NF-kappaB in solid tumors

Cancer is a multistep process during which cells acquire genetic alterations that drive the progressive transformation of normal cells into highly malignant cells. Self-sufficiency in growth, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, are signatures of transformed cells. NF-kappaB is a key actor in tumorigenesis given its ability to control the expression and the function of a number of genes involved in these processes. Indeed, constitutive activation of NF-kappaB is a common feature of many human tumors, while its sustained activation during inflammation predisposes normal cells to neoplastic transformation. Since suppression of NF-kappaB has been shown to inhibit oncogenic potential of transformed cells, targeting it should be effective in the prevention and treatment of cancer.     

Adhesion molecules in inflammatory bowel disease: therapeutic implications for gut inflammation.

Mucosal endothelium has become one of the major areas of investigation in gut inflammation. It is now well recognised that it plays an active role in the pathogenesis of both forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis, since endothelial cells regulate mucosal immune homeostasis, acting as "gatekeepers", controlling leukocyte accumulation in the interstitial compartment. This process is mediated by leukocyte-endothelial adhesion molecules. This paper reviews the major molecules that mediate leukocyte-endothelial interactions, and summarises the results of the most recent clinical trials targeting adhesion molecules in inflammatory bowel disease.     

Keratinocyte growth factor (KGF) decreases ICAM-1 and VCAM-1 cell expression on bronchial epithelial cells

Activation of leucocytes during airway inflammatory reaction involves adhesion to bronchial epithelial cells (BEC), a process implicating specific interactions between glycoproteins with epithelial cell surface proteins, mainly intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In this study, the effect of keratinocyte growth factor (KGF), a growth factor involved in pulmonary epithelium repair, was evaluated on adhesion molecule expression with BEAS-2B cells and BEC and granulocyte adherence to BEAS-2B. The modulation by KGF of membrane and mRNA expression of ICAM-1 and VCAM-1 was studied on confluent cells stimulated or not with tumour necrosis factor-alpha (TNF) (200 UI/ml) or TNF and interleukin (IL)-4 (50 UI/ml and 10 ng/ml). Levels of soluble-(s)ICAM-1 and sVCAM-1 were measured by ELISA. Although moderately, KGF significantly decreased membrane ICAM-1 expression in unstimulated BEAS-2B cells (24% inhibition at 100 ng/ml) or in TNF- or TNF + IL-4-stimulated cells (22.5 and 18.7% inhibition, respectively). Treatment with KGF tended to decrease VCAM-1 expression in TNF- and TNF + IL-4-stimulated BEAS-2B (P = n.s. and P < 0.05, 14 and 15% inhibition, respectively). In primary culture of BEC, adhesion molecule expression was also reduced. ICAM-1 and VCAM-1 mRNA expression were also inhibited by KGF. Levels of sICAM-1 and sVCAM-1 were not significantly increased in supernatants from KGF-treated cells (30% and 24% increase at 100 ng/ml, respectively) compared to controls. Moreover, KGF decreased by 31% the adherence of neutrophils to TNF-activated BEAS-2B. In conclusion, KGF decreases ICAM-1 and VCAM-1 expression and neutrophil adherence in BEC. These suggest its involvement in the resolution of the inflammatory reaction.     

Glomerular expression of alpha-smooth muscle actin reflects disease activity of IgA nephropathy

To elucidate the relationship between histological disease states and clinicopathological features in immunoglobulin A nephropathy (IgAN), 90 needle-biopsy specimens diagnosed as IgAN were analyzed. The specimens were divided into four groups according to histological grade and stage index. Immunohistochemical features of alpha-smooth muscle actin (alpha-SMA), macrophages positive for myeloid/histiocyte antigen (MAC387), and expression of type I, III and IV collagens were all examined. Glomerular expression scores of alpha-SMA and the degree of intraglomerular macrophage infiltration were highest in the active and non-sclerotic groups. Type I and IV collagens were significantly more abundant in the sclerotic groups than in the active groups. Type III collagen was strongly expressed in both the active and sclerotic groups. Double immunolabeling of alpha-SMA and intercellular adhesion molecule (ICAM)-1 revealed that ICAM-1 was expressed around the alpha-SMA-positive mesangial area. In multivariate analysis, the glomerular expression score of alpha-SMA was mostly correlated with histological grading in the 10 clinicopathological parameters. Type IV collagen score was mostly correlated with histological staging. These results suggest that glomerular alpha-SMA expression reflects the histological activity of IgAN. Immunohistological staining of alpha-SMA is valuable to estimate the degree of disease activity in IgAN.     

产科抗磷脂综合征患者血清对脐静脉内皮细胞活化的研究

目的观察产科抗磷脂综合征患者血清对脐静脉内皮细胞活化的影响。方法用采集的16例APS患者和10例健康对照者血清分别处理体外培养的脐静脉内皮细胞,用逆转录定量聚合酶链反应检测脐静脉内皮细胞上细胞间粘附分子-1（ICAM-1）和E-选择素（E-selectin）mRNA表达,用流式细胞仪检测二者蛋白的表达。结果APS血清处理后脐静脉内皮细胞上粘附分子ICAM-1和E-selectin mRNA和蛋白均比对照组明显升高,差异有显著性（P〈0.05）。结论抗磷脂综合征患者血清可激活脐静脉内皮细胞,使粘附分子表达增加。     

Endotoxin stimulates monocyte-endothelial cell interactions in mouse intestinal Peyer's patches and villus mucosa

Although monocyte-endothelial cell interactions represent an initial step in controlling the recruitment of monocytes in inflamed tissues, their dynamic processes in microvessels of lymphoid (Peyer's patches) and non-lymphoid (villus) regions in gut-associated lymphoid tissue remain poorly understood. We monitored the migration of fluorescence-labelled monocytes derived from the spleen in intestinal microvessels with or without lipopolysaccharide (LPS) treatment and investigated the role of adhesion molecules, P-selectin, vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). In control mice, there were few interactions between infused monocytes and the endothelium of intestinal microvessels. The monocyte-endothelial interactions (both rolling and adhesion) were significantly increased in intestinal microvessels of LPS-treated mice compared with those in controls. Anti-P-selectin monoclonal antibody (MoAb) significantly suppressed the LPS-induced increase in monocyte rolling in postcapillary venules of Peyer's patches and submucosal venules. Anti-VCAM-1 MoAbs significantly suppressed the LPS-induced increase in monocyte adhesion to postcapillary venules (PCVs) of Peyer's patches, submucosal venules, and villus capillaries. In contrast, anti-ICAM-1 MoAb significantly suppressed the number of adherent monocytes in PCV of Peyer's patches but not in submucosal venules or villus capillaries. These observations demonstrated that LPS treatment resulted in a significant increase in recruitment of monocytes both in microvessels of lymphoid and non-lymphoid regions and that P-selectin, VCAM-1 and ICAM-1 appeared to play important roles in LPS-induced interactions.     

Quantification of mucosal leucocyte endothelial cell interaction by in vivo fluorescence microscopy in experimental colitis in mice.

Leucocyte recruitment to sites of intestinal inflammation is a crucial, multi-step process that leads ultimately to the accumulation of cells in the inflamed tissue. We established a new in vivo model system of experimental colitis to quantify leucocyte-endothelial cell interaction and leucocyte extravasation in the inflamed mucosa of the colon. Furthermore, we investigated the pathophysiological role of ICAM-1 in the intestinal microcirculation in vivo. Using the model of dextran sodium sulphate (DSS)-induced acute and chronic colitis in mice, in vivo microscopy was performed in the colonic submucosal postcapillary venules and the submucosal collecting venules in normal or inflamed murine colonic segments. ICAM-1 expression was blocked by an anti-ICAM-1 monoclonal antibody or by suppressing NF-kappaB activation by gliotoxin. Significant increases in leucocyte adhesiveness (51-fold in postcapillary venules, 30-fold in collecting venules, P < 0.01) and extravasation (6.5-fold) could be demonstrated as early as day 2 of DSS-application in acute colitis (P < 0.01). This was paralleled by increases in both the histological damage scores and myeloperoxidase activities. In chronic dextran sodium sulphate-induced colitis significant increases in leucocyte-endothelium interactions and leucocyte extravasation were observed. Blocking ICAM-1 expression with a monoclonal antibody or gliotoxin, leucocyte sticking and extravasation were significantly down-regulated in vivo compared to controls (> 70%; P < 0.01). This new model system offers the possibility to specifically assess the role of adhesion molecules in the colonic mucosa in vivo as well as to investigate and quantify the effectiveness of experimental therapeutic approaches in acute or chronic intestinal inflammation.     

Small molecules useful in the treatment of inflammatory disease

A series of substituted N³-phenylhydantoins are claimed as the first small molecule, non-peptidic antagonists of the binding of intercellular adhesion molecules such as ICAM-1 with the leukointegrin LFA-1. The Boehringer-Ingelheim investigators describe the synthesis of 278 analogues, including a variety with substituents at each ring position as well as several thiocarbonyl variants. All compounds are evaluated for their ability to block LFA-1/ICAM-1 binding; supplementary biochemical data demonstrate the ability of representative compounds to block cell adhesion and aggregation, as well as the mixed lymphocyte reaction (MLR). Cellular toxicity data (MTT uptake) are included, and in vivo data in an allogeneic cell transplantation assay are described for several antagonists. LFA/ICAM antagonists may find utility in the treatment of a variety of inflammatory or immune disorders.