These cell death stimuli also induced activation of several types of caspases and loss of mitochondrial membrane potential (DeltaPsi) in heterozygous (+/-) Apaf-1 knockout ES cells. In addition, overexpression of Bcl-2 protected against these events in Apaf-1-expressing ES cells. In contrast, STS, UVB, and VP16 induced little or no caspase activation and apoptosis in homozygous (-/-) Apaf-1 knockout ES cells. Nevertheless, Apaf-1-deficient ES cells subjected to these cell death stimuli or deprived of growth factors did eventually die through a nonapoptotic mechanism associated with loss of DeltaPsi. Moreover, Bcl-2 overprotection preserved DeltaPsi, reduced the percentage of Apaf-1(-/)- ES cells undergoing cell death, and increased clonigenic survival. The extent of Bcl-2-mediated cytoprotection was not significantly different for heterozygous (-/+) versus homozygous (-/-) Apaf-1 knockout cells. Furthermore, although Bcl-2 could be readily coimmunoprecipitated with Bax, associations with Apaf-1 were undetectable under conditions where Apaf-1 interactions with procaspase-9 were observed. We conclude that Bcl-2 has cytoprotective functions independent of Apaf-1, preserving mitochondrial function through a caspase-independent mechanism.     

Bcl-xl does not have to bind Bax to protect T cells from death

Activated T cells die when antigen disappears from animals. This death is caused by proteins related to Bcl-2. Two hypotheses have been suggested to explain the actions of the different types of Bcl-2 proteins. One hypothesis suggests that, when T cells prepare to die, Bak and Bax, the proteins that actually kill activated T cells, are released from antiapoptotic proteins such as Bcl-2 and Bcl-xl. Another hypothesis suggests that Bak and Bax are normally free and are triggered to kill cells by release of messenger proteins, such as Bim, from Bcl-2 and Bcl-xl. Here, a form of Bcl-xl, which lacks a long unstructured loop, is used to show that the first hypothesis is not correct. Bcl-xl without its loop protects activated T cells from death, yet Bcl-xl without its loop cannot bind any form of Bak and Bax. Thus, binding of Bcl-xl to Bak or Bax is not involved in T cell life or death. The loop of Bcl-xl is also somewhat involved in Bcl-xl's binding of Bim because Bcl-xl without its loop binds Bim less well than wild-type Bcl-xl. Moreover, the loop may have additional, as yet unknown, functions because it changes its shape when Bcl-xl binds Bim.     

Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression

B chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of slow-dividing and long-lived monoclonal B cells arrested at the intermediate stage of their differentiation. We previously showed that interleukin 4 (IL-4) not only inhibits but also prevents the proliferation of B-CLL cells. We report here that IL-4 protects the B-CLL cells from death by apoptosis (programmed cell death [PCD]). IL-4 inhibits spontaneous and hydrocortisone (HC)-induced PCD of highly purified B cells from 12 unselected CLL patients, as shown by sustained cell viability and lack of DNA fragmentation. IL-1, -2, -3, -5, -6, -7, tumor necrosis factor alpha, and transforming growth factor beta have no protective effect. The in vitro rescue from apoptosis by IL-4 is reflected by an increased expression of Bcl-2 protein, a proto-oncogene directly involved in the prolongation of cell survival in vivo and in vitro. Hence, IL-4-treated B-CLL cells express significantly more Bcl-2 than unstimulated, HC-treated, or fresh B-CLL cells. Furthermore, subcutaneous injection of IL-4 into one CLL patient enhances Bcl-2 protein expression in the leukemic B cells. These data may suggest that IL-4 prevents apoptosis of B-CLL cells using a Bcl-2-dependent pathway. Given our recent observations that fresh T cells from B-CLL patients express IL-4 mRNA, we propose that IL-4 has an essential role in the pathogenesis of CLL disease, by preventing both the death and the proliferation of the malignant B cells.     

Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic β cell death and diabetes

Mutations in pancreatic duodenal homeobox (PDX1) are linked to human type 2 diabetes and maturity-onset diabetes of the young type 4. Consistent with this, Pdx1-haploinsufficient mice develop diabetes. Both apoptosis and necrosis of β cells are mechanistically implicated in diabetes in these mice, but a molecular link between Pdx1 and these 2 forms of cell death has not been defined. In this study, we introduced an shRNA into mouse insulinoma MIN6 cells to deplete Pdx1 and found that expression of proapoptotic genes, including NIP3-like protein X (Nix), was increased. Forced Nix expression in MIN6 and pancreatic islet β cells induced programmed cell death by simultaneously activating apoptotic and mitochondrial permeability transition-dependent necrotic pathways. Preventing Nix upregulation during Pdx1 suppression abrogated apoptotic and necrotic β cell death in vitro. In Pdx1-haploinsufficient mice, Nix ablation normalized pancreatic islet architecture, β cell mass, and insulin secretion and eliminated reactive hyperglycemia after glucose challenge. These results establish Nix as a critical mediator of β cell apoptosis and programmed necrosis in Pdx1-deficient diabetes.     

Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice

Interleukin (IL)-7 receptor (R) signaling is essential for T and B lymphopoiesis by promoting proliferation, differentiation, and survival of cells. Mice lacking either IL-7 or the IL-7Ralpha chain have abnormally low numbers of immature as well as mature T and B lymphocytes. Transgenic expression of the apoptosis inhibitor Bcl-2 rescues T cell development and function in IL-7Ralpha-deficient mice, indicating that activation of a proapoptotic Bcl-2 family member causes death of immature and mature T cells. BH3-only proteins such as Bim, which are distant proapoptotic members of the Bcl-2 family, are essential initiators of programmed cell death and stress-induced apoptosis. We generated Bim/IL-7Ralpha double deficient mice and found that loss of Bim significantly increased thymocyte numbers, restored near normal numbers of mature T cells in the blood and spleen, and enhanced cytotoxic T cell responses to virus infection in IL-7Ralpha-/- mice. These results indicate that Bim cooperates with other proapoptotic proteins in the death of IL-7-deprived T cell progenitors in vivo, but is the major inducer of this pathway to apoptosis in mature T cells. This indicates that pharmacological inhibition of Bim function might be useful for boosting immune responses in immunodeficient patients.     

Functional role of interleukin 1 beta (IL-1 beta) in IL-1 beta- converting enzyme-mediated apoptosis

Prointerleukin-1 beta (pro-IL-1 beta) is the only known physiologic substrate of the interleukin-1 beta (IL-1 beta)-converting enzyme (ICE), the founding member of the ICE/ced-3 cell death gene family. Since secreted mature IL-1 beta has been detected after apoptosis, we investigated whether this cytokine, when produced endogenously, plays a role in cell death. We found that hypoxia-induced apoptosis can be inhibited by either the IL-1 receptor antagonist (IL-1Ra) or by neutralizing antibodies to IL-1 or to its type 1 receptor. IL-1Ra also inhibits apoptosis induced by trophic factor deprivation in primary neurons, as well as by tumor necrosis factor alpha in fibroblasts. In addition, during the G1/S phase arrest, mature IL-1 beta induces apoptosis through a pathway independent of CrmA-sensitive gene activity. We also demonstrate that Ice, when expressed in COS cells, requires the coexpression of pro-IL-1 beta for the induction of apoptosis, which is inhibited by IL-1Ra. Interestingly, we found that mature IL-1 beta has antiapoptotic activity when added exogenously before the onset of hypoxia, which we found is caused in part by its ability to downregulate the IL-1 receptor. Our findings demonstrate that pro-IL-1 beta is a substrate of ICE relevant to cell death, and depending on the temporal cellular commitment to apoptosis, mature IL-1 beta may function as a positive or negative mediator of cell death.     

沉默信息调节因子2相关酶1通过PINK1-Parkin线粒体自噬减轻创伤性脑损伤研究

目的 探讨沉默信息调节因子2相关酶1(SIRT1)通过PINK1-Parkin线粒体自噬发挥在创伤性脑损伤(TBI)中的神经保护作用及机制.方法 第一阶段实验,小鼠随机分为4组:空白组(野生型小鼠建立假模型后接受溶剂处理)、对照组(野生型小鼠建立假模型后接受20 mg/kg SRT1720处理)、模型组(野生型小鼠建立...     

Increased renal vasodilator prostanoids prevent hypertension in mice lacking the angiotensin subtype-2 receptor

The angiotensin subtype-1 (AT(1)) receptor mediates renal prostaglandin E(2) (PGE(2)) production, and pharmacological blockade of the angiotensin subtype-2 (AT(2)) receptor potentiates the action of angiotensin II (Ang II) to increase PGE(2) levels. We investigated the role of the AT(2) receptor in prostaglandin metabolism in mice with targeted deletion of the AT(2) receptor gene. Mice lacking the AT(2) receptor (AT(2)-null) had normal blood pressure that was slightly elevated compared with that of wild-type (WT) control mice. AT(2)-null mice had higher renal interstitial fluid (RIF) 6-keto-PGF(1alpha) (a stable hydrolysis product of prostacyclin [PGI(2)]) and PGE(2) levels than did WT mice, and had similar increases in PGE(2) and 6-keto-PGF(1alpha) in response to dietary sodium restriction and Ang II infusion. In contrast, AT(2)-null mice had lower PGF(2alpha) levels compared with WT mice during basal conditions and in response to dietary sodium restriction or infusion of Ang II. RIF cAMP was markedly higher in AT(2)-null mice than in WT mice, both during basal conditions and during sodium restriction or Ang II infusion. AT(1) receptor blockade with losartan decreased PGE(2), PGI(2), and cAMP to levels observed in WT mice. To determine whether increased vasodilator prostanoids prevented hypertension in AT(2)-null mice, we treated AT(2)-null and WT mice with indomethacin for 14 days. PGI(2), PGE(2), and cAMP were markedly decreased in both WT and AT(2)-null mice. Blood pressure increased to hypertensive levels in AT(2)-null mice but was unchanged in WT. These results demonstrate that in the absence of the AT(2) receptor, increased vasodilator prostanoids protect against the development of hypertension.     

Essential roles of DC-derived IL-15 as a mediator of inflammatory responses in vivo

Interleukin (IL)-15 is expressed in a variety of inflammatory diseases. However, the contribution of dendritic cell (DC)-derived IL-15 to the development of diseases is uncertain. Using established models of Propionibacterium acnes (P. acnes)- and zymosan-induced liver inflammation, we observed granuloma formation in the livers of wild-type (WT) and RAG-2(-/-) mice but not in those of IL-15(-/-) mice. We demonstrate that this is likely caused by an impaired sequential induction of IL-12, IFN-gamma, and chemokines necessary for monocyte migration. Likewise, lethal endotoxin shock was not induced in P. acnes- and zymosan-primed IL-15(-/-) mice or in WT mice treated with a new IL-15-neutralizing antibody. In both systems, proinflammatory cytokine production was impaired. Surprisingly, neither granuloma formation, lethal endotoxin shock, nor IL-15 production was induced in mice deficient for DCs, and adoptive transfer of WT but not IL-15(-/-) DCs restored the disease development in IL-15(-/-) mice. Collectively, these data indicate the importance of DC-derived IL-15 as a mediator of inflammatory responses in vivo.     

15d-PGJ2 alleviates ConA-induced acute liver injury in mice by up-regulating HO-1 and reducing hepatic cell autophagy

ObjectiveIn this study, we confirmed a protective effect of 15d-PGJ2 in concanavalin A (ConA)-induced fulminant hepatitis in mice and investigated the potential mechanism.Materials and methodsBalb/C mice were injected with ConA (25 mg/kg) to induce acute fulminant hepatitis, and 15d-PGJ2 (2.5–10 μg) was administered 30 min after the ConA injection. The histological grade, pro-inflammatory cytokine and ROS levels, apoptosis and autophagy activity, the expression of HO-1, Nrf2, JNK and Bcl-2 activity were determined 2, 4, and 8 h after the ConA injection.ResultsFollowing ConA challenge, the expression of cytokines tumor necrosis factor α (TNF-α) and interleukin 1β (IL-1β) was up-regulated. Treatment with 15d-PGJ2 reduced the pathological effects of ConA-induced fulminant hepatitis and significantly reduced the levels of TNF-α, IL-1β and ROS after injection. 15d-PGJ2 inhibited apoptosis and autophagic cell death, facilitated Nrf2 nuclear translocation, increased HO-1 expression and suppressed the JNK activation.Conclusion15d-PGJ2 alleviates ConA-induced acute liver injury in mice by up-regulating the anti-oxidative stress factor HO-1 and reducing the production of cytokines and ROS, thereby inhibiting hepatic cell autophagy probably induced by ROS.