Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment

Successful implantation is an absolute requirement for the reproduction of species, including humans. The process by which a foreign blastocyst is accepted by the maternal endometrium is complex and requires interplay of many systems. Implantation occurs during the putative implantation window, in which the maternal endometrium is ready to accept the blastocyst, which on the other hand, also plays a specific role. It produces cytokines and chemokines and expresses adhesion molecules and certain classes of MHC molecules. We review the most important players in implantation. Concerning the cytokines, the establishment of controlled aggression is key; an excess of pro- or anti-inflammation is detrimental to pregnancy outcome. Chemokines control the orientation of the embryo. The adhesion molecules are necessary to establish the required physical interaction between mother and blastocyst. Finally, immune cells and in particular, uterine NK and regulatory T cells are pivotal in inducing tolerance to the blastocyst. The aim of this review is to discuss mechanisms at play and their relative importance to the establishment of pregnancy.     

Synaptic microenvironments--structural plasticity, adhesion molecules, proteases and their inhibitors

Proteolytic regulation might be essential in neural plasticity in mature brain as well as the developing brain. An increasing number of studies support the idea that structural changes in the synapses are closely associated with synaptic plasticity. Proteases and their inhibitors in a synaptic microenvironment are important in the regulation of dynamic changes in the extracellular matrix components associated with synaptic plasticity. In the present article, the possible roles of neuronal proteases, protease inhibitors and extracellular macromolecules are reviewed.     

细胞粘附分子与胚胎着床

细胞粘附分子(cell adhesion molecules,cAMs)是指由细胞合成,可存在于细胞内、细胞膜或细胞外,能促进细胞粘附的一大类分子的总称.主要包括免疫球蛋白超家族、整合素家族、细胞外基质(整合素的配体)、钙调素家族、选择素家族和近年来新发现的几种细胞粘附分子:trophinin、tastin、bystin.cAMs介导细胞与细胞、细胞与细胞外基质的相互作用,传递细胞间信息,参与胚胎发育,免疫应答,恶性肿瘤转移等一系列生理及病理过程.近几年研究发现,在女性子宫内膜,胚泡均有多种cAMs的表达,有的呈周期性变化,并与子宫内膜"着床窗"开放同步,与子宫内膜发育到"接受性"状态及胚泡的滋养层细胞发育到"浸润性"状态密切相关.本文着重对细胞粘附分子在子宫内膜及胚胎滋养层中的表达及其在胚胎着床过程中发挥的重要作用作一综述.     

Lymphocytes, cytokines and adhesion molecules in chronic graft versus host disease

Aims—To determine which inflammatory and immune pathways are implicated in the development of chronic graft versus host disease (GvHD) and whether differences between these pathways are responsible for the different presentations of chronic GvHD.     

促炎症细胞因子刺激人类关节滑膜B型细胞表达粘附分子

目的透析相关性淀粉样变（DRA）病人关节滑膜组织粘附分子表达增强,并与局部炎细胞浸润密切相关。旨在探讨DRA时诱导滑膜细胞粘附分子表达上调的机制。方法分离正常人关节滑膜B型细胞,与晚期糖基化终产物修饰的β     

Expression of activation, adhesion molecules and intracellular cytokines in acute pancreatitis.

Adhesion and activation molecules as well as cytokines play an important role in an immune scenario. In acute pancreatitis, we have studied some of these in order to evaluate dysregulation. For this we took peripheral blood mononuclear cells and pancreatitis tissue cells. We analysed activation markers like CD69, CD25 and HLA-DR and found a marked elevation of CD69 as well as CD25 in both peripheral blood cells and tissue mononuclear cells when compared to controls. In PBMC-CD69: P<0.01 and CD25: P<0.01; in tissue-CD69: P<0.001 and CD25: P<0.001. The HLA-DR levels, however, were reduced in the disease state (in acute pancreatitis patient blood (P<0.01) and tissue cells (P<0.001)). The adhesion molecules showed unanimous rise in the blood and the tissue samples. In blood samples, CD11a: P<0.05 and CD11b: P<0.05 and tissue samples CD11a: P<0.01 and CD11b: P<0.01and CD54 in peripheral blood (P<0.05) and tissue (P<0.01) of AP was high as compared to controls. By simultaneous flowcytometric analysis, we determined the co-expression of a surface marker (CD4/CD8/CD14) and intracellular cytokine (TNF-alpha and IFN-gamma) in individual cells. The IFN-gamma producing CD8+T cells were elevated in pancreatic tissue (P<0.01). TNF-alpha producing cell numbers were significantly higher in tissue cells than in blood and also in CD8+ T cells (P<0.001). We conclude that monocyte function is affected in AP as shown by reduced HLA-DR numbers and lowered TNF-alpha producing cells. Moreover, the CD8+T cells appear to play an important role in cytokine synthesis at the effector site.     

Immunohistochemical detection of tumor necrosis factor-alpha,other cytokines and adhesion molecules in human livers with alcoholic hepatitis

This immunohistochemical study was designed to investigate the possible contribution to and topographical distribution of some important cytokines, such as tumour necrosis factor (TNF) and interleukins, in acute alcoholic hepatitis. The well-known inductive capacity of these cytokines with respect to the expression and/or up-regulation of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1), was a further point to be studied. Moreover, the proposed induction of adhesion molecules might also be associated with the activation and attraction of a special population of inflammatory cells characteristic for alcoholic hepatitis. Frozen liver samples from patients who died with signs of acute alcoholic hepatitis were evaluated using the alkaline phosphatase anti-alkaline phosphatase immunostaining technique and also single and double indirect immunofluorescence. In acute alcoholic hepatitis TNF could be detected predominantly in ballooned hepatocytes, which often contained alcoholic hyalin (Mallory bodies). Moreover, TNF showed a co-distribution with ICAM-1 expressed in the membranes of hepatocytes and with the occurrence of CD11b positive polymorphonuclear leukocytes (neutrophils) suggesting a possible major role of the ₂-integrin Mac-1 as a ligand for ICAM-1. No induction of ELAM-1 could be found. In alcoholic hepatitis cytokines may be responsible for the induction of the adhesion molecule ICAM-1 on hepatocytic membranes and activate a defined population of inflammatory cells, thus contributing to the characteristic histological picture of acute alcoholic hepatitis with its concentration of neutrophils especially in areas with ballooned Mallory body-containing hepatocytes. Our results are in line with clinical findings showing high levels of TNF and interleukin-1 in sera of patients with alcoholic hepatitis and with the already reported expression of ICAM-1 on hepatocytes.     

Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia

Ischemic stroke is a leading cause of death and disability in developed countries. Yet, in spite of substantial research and development efforts, no specific therapy for stroke is available. Several mechnism for neuroprotection have been explored including ionchannels, excitatory amino acids and oxygen raicals yet none has culminated in an effective therapeutic effect. The review article on "inflammation and stroke" summarizes key data in support for the possibility that inflammatory cells and mediators are important contributing and confounding factors in ischemic brain injury. In particular, the role of cytokines, endothelial cells and leukocyte adhesion molecules, nitric oxide and cyclooxygenase (COX-2) products are discussed. Furthermore, the potential role for certain cytokines in modulation of brain vulnerability to ischemia is also reviewed.The data suggest that novel therapeutic strategies may evolve from detailed research on some specific inflammatory factors that act in spatial and temporal relationships with traditionally recognized neurotoxic factors. The dual nature of some mediators in reformatting of brain cells for resistance or sensitivity to injury demonstrate the delicate balance needed in interventions based on anti-inflammatory strategies.     

Increased cytokines,chemokines and soluble adhesion molecules in exhaled breath condensate of asthmatic children

Background Airway inflammation in asthma is characterized by the production of cytokines, chemokines and soluble adhesion molecules. The assessment of these inflammatory biomarkers in exhaled breath condensate (EBC) is hampered by low detection rates. However, the use of a glass condenser system combined with a sensitive analytical technique may increase the possibility to assess these biomarkers in EBC in a reliable way. Objective (1) To assess the detection rates of cytokines (IL‐1α, ‐1β, ‐2, ‐4, ‐5, ‐6, ‐10, ‐12p70, ‐13, ‐18, IFN‐γ, TNF‐α), chemokines [MIP1α (CCL3), MIF, eotaxin (CCL11), RANTES (CCL5), IP10 (CXCL10), IL8 (CXCL8), MCP1] and soluble adhesion molecules [soluble intercellular adhesion molecule (sICAM), soluble vascular adhesion molecule (sVCAM)] in EBC of children with asthma and healthy control children;
(2) To study the differences in the biomarker concentration between children with asthma and controls. Methods Sixty children were included: 31 asthmatics (71% atopic) and 29 controls. Exhaled breath condensate was collected using a glass condenser system. The inflammatory markers (IM) were analysed using multiplex immunoassay technology. Results Detection percentages of cytokines, chemokines and adhesion molecules ranged from 94% to 100%, except for eotaxin (CCL11) and RANTES (CCL5) (detection rates of 10% and 45% in healthy controls, respectively). The intra‐subject variability of biomarkers in EBC in the group as a whole ranged from 5.2% to 35.0%. In asthmatics, the levels of cytokines (IL‐2, ‐4, ‐5, ‐6, ‐13, IFN‐γ), chemokines (MIP1α [CCL3], MIF, RANTES [CCL5], IP10 [CXCL10], IL8 [CXCL8], MCP1) and adhesion molecules (sICAM, sVCAM) were significantly increased in comparison with controls (P<0.05). Conclusion If collected with a glass condenser and analysed by multiplex immunoassay technology, cytokines, chemokines and soluble adhesion molecules can be reliably demonstrated in EBC of children. Most of these IM were elevated in EBC of asthmatics compared with controls. Cite this as: C. M. H. H. T. Robroeks, G. T. Rijkers, Q. Jöbsis, H. J. E. Hendriks, J. G. M. C. Damoiseaux, L. J. I. Zimmermann, O. P. van Schayck, E. Dompeling, Clinical & Experimental Allergy, 2010 (40) 77–84.     

Immune receptors and adhesion molecules in human pulmonary leptospirosis

Pulmonary involvement in leptospirosis has been increasingly reported in the last 20 years, being related to the severity and mortality of the disease. The pathogenesis of pulmonary hemorrhage in leptospirosis is not understood. Lung endothelial cells have been proposed as targets in the pathogenesis of lung involvement in leptospirosis through the activation of Toll-like receptor 2 or the complement system, which stimulates the release of cytokines that lead to the activation of adhesion molecules. The aim of this study was to investigate the involvement of immune pathways and of the intercellular and vascular cell adhesion molecules (intercellular adhesion molecule and vascular cell adhesion molecule, respectively) in the lungs of patients with pulmonary involvement of leptospirosis. We studied the lungs of 18 patients who died of leptospirosis and compared them with 2 groups of controls: normal and noninfectious hemorrhagic lungs. Using immunohistochemistry and image analysis, we quantified the expression of the C3a anaphylatoxin receptor, intercellular adhesion molecule, vascular cell adhesion molecule, and Toll-like receptor 2 in small pulmonary vessels and in the alveolar septa. There was an increased expression of intercellular adhesion molecule (P < .03) and C3a anaphylatoxin receptor (P < .008) in alveolar septa in the leptospirosis group compared with the normal and hemorrhagic controls. In the vessels of the leptospirosis group, there was an increased expression of intercellular adhesion molecule (P = .004), vascular cell adhesion molecule (P = .030), and Toll-like receptor 2 (P = .042) compared with the normal group. Vascular cell adhesion molecule expression in vessels was higher in the leptospirosis group compared with the hemorrhagic group (P = .015). Our results indicate that immune receptors and adhesion molecules participate in the phenomena leading to pulmonary hemorrhage in leptospirosis.     

Integrins and adhesion mlecules: Cell adhesion molecules on the oocyte and preimplantation human embryo

The presence of cell adhesion molecules on human oocytes, earlyembryos, and pre-hatched blastocysts was examined by indirectimmunofluorescence and compared to the distribution found onfirst trimester villous placenta with the same antibodies. Sixintegrin subunits (3, V, 1, 3, 4, 5) were observed consistentlythroughout preimplantation development. Evidence was also obtainedfor the presence of integrin subunits 2, 4, L, 2, and 7 on asmall number of oocytes. A more restricted developmental analysisof E-cadherin, ICAM-1, NCAM, and VCAM-1 demonstrated that thesecell adhesion molecules are also present on oocytes and earlyembryos. L-selectin was detected on oocytes but was not foundon 8-cell embryos. The oocyte and early blastomeres have complexsurfaces in which the integrin and CAM families are represented.     

Inflammatory cytokines and cell adhesion molecules in a rat model of decompression sickness.

To characterize early blood and tissue markers predictive of decompression sickness (DCS), this study focused on identifying changes in inflammatory mediators during the 24-h period immediately following compression-decompression of female Sprague-Dawley rats. Early blood and tissue markers predictive of DCS include inflammatory cytokines and cell adhesion molecules (CAMs). Increased levels of inflammatory cytokines, especially tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma), were detected in the circulation 6 h after decompression. Increased levels of only IL-6 were observed at 24 h. Compared with control animals maintained at 1 atmospheres absolute pressure ATA (101 kPascal), significant increases in expression of E-selectin, and L-selectin, as well as intercellular adhesion molecule-1 (ICAM-1), were observed immunohistochemically in the lungs and brains of the rats 6 h after exposure to 2 (203 kPascal), 3 (303 kPascal), or 4 (404 kPascal) ATA, followed by rapid decompression. These levels drop by 24 h. In contrast to the observations in brain, greater increases in expression of E-selectin and L-selectin around vessels and connective tissue were seen at 24 h after decompression in the quadriceps of rats exposed to either 3 or 4 ATA. Significant increases in expression of the A(2A) receptor, which modulates inflammation by downregulating production of these cytokines, were detected only in the quadriceps removed at 24 h after decompression from 4 ATA. This study demonstrated that rapid decompression induces the release of mediators of inflammation and resulting tissue inflammation cascades, as well as a protective anti-inflammatory response.     

The distribution of adhesion molecules in human atherosclerosis

Chronic inflammatory cells are a recognized component of atherosclerotic plaques at all stages of development. As adhesion molecules play a fundamental role in inflammatory processes, we have carried out an immunohistochemical investigation of the distribution of endothelial leucocyte adhesion molecule-1 (ELAM-1)*, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human atherosclerotic lesions. Autopsy specimens from abdominal aorta and coronary arteries were obtained from 21 cases within 24 h of death. ELAM-1 and ICAM-1 were consistently expressed by the entire intimal endothelium of normal coronary arteries and also by the intimal endothelium overlying aortic fatty streaks. Both coronary artery and aortic lesions showed strong staining for ICAM-1 on and around macrophages. VCAM-1 was not detected on intimal endothelial cells, but strong staining of adventitial lymphoid aggregates for this molecule was seen. This work suggests a role for ELAM-1 and ICAM-1 in mononuclear cell recruitment during atherogenesis.     

Expression of leukocyte adhesion molecules in human endometrium

In the present investigation the distribution of molecules that are involved in the leukocyte binding was studied in human endometrium. The expression of intercellular adhesion molecule-1 (ICAM-1), lymphocyte function-associated antigen (LFA-1), and HLA-DR molecules was studied in 13 proliferative and 10 secretory endometria as well as cultures of endometrial glands and stroma by avidin-biotin complex (ABC) procedure using monoclonal antibodies. The ICAM-1 and HLA-DR molecules were both strongly expressed in the lymphoid and endothelial cells. ICAM-1 expression was uniform in the epithelium, whereas the HLA-DR molecules were preferentially expressed in the epithelial cells in the basalis. Expression of both epithelial HLA-DR and ICAM-1 molecules was enhanced adjacent to lymphoid aggregates. ICAM-1 molecule was uniformly expressed in the stromal cells in the basalis and the functionalis, whereas the HLA-DR molecules were expressed exclusively in the stromal cells surrounding the lymphoid cells. ICAM-1 expression in the epithelial and stromal cells was confirmed in the isolated intact stromal cells and glands by immunohistochemistry. Although stromal and epithelial cells propagated in vitro expressed ICAM-1, they were rarely HLA-DR positive. The expression of LFA-1 was confined to the lymphoid cells. The high level of expression of ICAM-1, LFA-1, and HLA-DR molecules in human endometrial constituents may contribute to the presence, aggregation, and preferential distribution of lymphoid cells in human endometrium.     

Sarcoptes scabiei (Acari: Sarcoptidae) mite extract modulates expression of cytokines and adhesion molecules by human dermal microvascular endothelial cells

The inflammatory and immune responses seen with the worldwide disease scabies, caused by the mite Sarcoptes scabiei (De Geer) (Acari: Sarcoptidae), are complex. Clinical symptoms are delayed for weeks in patients when they are infested with scabies for the first time. This study was undertaken to elucidate the role of the human dermal microvascular endothelial cell (HMVEC-D) in modulating the inflammatory and immune responses in the skin to S. scabiei. Extracts of S. scabiei were incubated with HMVEC-D and the expression of adhesion molecules and chemokine receptors on the cells and the secretion of selected cytokines were determined by enzyme-linked immunosorbent assay. S. scabiei extract was found to inhibit HMVEC-D expression of E-selectin and vascular cell adhesion molecule-1, although not intercellular adhesion molecule-1. The secretion of interleukin-8 also was inhibited by S. scabiei extract. S. scabiei extract increased expression of the chemokine receptor CXCR-1 and both down-regulated and up-regulated expression of CXCR-2, depending on the concentration tested. These findings help explain the delayed inflammatory reaction to infestation with S. scabiei.     

肾病综合征患儿PMN凋亡与细胞因子、粘附分子关系的探讨

目的:观察肾病综合征（NS）患儿周围血中性粒细胞（PMN）凋亡的变化，并检测周围血中细胞因子IL-8、IL-6、TNF-α、NO和粘附分子P-选择素(P-sel)、细胞间粘附分子-1（ICAM-1）的水平，探讨细胞因子和粘附分子对PMN凋亡的影响。 方法:采用流式细胞术检测28例NS病人周围血PMN凋亡，ELISA法检测细胞因子和粘附分子水平。 结果:活动期NS患者PMN凋亡率明显低于健康人对照组和缓解期NS患者,缓解期NS患者PMN凋亡率与对照组无明显差别,不同病情活动期NS患者之间PMN凋亡有显著差异,活动期NS患者周围血中IL-8、IL-6、TNF-α、NO、P-sel 、ICAM-1水平均高于对照组和缓解组，且与PMN凋亡呈负相关，与病情呈正相关。缓解组患者IL-8 、IL-6、TNF-α、NO、P-sel和ICAM-1水平与对照组无显著差异。 结论: NS患者PMN凋亡延迟，且与病情及疗效密切相关。炎性细胞因子产生过多、免疫细胞粘附分子表达上调可能是导致PMN凋亡延迟的重要机制，适度调控PMN凋亡有可能会改善NS预后。     

Distribution of lymphocytes and adhesion molecules in human cervix and vagina

Knowledge of the histological distribution of leucocytes and adhesion molecules in the human genital tract is scarce although local immunity in this region is important. Using immunohistochemical methods, we here describe the organization of CD3+, CD8+ and CD4+ T cells, CD19+ B cells, CD38+ plasma cells, major histocompatibility complex (MHC) class II+ antigen-presenting cells and CD14+ monocytes, as well as the expression of endothelial addressins in normal human ecto-cervical and vaginal mucosa. T cells were clustered in a distinct band beneath the epithelium and were also dispersed in the epithelium and the lamina propria, whereas CD38+ plasma cells were present only in the lamina propria. MHC class II+ cells were numerous in the lamina propria and in the epithelium, where they morphologically resembled dendritic cells. Lymphoid aggregates containing CD19+ and CD20+ B cells as well as CD3+, CD4+ and CD8+ cells were also found in the cervix. The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) was not expressed on the vascular endothelium in the cervical or vaginal mucosa. In contrast, intercellular adhesion molecule-1 (ICAM-1), vascular adhesion protein-1 (VAP-1) and P-selectin were expressed in all tissue samples, and vascular cell adhesion molecule-1 (VCAM-1) and E-selectin were found in four of seven samples. We conclude that the distribution of leucocytes and adhesion molecules is very similar in the ecto-cervical and the vaginal mucosa and that the regulation of lymphocyte homing to the genital tract is different from that seen in the intestine. Our results also clearly suggest that the leucocytes are not randomly scattered in the tissue but organized in a distinct pattern.