Glucocorticoid-induced tumour necrosis factor receptor-related protein-mediated macrophage stimulation may induce cellular adhesion and cytokine expression in rheumatoid arthritis

Glucocorticoid-induced tumour necrosis factor receptor (TNFR)-related protein (GITR) is one of the T cell co-stimulatory molecules and is associated with the pathogenesis of a number of autoimmune diseases. We investigated the expression patterns of GITR in human arthritic synovium and the role of GITR in the pathogenesis of rheumatoid arthritis (RA). Immunohistochemical analyses revealed the expression of GITR and its cognate ligand, GITRL, in macrophages in RA, but not in osteoarthritis (OA), synovium. To investigate the role of GITR in macrophage functions, primary macrophages from RA patients and a human macrophage cell line, THP-1, were analysed. Stimulation of the macrophages with anti-GITR monoclonal antibody induced up-regulation of intercellular adhesion molecule (ICAM)-1 and subsequent aggregation/adhesion, which was enhanced by the presence of extracellular matrix proteins and blocked by anti-ICAM-1 monoclonal antibody. The validity of these in vitro observations was confirmed by immunohistochemical analyses of RA synovium, which showed strong expression of ICAM-1 in GITR-positive macrophages. Additionally, GITR stimulation induced expression of proinflammatory cytokines/chemokines and matrix metalloproteinase-9 in synovial macrophages. These data indicate that GITR, expressed on macrophages in human RA synovium, may enhance inflammatory activation of macrophages by promoting cytokine gene expression and adhesion between cells and to extracellular matrix in RA synovium.     

Control of macrophage 3D migration: a therapeutic challenge to limit tissue infiltration

Macrophages are professional migrating cells found in all body tissues from the early embryonic stages till the end of the adult life. Tissue macrophages do not only play beneficial roles. In several diseases, macrophages recruited from blood monocytes have a deleterious action such as favoring cancer progression and destroying tissues in chronic inflammation. To migrate in 3D environments, all leukocytes use the amoeboid movement while macrophages use the amoeboid and the mesenchymal migration modes. Mesenchymal migration takes place in dense matrices and involves podosomes and proteolysis of the extracellular matrix to create paths. Podosome disruption has been correlated with reduced mesenchymal migration of macrophages and unaffected amoeboid migration. Therefore, podosomes are proposed as a therapeutic target. Inhibiting podosome regulators that are only expressed in macrophages and few cell types would avoid collateral effects often encountered when ubiquitous proteins are used as drug targets. With the current status of our knowledge on human macrophage podosomes and 3D migration, the tyrosine kinase Hck appears to be a good candidate.     

Increased expression of pro-inflammatory cytokines and metalloproteinase-1 by TGF-beta1 in synovial fibroblasts from rheumatoid arthritis and normal individuals

Transforming growth factor (TGF)-beta1 is expressed abundantly in the rheumatoid synovium. In this study, the inflammatory effect of TGF-beta1 in rheumatoid arthritis (RA) was investigated using cultured fibroblast-like synoviocytes (FLS) from RA and osteoarthritis (OA) patients, as well as non-arthritic individuals. mRNA expressions of IL-1beta, tumour necrosis factor (TNF)-alpha, IL-8, macrophage inflammatory protein (MIP)-1alpha and metalloproteinase (MMP)-1 were increased in RA and OA FLS by TGF-beta1 treatment, but not in non-arthritic FLS. Enhanced protein expression of IL-1beta, IL-8 and MMP-1 was also observed in RA FLS. Moreover, TGF-beta1 showed a synergistic effect in increasing protein expression of IL-1beta and matrix metalloproteinase (MMP)-1 with TNFalpha and IL-1beta, respectively. Biological activity of IL-1 determined by mouse thymocyte proliferation assay was also enhanced by 50% in response to TGF-beta1 in the culture supernatant of RA FLS. DNA binding activities of nuclear factor (NF)-kappaB and activator protein (AP)-1 were shown to increase by TGF-beta1 as well. These results suggest that TGF-beta1 contributes for the progression of inflammation and joint destruction in RA, and this effect is specific for the arthritic synovial fibroblasts.     

Blockade of tumour necrosis factor‐α in experimental autoimmune encephalomyelitis reveals differential effects on the antigen‐specific immune response and central nervous system histopathology

In various autoimmune diseases, anti‐tumour necrosis factor (TNF)‐α treatment has been shown to reduce both clinical disease severity and T helper type 1 (Th1)1/Th17 responses. In experimental autoimmune encephalomyelitis (EAE), however, the role of TNF‐α has remained unclear. Here, C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 and treated with anti‐TNF‐α, control antibody or vehicle. The clinical disease course, incidence and severity were assessed. On day 20 after immunization the antigen‐specific Th1/Th17 response was evaluated by enzyme‐linked immunospot (ELISPOT) in spleen and central nervous system (CNS). Also, the extent of spinal cord histopathology was analysed on semi‐ and ultrathin sections. Our results demonstrate that anti‐TNF‐α treatment reduced the incidence and delayed the onset of EAE, but had no effect on disease severity once EAE had been established. Whereas anti‐TNF‐α treatment induced an increase in splenic Th1/Th17 responses, there was no effect on the number of antigen‐specific Th1/Th17 cells in the spinal cord. Accordingly, the degree of CNS histopathology was comparable in control and anti‐TNF‐α‐treated mice. In conclusion, while the anti‐TNF‐α treatment had neither immunosuppressive effects on the Th1/Th17 response in the CNS nor histoprotective properties in EAE, it enhanced the myelin‐specific T cell response in the immune periphery.     

Lymphocytes and synovial fluid fibroblasts support osteoclastogenesis through RANKL, TNFalpha, and IL-7 in an in vitro model derived from human psoriatic arthritis

Psoriatic arthritis (PsA) is an inflammatory joint disease, characterized by extensive bone resorption, whose mechanisms have not been fully elucidated. Thus, in the present study we investigated the involvement of RANKL, TNFalpha, and IL-7 in the osteoclastogenesis of PsA patients. In vitro osteoclastogenesis models, consisting of unfractionated and T-cell-depleted mononuclear cells from peripheral blood (PBMCs) and synovial fluid (SFMCs) of 20 PsA patients as well as from healthy donors were studied. Freshly isolated T and B cells from PBMCs and T cells and fibroblasts from SFMCs of PsA patients were subjected to RT-PCR to detect the levels of RANKL, TNFalpha, and IL-7. Osteoclastogenesis was studied in the presence of RANK-Fc, anti-TNFalpha, and anti IL-7 functional antibodies. We demonstrate that lymphocytes and fibroblasts support osteoclast (OC) formation in PsA patients through the production of osteoclastogenic cytokines. In particular, OC formation was completely abolished in unstimulated T cell-depleted PBMC cultures, and reduced by approximately 70% in unstimulated T cell-depleted SFMC cultures. Freshly isolated T cells from PBMCs and SFMCs of PsA patients overexpressed RANKL and TNFalpha, while fibroblasts from synovial fluid produced only RANKL. We show that the presence of RANK-Fc and/or anti-TNFalpha functional antibodies reduced OC formation. Moreover, T and B cells from PBMCs as well as T cells and fibroblasts from SFMCs expressed IL-7 mRNA. Finally, the anti-IL-7 functional antibody significantly reduced osteoclastogenesis. Our results suggest that fibroblasts, B and T lymphocytes support OC formation by producing RANKL, TNFalpha, and IL-7, contributing to the aggressive bone resorption in PsA patients.     

The early immunological response to acute ischemic stroke: Differential gene expression in subpopulations of mononuclear cells

Peripheral blood mononuclear cells (PBMCs), i.e. lymphocytes, monocytes and macrophages are key players in the development of innate and adaptive immune responses. However, little is known about their properties in patients with acute stroke. Experimental procedures: We presently characterized the early time course of PBMC subpopulations in 19 patients with acute ischemic stroke and symptom onset below 6 h compared to 19 age-matched healthy subjects. Immediately after acute ischemic stroke, as well as 1 and 3 days thereafter, PBMC subpopulations (cluster of differentiation [CD]3+, CD14+, CD19+, CD68+) were isolated by magnetic bead system and the expression of proinflammatory (CD40, tumor necrosis factor-alpha [TNFα]), proapoptotic (caspase-3 [CPP32], poly(ADP-ribose) polymerase [PARP]) and adhesion relevant (CD38) genes was measured by quantitative polymerase chain reaction (PCR). Furthermore, besides routine parameters, plasma levels of oxidized low-density lipoproteins (oxLDL) were studied. Results: In comparison to healthy subjects, patients revealed (i) twofold elevated plasma oxLDL concentrations, (ii) decreased (15%) blood cholesterol levels, and (iii) a 40% decrease in total number of lymphocytes. Furthermore, the majority of PBMC subpopulations revealed an increased expression of proinflammatory, proapoptotic or adhesion-relevant genes. Significant positive correlations were observed between expression of most of these genes in PBMCs and individual plasma oxLDL concentrations. Conclusion: Elevated expression of proinflammatory, proapoptotic and adhesion genes in subsets of PBMCs after ischemic stroke may contribute to an immunodepressive syndrome, possibly due to increased plasma oxLDL levels.     

Identification and characterization of IgA and Vicia villosa-binding T cell subsets in rheumatoid arthritis.

Autoimmunity may be due to augmentation of immune responses by human CD8 cells which bind the lectin Vicia villosa (VV). We have investigated T cells in rheumatoid arthritis (RA) by double immunofluorescence flow cytometry, in order to assess VV-binding CD8 and CD4 cells from the peripheral blood and synovial fluid. A significant increase in CD8+VV adherent (P less than 0.0001) and CD4+VV adherent cells (P less than 0.001) was found in synovial fluid, as compared with peripheral blood from patients with RA. A significant increase in VV-binding CD8+ or CD4+ cells was, however, not found in the blood of patients with RA, as compared with controls. We suggest that the lack of VV-binding T cells separated from blood, in contrast to those from synovial fluid, may be due to an inhibiting agent expressing N-acetyl D-galactosamine. Indeed, IgA1 is rich in N-acetyl D-galactosamine, it inhibits VV binding to T cells and is significantly bound to CD8 cells (P less than 0.001). The IgA1 was then characterized and in about half the patients J chains and secretory component was found, suggesting that the IgA1 is of the polymeric and secretory variety. IgA bound to the T cells engaged the Fc alpha receptors and a significant decrease in the Fc alpha receptors was found in CD8 cells (P less than 0.0001) and CD4 cells (P less than 0.01). Desorption studies were then carried out on CD8 and CD4 cells which showed that a loss of cell-bound IgA1 was associated with an increase in VV binding. Conversely, adsorption of IgA to T cells was associated with a loss in VV binding. The results suggest that the failure of VV binding to CD8+ and CD4+ cells from peripheral blood of patients with RA can be ascribed to cell-bound IgA1. Cytophilic IgA1 may inhibit the function of CD8+VV binding cells, thereby preventing augmentation of the systemic immune response, consistent with the lack of extra-articular disease in these patients with RA.     

Changes in the phenotype of monocytes/macrophages and expression of cytokine mRNA in peripheral blood and synovial fluid of patients with rheumatoid arthritis.

Data from a previous study suggested that peripheral blood monocytes in patients with rheumatoid arthritis (RA) may be activated. Therefore, in this study we sought further evidence of 'presynovial' activation of monocytes. Our results show that phenotypic changes are demonstrable in peripheral blood monocytes in patients with RA, including increased expression of CR3 (CD11b/CD18) and FcRI (CD64). However, changes are most extensive in synovial monocytes/macrophages and especially for HLA-DR and intercellular adhesion molecule-1 (ICAM-1) (CD54). We conclude that monocyte/macrophage activation is most evident within the joint, and that 'presynovial' changes occur but are of limited extent.     

IL-6 regulates exercise and training-induced adaptations in subcutaneous adipose tissue in mice

Aim: The aim of this study was to test the hypothesis that IL‐6 regulates exercise‐induced gene responses in subcutaneous adipose tissue in mice. Methods: Four‐month‐old male IL‐6 whole body knockout (KO) mice and C57B wild‐type (WT) mice performed 1 h of treadmill exercise, where subcutaneous adipose tissue (AT) was removed either immediately after, 4 h or 10 h after exercise as well as from mice not running acutely. Moreover, AT was sampled at resting conditions after 5 weeks of exercise training. Results: AT leptin mRNA decreased immediately after a single running exercise bout in both genotypes and returned to baseline within 10 h of recovery in IL‐6 KO mice, but not WT mice. Leptin mRNA content decreased in WT and increased in IL‐6 KO mice with training, but without significant alterations in leptin protein. Acute exercise induced a decrease in the AT TNFα mRNA content in WT, but not in IL‐6‐KO mice, while training lowered resting levels of TNFα mRNA in both genotypes. In addition, an exercise‐induced decline in AT PPARγ mRNA content was absent in IL‐6 KO mice and in line training increased PPARγ mRNA only in IL‐6 KO mice. Conclusion: The present findings indicate a role of IL‐6 in regulating exercise‐ and training‐induced leptin and PPARγ expression in adipose tissue. In addition, while IL‐6 is required for TNF‐α mRNA reduction in response to acute exercise, IL‐6 does not appear to be mandatory for anti‐inflammatory effects of exercise training in adipose tissue.     

Degradation of aggregates of activated C3 (C3b) by monocytes of patients with rheumatoid arthritis is related to vasculitis

We investigated whether a decreased complement receptor expression or function of monocytes isolated from peripheral blood of 52 patients with rheumatoid arthritis (RA) and rheumatoid vasculitis (RV) could account for the previously observed diminished degradation of immune complexes by monocytes of patients with RA and RV. On average, monocytes from all patients expressed significantly less CR1, and degraded significantly less AC3b when compared with monocytes of healthy controls. In addition, monocytes from RV patients degraded significantly less AC3b when compared with monocytes from patients with RA. The expression of both CR1 and CR3 on monocytes of RV patients was lower compared with RA patients but this difference was only significant for CR3. No differences were found between AC3b degradation and the expression of CR1 and CR3 between patients with active and inactive RA. Using linear discriminant analysis on the variables AC3b, CR1 and CR3, 94% of the patients could be classified correctly as healthy controls, RA or RV, suggesting a true multi-variate relationship between these parameters and patients groups. Our results suggest that the diminished capacity of monocytes from RA patients to degrade AC3b is due partly to a decreased expression of CR1 and CR3.     

Serum thymosin α 1 levels in patients with chronic inflammatory autoimmune diseases

Thymosin alpha 1 (Tα1) is a powerful modulator of immunity and inflammation. Despite years of studies, there are a few reports evaluating serum Tα1 in health and disease. We studied a cohort of healthy individuals in comparison with patients affected by chronic inflammatory autoimmune diseases. Sera from 120 blood donors (healthy controls, HC), 120 patients with psoriatic arthritis (PsA), 40 with rheumatoid arthritis (RA) and 40 with systemic lupus erythematosus (SLE), attending the Transfusion Medicine or the Rheumatology Clinic at the Policlinico Tor Vergata, Rome, Italy, were tested for Tα1 content by means of a commercial enzyme‐linked immunosorbent assay (ELISA) kit. Data were analysed in relation to demographic and clinical characteristics of patients and controls. A gender difference was found in the HC group, where females had lower serum Tα1 levels than males (P < 0·0001). Patients had lower serum Tα1 levels than HC (P < 0·0001), the lowest were observed in PsA group (P < 0·0001 versus all the other groups). Among all patients, those who at the time of blood collection were taking disease‐modifying anti‐rheumatic drugs (DMARD) plus steroids had significantly higher Tα1 levels than those taking DMARD alone (P = 0·044) or no treatment (P < 0·0001), but not of those taking steroids alone (P = 0·280). However, whichever type of treatment was taken by the patients, serum Tα1 was still significantly lower than in HC and there was no treatment‐related difference in PsA group. Further prospective studies are necessary to confirm and deepen these observations. They might improve our understanding on the regulatory role of Tα1 in health and disease and increase our knowledge of the pathogenesis of chronic inflammatory autoimmune diseases.     

Early apoptosis of monocytes contributes to the pathogenesis of systemic inflammatory response and of bacterial translocation in an experimental model of multiple trauma

The objective of this study was to investigate the occurrence of apoptosis of monocytes in an experimental model of multiple trauma and its probable correlation to bacterial translocation. Thirty-two rabbits were applied in three groups: A, controls; B, myotomy of the right femur; and C, myotomy and fracture of the right femur. Blood was sampled for the estimation of endotoxins [lipopolysaccharide (LPS)], tumour necrosis factor (TNF)-alpha, malondialdehyde (MDA) and isolation of peripheral blood mononuclear cells (PBMCs). PBMCs, derived after centrifugation over Ficoll, were incubated in flasks and apoptosis of non-adherent lymphocytes and adherent monocytes was estimated after staining for Annexin-V and flow cytometry. TNF-alpha of supernatants of cultured monocytes was also determined. Tissue segments were cultured after death. Median survival of groups A, B and C was > 14, > 14 and 9.00 days, respectively. Apoptosis of lymphocytes in group C was higher than group A at 2, 4 and 48 h and of monocytes in group C higher than group A at 2 and 4 hours. LPS in group C was higher than group A at 2, 4 and 48 h. Apoptosis of lymphocytes and monocytes was correlated positively with serum TNF-alpha and negatively with TNF-alpha of monocyte supernatants. Cultures of organ segments of group A were sterile. Pseudomonas aeruginosa was isolated from liver, lung and spleen in five animals in group B (45.45%) and in six in group C (54.54%). Early apoptosis of blood monocytes supervened after multiple trauma; the phenomenon was accompanied by apoptosis of blood lymphocytes and subsequent bacterial translocation.     

Genetic background affects the expansion of macrophage subsets in the lungs of Mycobacterium tuberculosis‐infected hosts

M1 macrophages are more effective in the induction of the inflammatory response and clearance of Mycobacterium tuberculosis than M2 macrophages. Infected C57BL/6 mice generate a stronger cellular immune response compared with BALB/c mice. We hypothesized that infected C57BL/6 mice would exhibit a higher frequency and function of M1 macrophages than infected BALB/c mice. Our findings show a higher ratio of macrophages to M2 macrophages in the lungs of chronically infected C57BL/6 mice compared with BALB/c mice. However, there was no difference in the functional ability of M1 and M2 macrophages for the two strains in vitro. In vivo, a deleterious role for M2 macrophages was confirmed by M2 cell transfer, which rendered the infected C57BL/6, but not the BALB/c mice, more susceptible and resulted in mild lung inflammation compared with C57BL/6 mice that did not undergo cell transfer. M1 cell transfer induced a higher inflammatory response, although not protective, in infected BALB/c mice compared with their counterparts that did not undergo cell transfer. These findings demonstrate that an inflammation mediated by M1 macrophages may not induce bacterial tolerance because protection depends on the host genetic background, which drives the magnitude of the inflammatory response against M. tuberculosis in the pulmonary microenvironment. The contribution of our findings is that although M1 macrophage is an effector leucocyte with microbicidal machinery, its dominant role depends on the balance of M1 and M2 subsets, which is driven by the host genetic background.     

In vitro and in vivo macrophage function can occur independently of SLP-76

Expression of SH2 domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76), a hematopoietic cell-specific adapter protein, is required to couple Syk family tyrosine kinase activation to downstream mediators such as phospholipase C (PLC)-gamma following TCR, platelet collagen receptor and mast cell Fc epsilon R stimulation. In addition to T cells, mast cells and platelets, SLP-76 is expressed in monocytes and macrophages. To determine the role of SLP-76 in Fc gamma R-stimulated signaling pathways in macrophages, we examined cultured bone marrow-derived macrophages (BMM) from SLP-76(-/-) and wild-type mice. In this study, we show that Fc gamma R cross-linking rapidly induces tyrosine phosphorylation of SLP-76 in wild-type BMM. Surprisingly, however, BMM from SLP-76(-/-) mice activate ERK2 and phosphorylate PLC-gamma 2 following Fc gamma R ligation. Furthermore, SLP-76(-/-) BMM display normal Fc gamma R-dependent phagocytic function and reactive oxygen intermediate production. SLP-76(-/-) and SLP-76(+/+) BMM secrete comparable levels of IL-12 in response to lipopolysaccharide and IFN-gamma. To examine macrophage function in vivo, SLP-76(-/-) mice were challenged i.v. with Listeria monocytogenes. SLP-76(-/-) mice survive and efficiently contain the acute phase of infection similar to wild-type mice but exhibit a stable chronic infection attributed to the lack of mature T cells. These data show that, although SLP-76 is required to couple Syk family PTK activity to downstream mediators and effector functions in Fc gamma R-induced pathways in some cell types, activation of Fc gamma R-dependent pathways occurs independently of SLP-76 in BM     

Augmentation of the human monocyte/macrophage chemiluminescence response during short-term exposure to interferon-gamma and tumour necrosis factor-alpha.

The effects of short-term (30 min) pre-incubation of human monocytes and macrophages (3-day cultured monocytes) with leucocyte-derived human interferon-gamma (IFN-gamma) and recombinant human tumour necrosis factor-alpha (rTNF-alpha) were examined. Pre-incubation of either monocytes or macrophages with rTNF-alpha or IFN-gamma (100 U/5 x 10(5) cells) augmented their respiratory burst to formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), measured by the luminol- and lucigenin-dependent chemiluminescence assay. In addition, both cell types showed a burst of respiratory activity in the presence of rTNF-alpha or IFN-gamma only. The effects of IFN-gamma were removed by adsorption with an anti-IFN-gamma monoclonal antibody and those of rTNF-alpha were abolished by heating at 100 degrees C, or by the addition of anti-TNF-alpha monoclonal antibody. The results demonstrate that both IFN-gamma and rTNF-alpha are stimulators of monocytes and macrophages, and rapidly alter the capacity of the cells to respond to fMLP, which binds to cell surface receptors.     

Tumour necrosis factor soluble receptors behave as acute phase reactants following surgery in patients with rheumatoid arthritis, chronic osteomyelitis and osteoarthritis.

Tumour necrosis factor-alpha (TNF-alpha) is involved in diverse biological processes including immune and inflammatory reactions and the response to surgical stress. Two soluble TNF receptor protein fragments, TNF-sR55 (from the p55 kD TNF receptor) and TNF-sR75 (from the p75 kD TNF receptor), are released by cells during inflammation and may modulate the e effects of TNF-alpha. We have studied the kinetics of secretion of TNF-alpha, TNF-sR55 and TNF-sR75 in the sera of patients with rheumatoid arthritis (RA) and control subjects with osteoarthritis (OA) or chronic osteomyelitis (OM) before and after major surgery. Significantly higher pre-operative levels of TNF-sR55 and TNF-sR75 were found in RA and OM as compared with OA (P < 0.02). Following surgery, TNF-sR55 increased within 24 h in RA, OM and OA (P < 0.05), whereas TNF-sR75 increased significantly only in OM and OA patients (P < 0.05). By contrast, no TNF-alpha was detectable before and after surgery in any of the subjects, but this may have been due to impaired detection (by ELISA) of TNF-alpha when it is bound to TNF-sR. These findings suggest that TNF-sR55 and TNF-sR75 may be further markers of the host's reaction to inflammatory insults. They may also play a role in modulating the immune and inflammatory reactions by inhibiting the systemic effects of TNF-alpha.     

Cytokines and the regulation of apoptosis in reproductive tissues: a review.

PROBLEM: To determine the role of apoptosis-regulating genes bax and bcl-2 in reproduction. METHOD OF STUDY: Review of literature and current data. RESULTS: The bcl-2 family of apoptotic regulatory gene products interact and form dimers of anti- and pro-apoptotic proteins (e.g., bcl-2 and bax respectively), the ratio of which determines cell death or survival. Menses is associated with increased apoptosis in the glands, a change in bcl-2:bax ratio and increased levels of the pro-apoptotic cytokine TNFalpha. Apoptosis occurs in all placental cell types and increases from first to third trimester. Placental apoptosis is induced by TNFalpha in vitro and increased levels in utero characterize most failing pregnancies, intra-uterine growth restriction (IUGR) and labour. An increased bcl-2:bax ratio and apoptosis in the syncytiotrophoblast characterizes failing first trimester pregnancies. Apoptosis in the syncytiotrophoblast is also associated with IUGR. In a rat model, maternal vitamin A deficiency perturbs fetal development. This is associated with a placental infiltrate of TNFalpha positive neutrophils (day 20) and increased placental apoptosis in areas of infiltration. A similar infiltrate occurs in a mouse model of early pregnancy loss. In the fetal membranes, clusters of bcl-2 negative chorion trophoblast cells undergo apoptosis. This may allow passage of myometrial stimulatory factors that induce labour. CONCLUSION: The ratio of bcl-2:bax is crucial in the regulation of apoptosis, particularly in the human placenta. Changes in trophoblast apoptosis characterize (1) early pregnancy failure, (2) IUGR and (3) pre-term and term labour. Regardless of gestational age, TNFalpha plays a major role in the induction of placental apoptosis.     

趋化因子MCP-1在EAN中的作用及雷公藤多甙的影响

目的 探讨单核细胞趋化蛋白-1(MCP-1)在实验性变态反应性神经炎(experimental autoimmune neuritis,EAN)中的作用及雷公藤多甙(TWP)对其影响.方法 用兔坐骨神经匀浆免疫Wistar大鼠建立EAN模型,TWP灌胃治疗,观察大鼠发病情况和组织病理改变,用免疫组化技术检测MCP-1在坐骨神经中的表达.结果 EAN组大鼠在第15天发病达到高峰,且病理改变可见炎性细胞浸润及脱髓鞘,其MCP-1表达高峰在疾病早期(9 d),随后逐渐下降,与对照组相比有显著差异性(P＜0.001).EAN TWP组大鼠发病程度较EAN NS组轻,MCP-1表达的整体趋势较EAN NS组降低.结论 MCP-1可能对EAN 发病起始动作用.TWP可能通过抑制趋化因子MCP-1的表达来减轻EAN.