IL-33与免疫细胞的关系

IL-33是IL-1家族的新成员,在炎性刺激后由多种细胞表达IL-33,并且在细胞溶解过程中释放.IL-33的膜表面受体包括ST2和IL-1受体辅佐蛋白,机体广泛表达ST2,尤其是在Th2型细胞和肥大细胞等免疫细胞中.IL-33通过结合免疫细胞膜表面的ST2将活化信号传递到胞内,经过一系列的信号传递,引起IL-5等免疫因子的释放,起到调节免疫应答等功能.     

药物性肝损伤与免疫性肝损伤肝组织中lncRNA表达谱的差异分析

目的:研究长链非编码RNA(lncRNA)在药物性肝损伤及免疫性肝损伤中表达谱的变化,并分析二者的差异。方法:利用lncRNA芯片技术分别检测对乙酰氨基酚诱导的小鼠药物性肝损伤及刀豆蛋白A诱导的小鼠免疫性肝损伤肝组织的lncRNA表达谱,通过对原始数据进行预处理达到均一化后,筛选出差异表达lncRNA并进行分析。结果:与正常肝脏组织比较,变化1.5倍以上并且差异有统计学意义(P0.05)的lncRNA被认为是差异表达的lncRNA;药物性肝损伤肝组织中变化1.5倍以上的共68条,其中升高1.5倍以上的共21条,降低1.5倍以上的共47条;免疫性肝损伤肝组织中变化1.5倍以上的共60条,其中升高1.5倍以上的共17条,降低1.5倍以上的共43条。所有的lncRNA中有8条lncRNA同时在2种肝损伤肝组织中上调,在药物性肝损伤肝组织上调的lncRNA中占38%,在免疫性肝损伤肝组织中占47%;有28条lncRNA同时在2种肝损伤肝组织中下调,在药物性肝损伤肝组织下调的lncRNA中占59%,在免疫性肝损伤肝组织中占65%。结论:与正常肝脏组织比较,药物性肝损伤肝组织和免疫性肝损伤肝组织中lncRNA表达谱均发生明显变化,且2种不同肝损伤肝组织比较,lncRNA表达谱也存在差异,提示2种肝损伤肝组织中这些同时上、下调的lncRNA可能参与了2种肝损伤之间相似或是相同的病理生理过程,而那些表达不同的lncRNA可能参与相对特异的肝损伤机制的发生。     

Endogenous IL-33 enhances Th2 cytokine production and T-cell responses during allergic airway inflammation

IL-33 is an IL-1-related cytokine which has been implicated in T(h)2-associated biology and allergic diseases in humans and mice. IL-33 stimulates T(h)2 cells, mast cells, eosinophils, basophils, iNKT cells and circulating CD34(+) stem cells to proliferate and produce pro-allergic cytokines such as IL-5 and IL-13. IL-33 mediates its cytokine effects through a receptor consisting of ST2 and IL-1RAcP. Whereas IL-1RAcP is ubiquitously expressed, ST2 expression is cell-type restricted and determines responsiveness to IL-33. Studies employing ST2-deficient mice have reported variable results on the role of this receptor, and consequently IL-33, with regards to allergic lung inflammation. In this study, we demonstrate that IL-33 is important for allergic lung inflammation. Intra-nasal administration of IL-33 triggered an immediate allergic response in the airways, and more importantly, we show that endogenous IL-33 contributes to airway inflammation and peripheral antigen-specific responses in ovalbumin-induced acute allergic lung inflammation using IL-33-deficient mice. Our results suggest that IL-33 is sufficient and required for severe allergic inflammation in the lung and support the concept of IL-33 as a therapeutic target in allergic lung inflammation.     

IL-33-activated dendritic cells are critical for allergic airway inflammation

IL-33, a new member of the IL-1 family cytokine, is involved in Th2-type responses in a wide range of diseases and signals through the ST2 receptor expressed on many immune cells. Since the effects of IL-33 on DCs remain controversial, we investigated the ability of IL-33 to modulate DC functions in vitro and in vivo. Here, we report that IL-33 activates myeloid DCs to produce IL-6, IL-1b, TNF, CCL17 and to express high levels of CD40, CD80 OX40L and CCR7. Importantly, IL-33-activated DCs prime naive lymphocytes to produce the Th2 cytokines IL-5 and IL-13, but not IL-4. In vivo, IL-33 exposure induces DC recruitment and activation in the lung. Using an OVA-induced allergic lung inflammation model, we demonstrate that the reduced airway inflammation in ST2-deficient mice correlates with the failure in DC activation and migration to the draining LN. Finally, we show that adoptive transfer of IL-33-activated DCs exacerbates lung inflammation in a DC-driven model of allergic airway inflammation. These data demonstrate for the first time that IL-33 activates DCs during antigen presentation and thereby drives a Th2-type response in allergic lung inflammation.     

Immunological aspects of drug-induced liver injury

Drug induced liver injury(DILI) is a common condition of increasing incidence. Many environmental and genetic factors are involved in its pathogenesis,and immunological mechanisms are also thought to contribute to the development and severity of DILI. This review summarizes current understanding of the immunological pathogenesis of DILI and discusses the perspective for clinical applications.     

Integrin signalling and function in immune cells

Integrins not only mediate cell-cell and cell-extracellular matrix adhesion, but also affect the multitude of signal transduction cascades in control of cell survival, proliferation, differentiation and organ development. Mutations in integrins or the major effectors of integrin signalling pathways cause defective organ development, immunodeficiency, cancer or autoimmune disease. Understanding of the signalling events that drive integrin activation and signalling is therefore crucial to uncover the molecular mechanisms of these diseases. This review discusses the key signalling complexes regulating integrin activation and function in both 'inside-out' and 'outside-in' pathways in T lymphocytes, including kinases, SLP-76, VAV1, ADAP, SKAP-55, RapL, RIAM, Rap1, Talin and Kindlin.     

The roles of innate immune cells in liver injury and regeneration

For predominant abundance with liver-specific Kupffer cells, natural killer （NK） cells, and natural killer T （NKT） cdls and their rapid responses to several stimuli, the liver is considered as an organ with innate immune features. In contrast to their roles in the defense of many infectious agents like hepatitis viruses and parasites, hepatic innate immune cells are also involved in the immunopathogenesis of human clinical liver diseases and several murine hepatitis models such as concanavalin A （Con A）, lipopolysaccharide （LPS）, or polyinosinic-polycytidylic acid （Poly I：C）-induced liver injury. In this review, the destructive roles of NK cells, NKT cells and Kupffer cells in the processes of immune-mediated liver injury and regeneration will be discussed, and some putative mechanisms involving the impairment of liver regeneration caused by activated hepatic innate immune cells are also proposed.     

IL-33 induces skin inflammation with mast cell and neutrophil activation

Psoriasis is a common chronic autoimmune condition of the skin characterized by hyperplasia of epidermal keratinocytes associated with pro-inflammatory cytokines. IL-33 is a new member of the IL-1 superfamily that signals through the ST2 receptor and was originally defined as an inducer of T helper 2 (Th2) cytokines. Recently, broader immune activatory potential has been defined for IL-33 particularly via mast cell activation and neutrophil migration. Here, we show that ST2(-/-) mice exhibit reduced cutaneous inflammatory responses compared with WT mice in a phorbol ester-induced model of skin inflammation. Furthermore, injections of IL-33 into the ears of mice induce an inflammatory skin lesion. This inflammatory response was partially dependent on mast cells as mast cell-deficient mice (Kit(W-sh/W-sh) ) showed delayed responses to IL-33. IL-33 also recruited neutrophils to the ear, an effect mediated in part by increased production of the chemokine KC (CXCL1). Finally, we show that IL-33 expression is up-regulated in the epidermis of clinical psoriatic lesions, compared with healthy skin. These results therefore demonstrate that IL-33 may play a role in psoriasis-like plaque inflammation. IL-33 targeting may provide a new treatment strategy for psoriasis.     

IL-33 targeting attenuates intestinal mucositis and enhances effective tumor chemotherapy in mice

Intestinal damage and severe diarrhea are serious side effects of cancer chemotherapy and constrain the usage of most such therapies. Here we show that interleukin-33 (IL-33) mediates the severe intestinal mucositis in mice treated with irinotecan (CPT-11), a commonly used cancer chemotherapeutic agent. Systemic CPT-11 administration led to severe mucosal damage, diarrhea, and body weight loss concomitant with the induction of IL-33 in the small intestine (SI). This mucositis was markedly reduced in mice deficient in the IL-33R (ST2^−/−). Moreover, recombinant IL-33 exacerbated the CPT-11-induced mucositis, whereas IL-33 blockade with anti-IL-33 antibody or soluble ST2 markedly attenuated the disease. CPT-11 treatment increased neutrophil accumulation in the SI and adhesion to mesenteric veins. Supernatants from SI explants treated with CPT-11 enhanced transmigration of neutrophils in vitro in an IL-33-, CXCL1/2-, and CXCR2-dependent manner. Importantly, IL-33 blockade reduced mucositis and enabled prolonged CPT-11 treatment of ectopic CT26 colon carcinoma, leading to a beneficial outcome of the chemotherapy. These results suggest that inhibition of the IL-33/ST2 pathway may represent a novel approach to limit mucositis and thus improve the effectiveness of chemotherapy.     

急性免疫性血小板减少症患儿血清IL-33检测及其意义

为研究IL-33在儿童急性免疫性血小板减少症(ITP)发病机制中的作用及意义,我们采用ELISA法检测了37名ITP患儿和37名对照者血清IL-33水平,分析IL-33与患儿就诊时血小板计数及后期疗效的关系。我们发现,ITP患儿血清IL-33较对照者明显增高(P<0.01),且与血小板计数呈负相关(R2=0.10,P=0.05)。血清IL-33水平与治疗效果密切相关,采用IL-33预测ITP患儿疗效,预测敏感性为0.88,特异性为0.81。这些结果提示:IL-33参与了ITP的发病机制,血清IL-33水平可以作为预测患儿疗效的免疫学指标。     

IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis

Natural killer (NK) cells are traditionally considered as innate cells, but recent studies suggest that NK cells can distinguish antigens, and that memory NK cells expand and protect against viral pathogens. Limited information is available about the mechanisms involved in memory-like NK cell expansion, and their role in bacterial infections and vaccine-induced protective immune responses. In the current study, using a mouse model of tuberculosis (TB) infection, we found that interferon-gamma producing CD3−NKp46+CD27+KLRG1+ memory-like NK cells develop during Bacille Calmette–Guérin vaccination, expand, and provide protection against challenge with Mycobacterium tuberculosis (M. tb). Using antibodies, short interfering RNA and gene-deleted mice, we found that expansion of memory-like NK cells depends on interleukin 21 (IL-21). NKp46+CD27+KLRG1+ NK cells expanded in healthy individuals with latent TB infection in an IL-21-dependent manner. Our study provides first evidence that memory-like NK cells survive long term, expansion depends on IL-21, and involved in vaccine-induced protective immunity against a bacterial pathogen.     

Isoniazid-induced liver injury and immune response in mice

Abstract

Isoniazid (INH) is associated with one of the highest incidences of idiosyncratic drug-induced liver failure of any commonly prescribed drug. The mechanism of this liver injury remains uncertain, and a valid animal model would greatly facilitate mechanistic studies. Most studies of INH-induced liver toxicity have been acute studies performed in rats with high doses of the drug, and this is very different from the idiosyncratic liver injury that occurs in humans. It has previously been demonstrated that covalent binding of INH in the liver of mice is greater than in rats and more like that in humans. Therefore, mice should be a better species in which to develop an animal model of INH-induced liver injury. Treatment of Cbl-b^?/? and PD1^?/? mice, which have impaired immune tolerance, resulted in greater injury than their C57BL/6 background, but not liver failure. This suggested that the injury was mediated by the adaptive immune system; however, Rag^?/? mice, which do not have competent T- and B-cells, sustained more liver injury than C57BL/6 wild-type mice. This suggested that the adaptive immune system also played a protective role. INH treatment also led to a decrease in the inflammatory cytokines IL-1α and IL-12, which suggests that the drug may have immunosuppressive properties. In short, a mouse model was developed of INH-induced liver injury in which the immune system appears to play a both protective and pathogenic role, but this study was unable to develop a model of INH-induced liver failure.