Herpesvirus entry mediator (HVEM) attenuates signals mediated by the lymphotoxin β receptor (LTβR) in human cells stimulated by the shared ligand LIGHT

Signals mediated by members of the tumor necrosis factor receptor superfamily modulate a network of diverse processes including initiation of inflammatory responses and altering cell fate between pathways favoring survival and death. Although such pathways have been well-described for the TNF-α receptor, less is known about signaling induced by the TNF superfamily member LIGHT and how it is differentially altered by expression of its two receptors LTβR and HVEM in the same cell. We used cell lines with different relative expression of HVEM and LTβR to show that LIGHT-induced signals mediated by these receptors were associated with altered TRAF2 stability and RelA nuclear translocation. Production of the inflammatory chemokine CXCL10 was primarily mediated by LTβR. Higher expression of HVEM was associated with cell survival, while unopposed LTβR signaling favored pathways leading to apoptosis. Importantly, restoring HVEM expression in cells with low endogenous expression recapitulated the phenotype of cells with higher endogenous expression. Together, our data provide evidence that relative expression of HVEM and LTβR modulates canonical NF-κB and pro-apoptotic signals stimulated by LIGHT.     

The histopathological and electron-microscopic examination of the stereotactic pulsed radiofrequency and conventional radiofrequency thermocoagulation lesions in rat brain

Abstract

Objective: Neurodestructive procedures have been used for treating intractable pain for a long time. Pulsed radiofrequency (RF) is a newly defined energy type. Pulsed RF may be used in the treatment of patients with some pain syndromes in whom the pain could not be controlled by the alternative techniques. The objective of the present study was to examine the histological and electron microscopical changes in rat brain after pulsed RF application.

Methods: Forty-five male rats were used in these experiments. Lesions were applied stereotactically to the target areas of the rat brains. Two different RF energy type were used as representative models of pulsed-RF and conventional-RF procedures. The rats were kept alive for 21 days and then killed. The effect of pulsed RF lesions on cerebral tissue ultrastructure was studied.

Results: In the pulsed RF group, intracytoplasmic edema, clarity of the mitochondrial cristas and opening in the cell membrane pores were observed on the electron microscopic examination. In the conventional RF group, these findings were more prominent. In the pulsed RF group, the ratio of the effected neurons was 5.5% on light microscopic examination. In the conventional RF group, the ratio of the effected neurons was 14.26% and central necrosis was observed additionally.

Discussion: Pulsed RF caused ultrastructural changes in the neurons. The pulsed RF may possibly cause a depression on the cell membrane potential by opening the cell membrane pores and resulting in the ion entrance into the cell cytoplasm and intracytoplasmic edema. However, it seems that all these changes were reversible.     

Investigation of osteoclastogenic signalling of the RANKL substitute LIGHT

LIGHT (TNFSF14) is a member of the TNF superfamily and is known to substitute for RANKL to induce osteoclast differentiation. LIGHT binds HVEM and LTβR, but it is not known whether these receptors play a role in osteoclast formation or whether LIGHT acts via RANKL signalling pathways. We found that both RANKL and LIGHT strongly induced phosphorylation of Akt and NFκB but not JNK in mouse osteoclast precursor cells. The addition of an Akt inhibitor showed decreased osteoclast differentiation and resorption mediated by both RANKL and LIGHT. RT-PCR and FACS analysis showed that CD14⁺ human osteoclast precursors expressed HVEM and LTβR; expression levels of HVEM increased in the course of osteoclastogenesis and a decrease in LIGHT expression was associated with an increase in HVEM suggesting that there is a feedback loop related to this receptor. Our findings show that LIGHT is not inhibited by the soluble RANKL receptor OPG and that LIGHT is a potent osteoclastogenesis factor that activates the Akt, NFκB and JNK pathways.     

LIGHT-HVEM—BTLA共信号分子的研究进展

BTLA是新近发现的一个CD28超家族共抑制分子,它的配体不是B7家族成员而是TNF受体超家族成员HVEM。HVEM同时还存在一个TNF超家族的配体,即T细胞上可诱导表达的与HSV的糖蛋白D竞争结合HVEM的淋巴毒素类似物（LIGHT）。HVEM可以作为一个分子开关,通过结合LIGHT或BTLA7E免疫调节中发挥不同的作用。     

Light诱导类风湿关节炎滑膜细胞向破骨细胞转化

目的 观察Light在类风湿关节炎(RA)滑膜细胞向破骨细胞转化过程中的作用.方法 取8例RA患者滑膜组织,胶原酶消化获取滑膜细胞,每例滑膜细胞分成5份培养,第1组加入巨噬细胞集落刺激因子(MCSF)作阴性对照,第2组加入MCSF和LIGHT,第3组加入MCSF和核因子(NF)-κB受体激动剂配体(RANKL),第4组加入MCSF、LIGHT和RANKL,第5组加入LIGHT.体外培养2周后,行抗酒石酸酸性磷酸酶(TRAP)染色,F肌动蛋白(F-actin)染色以及象牙片上骨吸收陷窝观察破骨细胞的形成和活性.结果 第1组和第5组TRAP(-),F-actin(-),象牙片上无骨吸收陷窝形成;第2组TRAP(+),F-actin(+),骨陷窝形成(+),多核破骨细胞呈圆形和椭圆形,体积较小,骨陷窝分散,体积较小;第3组TRAP(++).F-actin(++),骨陷窝形成(++),多核破骨细胞体积大,骨陷窝较多,体积大,形态不规则;第4组TRAP(+++),F-actin(+++),骨陷窝形成(++++),多核破骨细胞更多,骨陷窝大且有融合趋势.结论 Light能诱导RA滑膜细胞向破骨细胞转化,并能促进RANKL诱导滑膜细胞向破骨细胞转化的能力.     

Transgenic expression of decoy receptor 3 protects islets from spontaneous and chemical-induced autoimmune destruction in nonobese diabetic mice

Decoy receptor 3 (DCR3) halts both Fas ligand- and LIGHT-induced cell deaths, which are required for pancreatic beta cell damage in autoimmune diabetes. To directly investigate the therapeutic potential of DCR3 in preventing this disease, we generated transgenic nonobese diabetic mice, which overexpressed DCR3 in beta cells. Transgenic DCR3 protected mice from autoimmune and cyclophosphamide-induced diabetes in a dose-dependent manner and significantly reduced the severity of insulitis. Local expression of the transgene did not alter the diabetogenic properties of systemic lymphocytes or the development of T helper 1 or T regulatory cells. The transgenic islets had a higher transplantation success rate and survived for longer than wild-type islets. We have demonstrated for the first time that the immune-evasion function of DCR3 inhibits autoimmunity and that genetic manipulation of grafts may improve the success and survival of islet transplants.     

LIGHT is dispensable for CD4+ and CD8+ T cell and antibody responses to influenza A virus in mice

The tumor necrosis factor family ligands, LIGHT (lymphotoxin like, exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes), 4-1BBL and CD70, are found in the same gene cluster on mouse chromosome 17. Although the roles of 4-1BB-4-1BBL and CD27-CD70 interactions in anti-viral T cell responses have been well established, the role of LIGHT in T cell activation/expansion in vivo is less clear. Under conditions that were previously employed to demonstrate a role for 4-1BBL in CD8+ T cell memory, wild-type and LIGHT-/- mice were infected with influenza A virus and primary and memory/recall responses were measured at various time points thereafter. Neither primary expansion nor memory/recall CD8+ T cell responses were affected by the absence of LIGHT, as measured up to 2 months post-infection. CD4+ T cell responses were also unaffected by LIGHT deficiency. Furthermore, we found that LIGHT played no role in the induction of influenza-specific IgG1 and IgG2a serum antibodies. Taken together, these data suggest that LIGHT is dispensable for the acquired immune response to influenza virus in mice with no effect on the induction, maintenance or reactivation of CD8+ T cell memory.     

LIGHT/HVEM/LTβR Interaction as a Target for the Modulation of the Allogeneic Immune Response in Transplantation

The exchange of information during interactions of T cells with dendritic cells, B cells or other T cells regulates the course of T, B and DC‐cell activation and their differentiation into effector cells. The tumor necrosis factor superfamily member LIGHT (homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) is transiently expressed upon T cell activation and modulates CD8 T cell‐mediated alloreactive responses upon herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR) engagement. LIGHT‐deficient mice, or WT mice treated with LIGHT‐targeting decoy receptors HVEM‐Ig, LTβR‐Ig or sDcR3‐Ig, exhibit prolonged graft survival compared to untreated controls, suggesting that LIGHT modulates the course and severity of graft rejection. Therefore, targeting the interaction of LIGHT with HVEM and/or LTβR using recombinant soluble decoy receptors or monoclonal antibodies represent an innovative therapeutic strategy for the prevention and treatment of allograft rejection and for the promotion of donor‐specific tolerance.