IL-1β regulates a novel myeloid-derived suppressor cell subset that impairs NK cell development and function

Chronic inflammation is associated with promotion of malignancy and tumor progression. Many tumors enhance the accumulation of myeloid-derived suppressor cells (MDSC), which contribute to tumor progression and growth by suppressing anti-tumor immune responses. Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC possessing an enhanced capacity to suppress T cells. In this study, we found that the enhanced suppressive potential of IL-1β-induced MDSC was due to the activity of a novel subset of MDSC lacking Ly6C expression. This subset was present at low frequency in tumor-bearing mice in the absence of IL-1β-induced inflammation; however, under inflammatory conditions, Ly6C(neg) MDSC were predominant. Ly6C(neg) MDSC impaired NK cell development and functions in vitro and in vivo. These results identify a novel IL-1β-induced subset of MDSC with unique functional properties. Ly6C(neg) MDSC mediating NK cell suppression may thus represent useful targets for therapeutic interventions.     

Tumor-induced myeloid-derived suppressor cell function is independent of IFN-γ and IL-4Rα

Myeloid-derived suppressor cells (MDSCs) are present in most cancer patients and experimental animals where they exert a profound immune suppression and are a significant obstacle to immunotherapy. IFN-γ and IL-4 receptor alpha (IL-4Rα) have been implicated as essential molecules for MDSC development and immunosuppressive function. If IFN-γ and IL-4Rα are critical regulators of MDSCs, then they are potential targets for preventing MDSC accumulation or inhibiting MDSC function. Because data supporting a role for IFN-γ and IL-4Rα are not definitive, we have examined MDSCs induced in IFN-γ-deficient, IFN-γR-deficient, and IL-4Rα-deficient mice carrying three C57BL/6-derived (B16 melanoma, MC38 colon carcinoma, and 3LL lung adenocarcinoma), and three BALB/c-derived (4T1 and TS/A mammary carcinomas, and CT26 colon carcinoma) tumors. We report that although MDSCs express functional IFN-γR and IL-4Rα, and have the potential to signal through the STAT1 and STAT6 pathways, respectively, neither IFN-γ nor IL-4Rα impacts the phenotype, accumulation, or T-cell suppressive potency of MDSCs, although IFN-γ and IL-4Rα modestly alter MDSC-macrophage IL-10 crosstalk. Therefore, neither IFN-γ nor IL-4Rα is a key regulator of MDSCs and targeting these molecules is unlikely to significantly alter MDSC accumulation or function.     

Relationships among cell morphology,intrinsic cell stiffness and cell–substrate interactions

Cell modulus (stiffness) is a critical cell property that is important in normal cell functions and increasingly associated with disease states, yet most methods to characterize modulus may skew results. Here we show strong evidence indicating that the fundamental nature of free energies associated with cell/substrate interactions regulates adherent cell morphology and can be used to deduce cell modulus. These results are based on a mathematical model of biophysics and confirmed by the measured morphology of normal and cancerous liver cells adhered on a substrate. Cells select their final morphology by minimizing the total free energy in the cell/substrate system. The key mechanism by which substrate stiffness influences cell morphology is the energy tradeoff between the stabilizing influence of the cell-substrate interfacial adhesive energy and the destabilizing influence of the total elastic energies in the system. Using these findings, we establish a noninvasive methodology to determine the intrinsic modulus of cells by observing global changes in cell morphology in response to substrate stiffness. We also highlight the importance of selecting a relevant morphological index, cell roundness, that reflects the interchange between forms of energy governing cell morphology. Thus, cell-substrate interactions can be rationalized by the underlying biophysics, and cell modulus is easily measured.     

Induction of suppressive phenotype in monocyte-derived dendritic cells by leukemic cell products and IL-1β

Professional antigen-presenting cells, dendritic cells (DCs) play an important role in controlling tumors. It is known that solid tumor cell products inhibit DC differentiation. Recently a similar effect produced by leukemic cell products has been demonstrated. In this case, leukemic cell products induced the secretion of IL-1β by monocytes undergoing differentiation. The aim of the present work was to characterize and to compare the development of monocyte-derived DCs under the influence of leukemic cell products (K562 supernatant) or exogenous IL-1β. It became clear that leukemic cell products and IL-1β differentially modulate some of the parameters studied on monocytes stimulated to differentiate into DCs. In the presence of K562 supernatant, the expression of the macrophage markers CD16 and CD68 were higher than in immature DCs control. Contrasting with IL-1β, leukemic cell products possibly favor the development of cells with macrophage markers. In addition, CD80 and CD83 expressions were also higher in the presence of tumor supernatant whereas HLA-DR was lower. In the presence of IL-1β, only CD80 was increased. Furthermore, it was observed that when monocytes were induced to differentiate into DCs in the presence of tumor supernatant and then activated, they expressed less CD80 and CD83 than activated DCs control. A reduced expression of CD83 following activation was also seen in cells differentiated with IL-1β. TGF-β and VEGF were found in the tumor supernatants. Moreover, the exposure to tumor supernatant or IL-1β stimulated IL-10 production while decreased IL-12 production by activated DCs. Finally, these results suggest that the addition of products released by leukemic cells or, more discreetly, the addition of IL-1β affects DC differentiation, inducing a suppressive phenotype.     

Dendritic cell–epithelial cell crosstalk in the gut

Intestinal epithelial cells are fundamental to maintain barrier integrity and to participate in food degradation and absorption, but they can also decipher signals coming from the outside world and ‘educate’ the immune system accordingly. In particular, they interact with dendritic cells (DCs) and other intraepithelial immune cells to drive tolerogenic responses under steady state, but they can also release immune mediators to recruit inflammatory cells and to elicit immunity to infectious agents. When these interactions are deregulated, immune disorders can develop. In this review, we discuss some important features of epithelial cells and DCs and their fruitful interactions.     

人白细胞介素家族的新成员——IL-19、IL-20、IL-21、IL-22、IL-23

白细胞介素是激活的 T细胞分泌的一类细胞因子 ,它们在免疫调节中发挥重要作用 ,具有很高的临床应用价值。迄今为止 ,已有 2 3种人白细胞介素被发现 ,构成了一个庞大的家族。其中 2 0 0 0～ 2 0 0 1年间 ,就有 5种人白细胞介素家族最新成员的序列被阐明。本文简单介绍了它们的结构、诱导表达方式、功能、及其信号相关受体等各个方面的最新研究进展     

Does IL-4 play a role in the expansion of V beta 8a T cell receptor-bearing cells?

BACKGROUND: Peripheral blood mononuclear cells (PBMC) of subjects allergic to the insect-derived allergen Chi t 1--9 are characterized by an allergen-induced pronounced proliferation and increased expression of activation markers (CD25, HLA-DR, CD23). T cell lines showed an elevated percentage of V beta 8a-positive cells following stimulation by Chi t 1--9. OBJECTIVE: The aim of the present study was to investigate whether V beta 8a dominance plays an important role in PBMC short-term cultures (24 h) as well. The role of exogenous added cytokines, especially IL-4, has been determined. METHODS: The T cell receptor repertoire was measured with 16 monoclonal antibodies to epitopes on the variable region of the beta chain by flow cytometry. Patients allergic to Chi t 1--9 were compared to nonallergic subjects as well as to subjects with other occupational allergies. In addition, cytokines were determined intracellulary by flow cytometry. Studies were performed with PBMC cultured for 24 h. RESULTS: After cultivation for 24 h without or with different stimuli (cytokines, allergen, phytohaemagglutinin), changes in the T cell receptor profile and the cytokine profile were measurable compared to the baseline value (without cultivation). Stimulation with IL-4 revealed increased percentages of V beta 8a-expressing cells in Chi t 1--9-sensitized patients. This IL-4-induced V beta 8a increase did not occur in PBMC from the two control subject groups (non-allergic and allergic to other allergens than Chi t 1--9). CONCLUSION In conclusion, the dominance of certain T cell receptor types seems to arise due to the exposure to specific allergens and cytokine production. Some T cell receptors are often affected, for example V beta 8a, whereas others only show minor variations. V beta 8a expression obviously plays an important role in Chi t 1-9 allergy.     

多发伤患者血清IL-1β、IL-4、IL-6、IL-8、IL-10检测的临床意义

本文应用酶联免疫吸附法(ELISA双抗体夹心法)检测多发伤患者血清中IL-1β、IL-4、IL-6、IL-8、IL-10的含量变化,探讨其在多发伤病程中的作用.     

IL-1家族新成员IL-36、IL-37和IL-38在炎症性疾病中的作用

IL-1参与多种炎症和自身免疫性疾病过程。IL-1家族新成员IL-36、IL-37和IL-38在炎症性疾病中发挥不同的调节作用。它们参与银屑病、类风湿关节炎、痛风、系统性红斑狼疮和克罗恩病等炎症性疾病的发病过程。IL-36作为促炎细胞因子能促进更多炎症介质的活化;相反,IL-37和IL-38是抑炎细胞因子,能抑制炎症反应。因此,研究IL-1家族成员的失衡对未来相关疾病的治疗十分重要。本文综述了IL-1家族新成员IL-36、IL-37和IL-38的表达及在相关炎症性疾病中作用的研究进展。     

未服药精神分裂症患者血清IL-2、IL-4、IL-6、IL-10和IL-17A的水平

目的:探讨未服药的精神分裂症患者血清白细胞介素2(interleukin 2,IL-2)、IL-4、IL-6、IL-10和IL-17A水平以及和症状之间的相关性。方法:选取2015年3月-2017年3月在我院精神科住院的精神分裂症患者38例为研究对象,以我院的健康医护人员30例作为对照组。采用酶联免疫吸附试验检测血清各IL浓度,应用阳性和阴性症状量表(PANSS)评定症状的严重性。结果:研究组的血清IL-6水平为(25.03±11.23)pg/ml显著高于对照组的(19.02±9.49)pg/ml,差异有统计学意义(t=2.343,P0.05);其余各血清IL水平两组差异无统计学意义。血清IL-6水平与PANSS总分呈正相关,主要与阴性症状和一般病理学症状有关(r=0.470,0.343,0.335;P0.05)。结论:精神分裂症起病的早期阶段机体存在炎性反应活化状态,血清IL-6水平有望成为早期诊断精神分裂症的外周免疫标记物。     

IL-1刺激内皮细胞产生 IL-6

白细胞与血管内皮细胞在炎症及免疫反应中的关系相当密切,淋巴因子在介导两者     

IL-1可诱导产生IL-1

白细胞介素1(IL-1)作为炎症介质近来引起了人们的关注。据Dinarello等人报道,用IL-1可以诱发IL-1的产生。他们给家兔注射大量的重组IL-1α,以便观察双峰性发热现象。大约注射后3小时出现发热的第二峰,推测这就是由内源性产生的IL-1所致。用此时引起发热的血清再诱导其他家兔发热,在血清中分子量为30～40KD以及15KD的组份中可发现