IL-23／IL-17炎症轴在实验性自身免疫性肝炎中的作用

目的通过建立实验性自身免疫性肝炎小鼠模型,观察外源性IL-23对实验性自身免疫性肝炎模型小鼠中IL-17的影响,探讨其可能的作用机制。方法以肝抗原S-100免疫C57BL／6小鼠制作自身免疫性肝炎动物模型,提取出脾淋巴细胞,将IL-23加入到抗CD,抗体活化后的脾淋巴细胞中进行培养,免疫组化观察IL-17在肝细胞中的分布及表达水平,RT-PCR和ELISA检测IL-17在脾淋巴细胞中的表达。结果与对照组相比,模型组肝细胞中IL-17表达升高;IL-23作用于模型组活化的脾淋巴细胞后IL-17的表达水平明显高于对照组。结论IL-23／IL-17炎症轴在EAH的病理机制中发挥着重要的作用,IL-23可能通过上调IL-17的表迭使AIH模型小鼠症状加重,并为AIH的治疗提供了新的靶点。     

A COX-2 metabolite of the endogenous cannabinoid, 2-arachidonyl glycerol, mediates suppression of IL-2 secretion in activated Jurkat T cells

Previous studies from this laboratory have demonstrated that a COX-2 metabolite of the endogenous cannabinoid, 2-arachidonyl glycerol (2-AG), inhibits IL-2 secretion in activated T cells through PPARgamma activation independent of the cannabinoid receptors, CB1/CB2. Because numerous cyclooxygenase (COX) products have been shown to activate PPARgamma, the primary purpose of the present studies was to determine the role of COX metabolism in the inhibition of IL-2 secretion by 2-AG. Pretreatment with nonselective and COX-2-specific inhibitors completely abrogated 2-AG-mediated suppression of IL-2 secretion. In contrast, pretreatment with COX-1-specific inhibitors had no effect upon 2-AG-mediated inhibition of IL-2 secretion. Interestingly, the current studies also demonstrate that while the potency of 2-AG is comparable between human Jurkat T cells and murine splenocytes, anandamide (AEA) is markedly more potent in suppressing IL-2 production in Jurkat T cells compared to murine splenocytes. Additionally, the present studies also demonstrate that COX-2 protein is readily detectable in resting Jurkat T cells, which is in contrast to resting murine splenocytes in which COX-2 protein is virtually undetectable. Furthermore, COX-2 protein and mRNA levels are significantly increased over basal levels by 2h following activation of Jurkat cells, whereas increases in COX-2 protein in murine splenocytes are not observed until 4h after cellular activation. These studies suggest that the potency of AEA in the suppression of IL-2 secretion may correlate with COX-2 protein levels in different T cell models. The present studies are also significant in that they demonstrate 2-AG-mediated inhibition of IL-2 secretion is dependent upon COX-2 metabolism.     

The multikinase inhibitor Sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE2 in murine macrophages

Classical activating stimuli like LPS drive macrophages to secrete a battery of inflammatory cytokines, including interleukin (IL)-12/23, through Toll-like receptor (TLR) signaling. TLR activation in the presence of some factors, including prostaglandin E₂ (PGE₂), promotes an anti-inflammatory cytokine profile, with production of IL-10 and suppression of IL-12/23 secretion. Extracellular signal-regulated kinase (ERK) is a key regulator of macrophage IL-10 production. Since it inhibits ERK, we investigated the impact of Sorafenib on the cytokine profile of macrophages. In the presence of PGE₂, Sorafenib restored the secretion of IL-12 and suppressed IL-10 production. Moreover, IL-12 secretion was enhanced by Sorafenib under conditions of TLR ligation alone. Furthermore, the impact of tumor culture supernatants, cholera toxin, and cAMP analogs (which suppress IL-12 secretion), was reversed by Sorafenib. Sorafenib inhibited the activation of the MAP kinase p38 and its downstream target mitogen and stress activated protein kinase (MSK), and partially inhibited protein kinase B (AKT) and its subsequent inactivation of the downstream target glycogen synthase kinase 3-β (GSK3-β). Interference with these pathways, which are pivotal in determining the balance of inflammatory versus anti-inflammatory cytokines, provides a potential mechanism by which Sorafenib can modulate the macrophage cytokine phenotype. These data raise the possibility that the use of Sorafenib as cancer therapy could potentially reverse the immunosuppressive cytokine profile of tumor-associated macrophages, rendering the tumor microenvironment more conducive to an anti-tumor immune response.     

IL-17-expressing cells as a potential therapeutic target for treatment of immunological disorders

IL-17 is a multifunctional cytokine produced by activated CD4+ and CD8+ lymphocytes as well as stimulated unconventional Tγδ and natural killer T cells. IL-17 induces expression of chemokines, proinflammatory cytokines and metalloproteinases, thereby stimulating the inflammation and chemotaxis of neutrophils. Elevation of proinflammatory cytokines is associated with asthma and autoimmune disorders, such as multiple sclerosis, rheumatoid arthritis and psoriasis. Although the role of IL-17 in these disorders is not always easy to define, extensive research has demonstrated an aggravating influence of IL-17 in some animal models. Thus, the development of therapeutics to reduce IL-17 levels is a promising strategy for ameliorating inflammatory diseases. This review briefly summarizes recent knowledge about stimulants and intracellular signaling pathways that induce development and maturation of IL-17-expressing cells. Its positive and negative roles on disease progression and its importance in vaccine-induced memory are also discussed. Finally, recent literature describing potential therapeutic approaches for targeting IL-17 is presented.     

IL-23: changing the verdict on IL-12 function in inflammation and autoimmunity

IL-12 and IL-23 are molecules mainly produced by activated accessory and antigen-presenting cells. The tools for studying the biology of IL-12 in man and laboratory rodents have greatly advanced our appreciation of the central role of this molecule in cell-mediated immunity and inflammation. In particular, IL-12 is thought to be the prime-regulator of T_H1 development. Targeting what was thought to be IL-12 function in vivo, resulted in drastic amelioration of inflammation and autoimmunity firmly linking T_H1 polarisation to autoimmune development. Upon discovery of IL-23 and the fact that the large subunit of IL-23 is shared by IL-12, the research community only begins to grasp that the features attributed to IL-12 and T_H1 development in inflammation are, in fact, dependent on IL-23 and not on IL-12. Hence, the perception of IL-12 biology is, to a large extent, based on a mistaken identity. In this review, the authors provide an overview of their current understanding of IL-12 and IL-23 biology in inflammation and autoimmunity, and how this viewpoint has been readjusted over the past 15 years.     

IL-23 in Infections,Inflammation, Autoimmunity and Cancer: Possible Role in HIV-1 and AIDS

The growing family of interleukin (IL)-12-like cytokines produced by activated macrophages and dendritic cells became the important players in the control of infections, development of inflammation, autoimmunity and cancer. However, the role of one of them—heterodimer IL-23, which consists of IL12p40 and the unique p19 subunit in HIV-1 infection pathogenesis and progression to AIDS, represent special interest. We overviewed findings of IL-23 involvement in control of peripheral bacterial pathogens and opportunistic infection, central nervous system (CNS) viral infections and autoimmune disorders, and tumorogenesis, which potentially could be applicable to HIV-1 and AIDS.     

Targeting IL-23 in autoimmunity

Dysregulated cell-mediated immune responses may lead to chronic inflammation and autoimmune disorders. The recent discovery of the dimeric interleukin (IL)-12-related cytokine IL-23 now adds to our understanding of the fine-tuning of cellular immunity. The critical implication of the role that IL-12p40 plays in autoimmune inflammation has long been misinterpreted and only recently have studies revealed that it is IL-23, and not IL-12, that is the decisive factor in this immune deviation. Therefore, targeting of IL-23 or the IL-23 receptor is a promising therapeutic approach for autoimmune diseases. This review summarizes recent findings regarding IL-23-mediated autoreactive inflammatory responses, and introduces possible therapeutic interventions that are aimed at mitigating autoimmune inflammation.     

IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases

IL-19, IL-20 and IL-24 are members of the IL-10 family of cytokines, the human IL-19, IL-20 and IL-24 genes are all located on the q32 region of chromosome 1, and the three cytokines also share a common receptor IL-20R1/IL-20R2 heterodimer. These cytokines due to the similarity and shared receptor usage, are quite overlapping in function. Recently, the available evidence has indicated that interaction of these cytokines with their receptors might exhibit pro-inflammatory effects on autoimmune diseases, particularly psoriasis and rheumatoid arthritis. Since an imbalance between anti- and pro-inflammatory cytokines contribute to the development of autoimune diseases, these cytokines may be implicated in the pathogenesis of autoimmunity. In this paper, we concisely discuss the biological features of IL-19, IL-20 and IL-24, and focus on their potential roles in autoimmune diseases. Hopefully the information obtained will lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for autoimmune diseases.     

白细胞介素-35在类风湿关节炎中作用的研究进展

类风湿关节炎(RA)是一种慢性炎症性疾病,疾病晚期可出现关节畸形和功能障碍,严重危害人类健康.RA的确切发病机制目前尚未阐明,遗传、免疫及环境等因素均发挥了一定作用.白细胞介素-35(IL-35)是由人类疱疹病毒4型(HHV-4))又称EB病毒(EBv)诱导基因3(EBI3)和p35两个亚基所组成的异源二聚体蛋白,是白细胞介素-12(IL-12)家族细胞因子成员之一.IL-35由调节性T细胞(Treg)分泌,具有抑制效应T细胞活性的作用,参与多种自身免疫性疾病、炎症性疾病以及感染性疾病的发生和发展.研究发现IL-35与RA之间有重要关系.该文对IL-35在RA的作用方面进行综述.     

Luteolin suppresses IL-31 production in IL-33-stimulated mast cells through MAPK and NF-κB signaling pathways

IL-31 and IL-33 are cytokines, which are expressed in many inflammatory and pathological disorders, thus suggesting an IL-31/IL-33 axis interaction in pathological diseases. Luteolin from natural products is known for its anti-inflammatory activities associated with the regulation of inflammatory signaling pathways. Here, we investigated the effects of luteolin in the regulation of IL-33-stimulated production and secretion of IL-31 in HMC-1.2 mast cells. Human mast cells (HMC-1.2) were treated with luteolin and stimulated with IL-33. Real-time PCR was used to measure IL-31 mRNA expression. Western blot and immunofluorescence assays were used to measure IL-31 expression. ELISA techniques were used to measure IL-31 secretion and NF-κB-DNA-binding activities. The results revealed that luteolin inhibited the expression of IL-31 in IL-33-stimulated HMC-1.2 cells at the mRNA and protein levels. Also, Luteolin inhibited the secretion of IL-31 into the cell culture media of the IL-33-stimulated HMC-1.2 cells. Further findings demonstrated that luteolin inhibited the activation of ERK, JNK, p38, and NF-κB p65 in the IL-33-stimulated HMC-1.2 cells. In addition, luteolin also prevented the nuclear translocation and binding of p65 to its DNA-binding site. Based on the results, luteolin may be considered as a potential therapeutic or functional food agent for the prevention and/or treatment of IL-31 and IL-33-related diseases.     

Role of cannabinoid receptors in Delta-9-tetrahydrocannabinol suppression of IL-12p40 in mouse bone marrow-derived dendritic cells infected with Legionella pneumophila

Delta-9-tetrahydrocannabinol (THC) injection suppresses serum interleukin-12 (IL-12) levels in Legionella pneumophila-infected mice. Dendritic cells are a major producer of IL-12 and mouse, bone marrow-derived dendritic cell cultures produced high levels of the IL-12p40 following L. pneumophila infection. Treatment with THC suppressed this cytokine response in a concentration-dependent manner and the endocannabinoid, 2-arachidonoyolglycerol, less potently suppressed cytokine production. Dendritic cells expressed mRNA for cannabinoid receptor 1 (CB(1)), cannabinoid CB(2) receptor, and vanilloid receptor 1 (TRPV1) and the addition of the G(i) inhibitor, pertussis toxin, completely attenuated suppression induced by 3 and 6 muM THC but not by 10 muM THC. Furthermore, THC suppression was partially attenuated in dendritic cells from cannabinoid CB(1) receptor and CB(2) receptor knockout mice and in dendritic cells co-treated with THC and cannabinoid receptor antagonists. Cytokine suppression was not attenuated by pretreatment with the TRPV1 antagonist, capsazepine. These results suggest that THC-induced suppression of serum IL-12 is partly due to a suppression of IL-12 production by dendritic cells and that G(i) signaling and cannabinoid receptors, but not TRPV1, are involved in this suppressive effect.     

The immunoregulatory and neuroprotective effects of human adipose derived stem cells overexpressing IL-11 and IL-13 in the experimental autoimmune encephalomyelitis mice

Multiple sclerosis (MS) is an inflammatory demyelination disease in the central nervous system (CNS) characterized by incomplete endogenous remyelination in the chronic phase. A shift of the balance between pro and anti-inflammatory cytokines is one of the important markers in the pathogenesis of MS. This study aimed to evaluate the effects of human adipose derived stem cells (hADSCs) overexpressing interleukin 11 and interleukin 13 (IL-11, 13-hADSCs) on the experimental autoimmune encephalomyelitis (EAE), an animal model of MS. 12 days after immunization of C57Bl/6 female mice with MOG35-55 and initial clinical symptoms appearance, the IL-11, 13-hADSCs were injected via the tail vein into the EAE mice. Then, the mice were sacrificed at 30 days post-immunization (DPI) and the spinal cords of experimental groups were extracted for histopathological and real-time RT-PCR studies. The results indicated that the clinical scores and mononuclear cells infiltration into the spinal cords of EAE mice were significantly reduced in mice treated with IL-11, 13-hADSCs. Likewise, the remyelination and oligodendrogenesis were significantly enhanced in the mentioned treatment group. Real-time results demonstrated that pro/anti-inflammatory cytokine genes expression was reversed in IL-11, 13-hADSCs treatment group in comparison to the untreated EAE group. Expression of IL-11 as a neurotrophic cytokine and IL-13 as an anti-inflammatory cytokine by hADSCs could increase the immunomodulatory and neuroprotective effects of hADSCs and be a powerful candidate in stem cell therapy for future treatment of MS.     

Pathophysiology of interleukin-23 in experimental autoimmune encephalomyelitis

Interleukin-23 (IL-23) is a heterodimeric cytokine that is composed of a p40 subunit, shared with the closely related cytokine IL-12, and a smaller IL-23p19 subunit. It belongs to a family of heterodimeric cytokines that also includes IL-12 and IL-27. Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease that serves as a model for multiple sclerosis, an inflammatory demyelinating disease of the central nervous system that is a frequent cause of disability in young adults. EAE is thought to be initiated by CD4+ T cells. The production of interferon-gamma and tumor necrosis factor-alpha (T helper 1 [Th1] phenotype) was considered a marker for the ability of such cells to induce disease. Consistent with this view, IL-12, a cytokine that induces the differentiation of Th1 cells, was considered essential for EAE susceptibility. However, it is now clear that IL-23 rather than IL-12 is required for EAE susceptibility. IL-23 induces a population of IL-17-producing cells that is more critically involved in EAE pathogenesis than Th1 cells. Here, we review the role of the IL-23 system in the pathophysiology of EAE.     

Crotalphine Attenuates Pain and Neuroinflammation Induced by Experimental Autoimmune Encephalomyelitis in Mice

Multiple sclerosis (MS) is a demyelinating disease of inflammatory and autoimmune origin, which induces sensory and progressive motor impairments, including pain. Cells of the immune system actively participate in the pathogenesis and progression of MS by inducing neuroinflammation, tissue damage, and demyelination. Crotalphine (CRO), a structural analogue to a peptide firstly identified in Crotalus durissus terrificus snake venom, induces analgesia by endogenous opioid release and type 2 cannabinoid receptor (CB2) activation. Since CB2 activation downregulates neuroinflammation and ameliorates symptoms in mice models of MS, it was presently investigated whether CRO has a beneficial effect in the experimental autoimmune encephalomyelitis (EAE). CRO was administered on the 5th day after immunization, in a single dose, or five doses starting at the peak of disease. CRO partially reverted EAE-induced mechanical hyperalgesia and decreased the severity of the clinical signs. In addition, CRO decreases the inflammatory infiltrate and glial cells activation followed by TNF-α and IL-17 downregulation in the spinal cord. Peripherally, CRO recovers the EAE-induced impairment in myelin thickness in the sciatic nerve. Therefore, CRO interferes with central and peripheral neuroinflammation, opening perspectives to MS control.     

Differential effects of pentoxifylline, a non-specific phosphodiesterase inhibitor, on the production of IL-10, IL-12 p40 and p35 subunits by murine peritoneal macrophages

Pentoxifylline (PTX), a methylxanthine derivative, has been reported to be an effective drug in inhibiting TNF-alpha responses during septic shock. The inhibition of TNF-alpha production seems to be correlated with increased intracellular cAMP levels. PTX also affects the production of other cytokines such as IL-1, IL-6, IL-10, IL-12, and IFN-gamma. However, inhibition, as well as enhancement of cytokine production, has been observed in vitro, depending on the PTX concentration and cell type used.IL-12 is a heterodimeric cytokine that plays an important role in the development of Th1-mediated inflammatory responses. IL-12 along with TNF-alpha and other proinflammatory cytokines has shown to be responsible for the pathological reaction, which may lead to septic shock. For biological activity, the expression of both subunits of IL-12, p35 and p40, is required. Moreover, the p40 chain of IL-12 specifically inhibits the effects of the IL-12 heterodimer.In this study, we investigated the effects of PTX on the production of both proinflammatory (TNF-alpha, IL-6, IL-12) and anti-inflammatory (IL-10) cytokines by murine macrophages (Mφ). We have found that PTX, at concentrations below 100 microg/ml, selectively inhibited the production of TNF-alpha. Forskolin, a cAMP-elevating agent, similarly affected the production of the cytokines tested. However, at higher concentrations, PTX inhibited the production of TNF-alpha, IL-10, and IL-12 p35, but surprisingly, PTX enhanced the production of IL-12 p40. Concentrations of IL-10 were negatively correlated with the concentrations of IL-12 p40 subunit. These results further confirm the relevance of the use of PTX in clinical trials of immunological disorders characterised by inappropriate Th1 type immune responses.     

Anti-inflammatory effects of aromatic-turmerone through blocking of NF-κB, JNK, and p38 MAPK signaling pathways in amyloid β-stimulated microglia

Amyloid β (Aβ) induces the production of neuroinflammatory molecules, which may contribute to the pathogenesis of numerous neurodegenerative diseases. Therefore, suppression of neuroinflammatory molecules could be developed as a therapeutic method. Aromatic (ar)-turmerone, turmeric oil isolated from Curcuma longa, has long been used in Southeast Asia as both a remedy and a food. In this study, we investigated the anti-inflammatory effects of ar-turmerone in BV2 microglial cells. Aβ-stimulated microglial cells were tested for the expression and activation of MMP-9, iNOS, and COX-2, the production of proinflammatory cytokines, chemokines, and ROS, as well as the underlying signaling pathways. Ar-turmerone significantly suppressed Aβ-induced expression and activation of MMP-9, iNOS, and COX-2, but not MMP-2. Ar-turmerone also reduced TNF-α, IL-1β, IL-6, and MCP-1 production in Aβ-stimulated microglial cells. Further, ar-turmerone markedly inhibited the production of ROS. Impaired translocation and activation of NF-κB were observed in Aβ-stimulated microglial cells exposed to ar-turmerone. Furthermore, ar-turmerone inhibited the phosphorylation and degradation of IκB-α as well as the phosphorylation of JNK and p38 MAPK. These results suggest that ar-turmerone impaired the Aβ-induced inflammatory response of microglial cells by inhibiting the NF-κB, JNK, and p38 MAPK signaling pathways. Lastly, ar-turmerone protected hippocampal HT-22 cells from indirect neuronal toxicity induced by activated microglial cells. These novel findings provide new insights into the development of ar-turmerone as a therapeutic agent for the treatment of neurodegenerative disorders.     

IL-23／IL-17轴对寻常型银屑病病情的影响

目的：通过观察甲砜霉素联合异维A酸胶丸治疗寻常型银屑病的疗效,检测患者血清辅助T细胞17（ Th17）相关因子白介素17（IL-17）、白介素22（IL-22）和白介素23（IL-23）水平的变化,分析其与疾病严重程度及转归的关系,探讨银屑病可能的发病机制。方法治疗组为寻常型银屑病40例,对照组为健康体检者40例;治疗组给予甲砜霉素、异维A酸胶丸口服及丁酸氢化可的松乳膏外用。以4周为1个疗程,2个疗程后进行疗效判定。治疗组治疗前后分别检测血清IL-17、IL-22和IL-23的水平,与对照组进行比较,分析IL-17、IL-22、IL-23与严重程度指数（psoriasis area and severity index,PASI）相关性。结果治疗组治疗前后血清IL-17、IL-22、IL-23水平较对照组高,差异有统计学意义（P＜0．01）,治疗8周后IL-17、IL-22、IL-23水平较治疗前明显下降（ P＜0.01）。治疗组治疗前IL-17、IL-22与IL-23表达水平与PASI评分之间均呈正相关（ r分别为0.77、0．76、0．60,P均＜0．05）。结论 IL-23／IL-17轴可能在寻常型银屑病的发病机制中起重要作用,IL-17、IL-22、IL-23可以作为判断寻常型银屑病严重程度的重要指标,降低IL-17、IL-22、IL-23表达可能成为治疗寻常型银屑病的新的方向。