Interferon γ–independent Rejection of Interleukin 12–transduced Carcinoma Cells Requires CD4+ T Cells and Granulocyte/Macrophage Colony–stimulating Factor

We analyzed the ability of interferon (IFN)-γ knockout mice (GKO) to reject a colon carcinoma transduced with interleukin (IL)-12 genes (C26/IL-12). Although the absence of IFN-γ impaired the early response and reduced the time to tumor onset in GKO mice, the overall tumor take rate was similar to that of BALB/c mice. In GKO mice, C26/IL-12 tumors had a reduced number of infiltrating leukocytes, especially CD8 and natural killer cells. Analysis of the tumor site, draining nodes, and spleens of GKO mice revealed reduced expression of IFN- inducible protein 10 and monokine induced by γ-IFN. Despite these defects, GKO mice that rejected C26/IL-12 tumor, and mice that were primed in vivo with irradiated C26/IL-12 cells, showed the same cytotoxic T lymphocyte activity but higher production of granulocyte/macrophage colony–stimulating factor (GM-CSF) as compared with control BALB/c mice. Treatment with monoclonal antibodies against GM-CSF abrogated tumor regression in GKO but not in BALB/c mice. CD4 T lymphocytes, which proved unnecessary or suppressive during rejection of C26/IL-12 cells in BALB/c mice, were required for tumor rejection in GKO mice. CD4 T cell depletion was coupled with a decline in GM-CSF expression by lymphocytes infiltrating the tumors or in the draining nodes, and with the reduction and disappearance of granulocytes and CD8 T cells, respectively, in tumor nodules. These results suggest that GM-CSF can substitute for IFN-γ in maintaining the CD8–polymorphonuclear leukocyte cross-talk that is a hallmark of tumor rejection.     

Lansoprazole, a Proton Pump Inhibitor, Suppresses Production of Tumor Necrosis Factor-α and Interleukin-1β Induced by Lipopolysaccharide and Helicobacter Pylori Bacterial Components in Human Monocytic Cells via Inhibition of Activation of Nuclear Factor-κB and Extracellular Signal-Regulated Kinase

Pathogenic bacterial components play critical roles in initiation of gastrointestinal inflammation via activation of intracellular signaling pathways which induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Lansoprazole (LANSO), a proton pump inhibitor, has been widely used for the treatment of peptic ulcers and reflux esophagitis due to its potent acid-suppressive effect. It has also been reported to have anti-inflammatory effects. In this study we investigated the effects of LANSO on the production of TNF-α and IL-1β induced by lipopolysaccharide (LPS) and Helicobacter pylori water-soluble extract (HpWE) in the human monocytic cell line (THP-1). LANSO (100 µM) significantly reduced mRNA expression and production of TNF-α and IL-1β by THP-1 cells stimulated by LPS and HpWE. LANSO inhibited phosphorylation and degradation of inhibitory factor κB-α (IκB-α) and phosphorylation of extracellular signal-regulated kinase (ERK) induced by LPS and HpWE in THP-1 cells. These findings suggest that LANSO exerts anti-inflammatory effects by suppressing induction of TNF-α and IL-1β via inhibition of nuclear factor (NF)-κB and ERK activation.     

Transforming Growth Factor β Production Is Inversely Correlated with Severity of Murine Malaria Infection

We have examined the role of the immunomodulatory cytokine transforming growth factor (TGF)-β in the resolution and pathology of malaria in BALB/c mice. Circulating levels of TGF-β, and production of bioactive TGF-β by splenocytes, were found to be low in lethal infections with Plasmodium berghei. In contrast, resolving infections with P. chabaudi chabaudi or P. yoelii were accompanied by significant TGF-β production. A causal association between the failure to produce TGF-β and the severity of malaria infection was demonstrated by treatment of infected mice with neutralizing antibody to TGF-β, which exacerbated the virulence of P. berghei and transformed a resolving P. chabaudi chabaudi infection into a lethal infection, but had little effect on the course of P. yoelii infection. Parasitemia increased more rapidly in anti–TGF-β–treated mice but this did not seem to be the explanation for the increased pathology of infection as peak parasitemias were unchanged. Treatment of P. berghei–infected mice with recombinant TGF-β (rTGF-β) slowed the rate of parasite proliferation and prolonged their survival from 15 to up to 35 d. rTGF-β treatment was accompanied by a significant decrease in serum tumor necrosis factor α and an increase in interleukin 10. Finally, we present evidence that differences in TGF-β responses in different malaria infections are due to intrinsic differences between species of malaria parasites in their ability to induce production of TGF-β. Thus, TGF-β seems to induce protective immune responses, leading to slower parasite growth, early in infection, and, subsequently, appears to downregulate pathogenic responses late in infection. This duality of effect makes TGF-β a prime candidate for a major immunomodulatory cytokine associated with successful control of malaria infection.     

γδ TCR T lymphoblastic leukemia in a child presenting with marked hyperleukocytosis

γδ TCR T lymphoblastic leukemia is rare in children and should be differentiated mainly from hepatosplenic T‐cell lymphoma in this age group.     

Effects of Oxidized Frying Oil on Proteins Related to α-Tocopherol Metabolism in Rat Liver

An oxidized frying oil (OFO) diet has been reported to induce an increase in lipid peroxidation and a reduction in vitamin E status in animal tissues. This study was performed to investigate how vitamin E metabolism is influenced by OFO. Male Wistar rats were divided into three groups, a control group (CO) and two OFO-fed groups (OF and OFE). The diet of the OFE group was supplemented with an extra 50 mg/kg of α-tocopherol acetate and thus contained twice as much vitamin E as that of the OF group. After six weeks on these diets, liver α-tocopherol levels in the OF group were the significantly lowest among the three groups. Excretion of the α-tocopherol metabolite, α-carboxyethyl hydroxychroman (α-CEHC) in the urine was significantly lower in the OF group than in the other two groups. There were no significant differences in protein levels of α-tocopherol transfer protein (α-TTP) and multidrug resistance protein among the three groups. Protein levels of cytochrome P450 monooxygenase (CYP) 3A, CYP4A, and catalase were markedly increased in both groups on the OFO diet. This suggests that an OFO diet may interfere with medicine metabolism and needs further investigation.     

CD161 (NKR-P1A) Costimulation of CD1d-dependent Activation of Human T Cells Expressing Invariant Vα24JαQ T Cell Receptor α Chains

A population of human T cells expressing an invariant Vα24JαQ T cell antigen receptor (TCR) α chain and high levels of CD161 (NKR-P1A) appears to play an immunoregulatory role through production of both T helper (Th) type 1 and Th2 cytokines. Unlike other CD161⁺ T cells, the major histocompatibility complex–like nonpolymorphic CD1d molecule is the target for the TCR expressed by these T cells (Vα24^invt T cells) and by the homologous murine NK1 (NKR-P1C)⁺ T cell population. In this report, CD161 was shown to act as a specific costimulatory molecule for TCR-mediated proliferation and cytokine secretion by Vα24^invt T cells. However, in contrast to results in the mouse, ligation of CD161 in the absence of TCR stimulation did not result in Vα24^invt T cell activation, and costimulation through CD161 did not cause polarization of the cytokine secretion pattern. CD161 monoclonal antibodies specifically inhibited Vα24^invt T cell proliferation and cytokine secretion in response to CD1d⁺ target cells, demonstrating a physiological accessory molecule function for CD161. However, CD1d-restricted target cell lysis by activated Vα24^invt T cells, which involved a granule-mediated exocytotic mechanism, was CD161-independent. In further contrast to the mouse, the signaling pathway involved in Vα24^invt T cell costimulation through CD161 did not appear to involve stable association with tyrosine kinase p56^Lck. These results demonstrate a role for CD161 as a novel costimulatory molecule for TCR-mediated recognition of CD1d by human Vα24^invt T cells.     

Menthol Enhances an Antiproliferative Activity of 1α,25-Dihydroxyvitamin D3 in LNCaP Cells

1α,25-dihydroxyvitamin D₃ [1α,25(OH)₂D₃], the most active form of vitamin D₃, and its analogues have therapeutic benefits for prostate cancer treatment. However, the development of hypercalcemia is an obstacle to clinical applications of 1α,25(OH)₂D₃ for cancer therapy. In this study, we provide evidence that menthol, a key component of peppermint oil, increases an anti-proliferation activity of 1α,25(OH)₂D₃ in LNCaP prostate cancer cells. We found that menthol per se does not exhibit antiproliferative activity, but it is able to enhance 1α,25(OH)₂D₃-mediated growth inhibition in LNCaP cells. Fluorometric assays using Fura-2 showed that 1α,25(OH)₂D₃ does not induce acute Ca²⁺ response, whereas menthol evokes an increase in [Ca²⁺]_i, which suggests that cross-talks of menthol-induced Ca²⁺ signaling with 1α,25(OH)₂D₃-mediated growth inhibition pathways. In addition, Western blot analysis revealed that 1α,25(OH)₂D₃ and menthol cooperatively modulate the expression of bcl-2 and p21 which provides the insight into the molecular mechanisms underlying the enhanced 1α,25(OH)₂D₃-mediated growth inhibition by menthol. Thus, our findings suggest that menthol may be a useful natural compound to enhance therapeutic effects of 1α,25(OH)₂D₃.     

The Degradation and Regeneration of α-Lipoic Acid under the Irradiation of UV Light in the Existence of Homocysteine

α-Lipoic acid (LA) is the one of the strongest antioxidants to be utilized in supplement, skin ointment and so on. The distorted five membered dithiolane ring of LA, which is necessary structure to work as a cofactor of enzyme, is considerably vulnerable to UV irradiation. LA is easily decomposed by photoirradiation resulting in the loss of its characteristic absorption band at 333 nm. The photodegradation of LA means loss of its physiological activity, so that protection of LA from UV light is eagerly desired. Thiol compounds can be regarded as a potential candidate. In order to pursue the possibility of the thiol compounds in prevention of LA degradation, we examined the photoirradiation of LA in the presence and absence of homocysteine.     

β-arrestin2通过调控自噬水平在结肠炎中的作用

目的 研究β-抑制蛋白2 （β-arrestin2）是否通过调控自噬水平在结肠炎中发挥作用。方法 β-arrestin2野生型（WT）小鼠和β-arrestin2基因敲除（KO）小鼠各20只,随机分为4组,每组各10只,分别为β-arrestin2 WT对照组和实验组,β-arrestin2 KO对照组和实验组。实验组小鼠自由饮用3%葡聚糖硫酸钠7 d诱导急性溃疡性结肠炎,对照组给予无菌ddH₂O。观察并记录各组小鼠的疾病活动指数。收集小鼠结肠组织,免疫组织化学和蛋白免疫印迹法检测自噬相关蛋白微管相关蛋白1轻链3β（LC3B）、Beclin1的表达水平。在HCoEpiC细胞中,通过siRNA沉默β-arrestin2的表达,Earle's平衡盐溶液（EBSS）处理细胞以诱导细胞自噬的发生,检测LC3B表达水平。结果 β-arrestin2 WT实验组小鼠的结肠黏膜自噬相关蛋白表达水平上调,而β-arrestin2 KO实验组小鼠的结肠炎症程度明显改善,自噬相关蛋白LC3B-Ⅱ/Ⅰ表达水平下降（P < 0.05）,但Beclin1表达水平比较差异无统计学意义（P > 0.05）。在HCoEpiC细胞中沉默β-arrestin2的表达,EBSS处理后,LC3B-Ⅱ/Ⅰ表达水平下调。结论 在结肠炎中,β-arrestin2调控自噬水平,当β-arrestin2缺失时,可以通过抑制自噬改善结肠炎。     

Induction of HIV-1 Replication in Latently Infected CD4+ T Cells Using a Combination of Cytokines

Although it has been demonstrated that certain cytokines, particularly proinflammatory cytokines, can enhance ongoing viral replication in peripheral blood mononuclear cells (PBMCs) of HIV-1–infected individuals, it is unclear what role these cytokines play in the induction of HIV-1 replication in latently infected, resting CD4⁺ T cells. This study demonstrates that the in vitro combination of the proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α together with the immunoregulatory cytokine IL-2 are potent inducers of viral replication in highly purified, latently infected, resting CD4⁺ T cells derived from HIV-infected individuals who are antiretroviral therapy–naive as well as those who are receiving highly active antiretroviral therapy (HAART). Viral replication induced by this combination of cytokines was completely suppressed in the presence of HAART in vitro. Given that an array of cytokines, including IL-6, TNF-α, and IL-2, are copiously expressed in the microenvironment of the lymphoid tissues, which harbor the latent viral reservoirs, induction of HIV by this combination of cytokines may in part explain the commonly observed reappearance of detectable plasma viremia in HIV-infected individuals in whom HAART was discontinued. Moreover, since it is likely that these infected cells die upon activation of virus and that HAART prevents spread of virus to adjacent cells, the observation that this combination of cytokines can markedly induce viral replication in this reservoir may have important implications for the activation-mediated diminution of the latent reservoir of HIV in patients receiving HAART.