Explore the vast range of titles available.

The medical management of idiopathic inflammatory bowel disease (IBD) has historically been based upon the use of broad-spectrum anti-inflammatory drugs such as corticosteroids and thiopurines. Recently, the identification of novel mechanisms central to the pathophysiology of IBD has provided more specific targets, including inhibition of leukocyte trafficking to the gut. In this article, we discuss the molecular biology of intestinal leukocyte trafficking and review the emerging therapies that target this process, including vedolizumab, natalizumab, etrolizumab, PF-547659, alicaforsen, efalizumab, and emerging members of this class.

The recognition and attachment of virus to its host cell surface is a critical step for viral infection. Recent research revealed that β-integrin was involved in White spot syndrome virus (WSSV) infection. In this study, the interaction of β-integrin with structure proteins of WSSV and motifs involved in WSSV infection was examined. The results showed that envelope proteins VP26, VP31, VP37, VP90 and nucleocapsid protein VP136 interacted with LvInt. RGD-, YGL- and LDV-related peptide functioned as motifs of WSSV proteins binding with β-integrin. The β-integrin ligand of RGDT had better blocking effect compared with that of YGL- and LDV-related peptides. In vivo assay indicated that RGD-, LDV- and YGL-related peptides could partially block WSSV infection. These data collectively indicate that multiple proteins were involved in recognition of β-integrin. Identification of proteins in WSSV that are associated with β-integrin will assist development of new agents for effective control of the white spot syndrome.

Background Mechanical strain plays a great role in growth and differentiation of osteoblast. A previous study indicated that integrin-β (β1, β5) mediated osteoblast proliferation promoted by mechanical tensile strain. However, the involvement of integrin-β in osteoblastic differentiation and extracellular matrix (ECM) formation induced by mechanical tensile strain, remains unclear. Results After transfection with integrin-β1 siRNA or integrin-β5 siRNA, mouse MC3T3-E1 preosteoblasts were cultured in cell culture dishes and stimulated with mechanical tensile strain of 2500 microstrain (με) at 0.5 Hz applied once a day for 1 h over 3 or 5 consecutive days. The cyclic tensile strain promoted osteoblastic differentiation of MC3T3-E1 cells. Transfection with integrin-β1 siRNA attenuated the osteoblastic diffenentiation induced by the tensile strain. By contrast, transfection with integrin-β5 siRNA had little effect on the osteoblastic differentiation induced by the strain. At the same time, the result of ECM formation promoted by the strain, was similar to the osteoblastic differentiation. Conclusion Integrin-β1 mediates osteoblast differentiation and osteoblastic ECM formation promoted by cyclic tensile strain, and integrin-β5 is not involved in the osteoblasts response to the tensile strain.

Integrin αvβ6 is an epithelial-specific receptor that binds and activates latent transforming growth factor-β1 (TGF-β1). TGF-β1 has been implicated as an endogenous inducer of hair follicle (HF) regression during hair cycling. We hypothesized that αvβ6 integrin–mediated TGF-β1 signaling regulates hair regeneration and HF involution. In wild-type (WT) mice, the expression of integrin αvβ6 was strongly upregulated in the outer root sheath (ORS) during early hair regeneration, and was specifically enhanced in the HF bulge region. Expression gradually decreased in late anagen and remained restricted to the bulge region in the catagen and telogen stage HFs. The first spontaneous hair cycle was not altered in β6 integrin knockout (β6−/−) mice. However, after depilation, β6−/− mice exhibited retarded HF regression compared with WT controls. β6−/− follicles contained significantly higher numbers of proliferating Ki67-positive keratinocytes than WT follicles at an identical cycle stage. The β6−/− follicles also demonstrated significantly reduced levels of TGF-β1 expression and Smad2 phosphorylation during early anagen and anagen–catagen transition. Our study indicates that αvβ6 integrin has an important inhibitory role in keratinocyte proliferation in both HFs and interfollicular epidermis. Thus, downregulated TGF-β1 signaling in β6−/− mice may affect bulge niche stem cell behavior.

Germinal matrix hemorrhage (GMH), affecting about 1 in 300 births, is a major perinatal disease with lifelong neurological consequences. Yet despite advances in neonatal medicine, there is no effective intervention. GMH is characterized by localized bleeding in the germinal matrix (GM), due to inherent vessel fragility unique to this developing brain region. Studies have shown that reduced TGFβ signaling contributes to this vascular immaturity. We have previously shown that a region-specific G-protein coupled receptor pathway in GM neural progenitor cells regulates integrin β8, a limiting activator of pro-TGFβ. In this study, we use mice to test if this regional pathway can be harnessed for GMH intervention. We first examined the endogenous dynamics of this pathway and found that it displays specific patterns of activation. We then investigated the functional effects of altering these dynamics by chemogenetics. To our surprise, we found that there is a narrow developmental window during which this pathway is amenable to manipulation. While high-level activity in this time window interferes with vessel growth, moderate enhancement promotes vessel maturation without compromising growth. Furthermore, we found that enhancing the activity of this pathway in a mouse model rescues all GMH phenotypes. Altogether, these results demonstrate that enhancing neurovascular signaling through pharmacological targeting of this pathway may be a viable approach for tissue-specific GMH intervention. They also demonstrate that timing and level are likely two major factors critical for success. These findings thus provide critical new insights into both brain neurovascular biology and the intervention of GMH.

We assessed expression of IL-20 and its receptors in psoriasis, given the recent implication of IL-20 in epidermal hyperplasia. Psoriatic lesional (LS) skin consistently expressed more IL-20 mRNA than nonlesional (NL) skin. Immunoreactivity to IL-20 protein was greater in LS tissue and mainly localized to infiltrating CD68+/CD11c+ (myeloid-derived) dermal leukocytes. Because this contrasted with earlier reports of a keratinocyte source, we assessed IL-20 mRNA expression in a variety of cells in vitro, and confirmed a myeloid-derived cellular source (monocytes). Plastic adhesion, activation of β2 integrins, and incubation with tumor necrosis factor-α stimulated expression in these cells. IL-20 receptor (IL-20R)α and IL-20Rβ mRNA was decreased in LS versus NL skin, which also contrasted with earlier findings. To investigate the relationship between IL-20 and disease activity, we examined psoriasis patients treated with the CD2-targeted agent alefacept. In therapeutic responders, lesional IL-20 mRNA decreased to NL levels, suggesting that CD2+ leukocytes may proximally regulate IL-20. Finally, to assess IL-20 function, we used microarrays to screen IL-20-treated keratinocytes, which demonstrated upregulation of disease-related and IFN-γ-induced genes. Hence, IL-20 may influence inflammation through IFN-like effects. Together, these data indicate that IL-20 may be an important effector cytokine in psoriasis, and that its inhibition may represent a potential therapeutic target.

L-selectin (CD62L) and β7 integrins are important for trafficking of naive T cells under steady-state conditions. The objectives of this study were to dissect the requirements for T cell–associated CD62L and β7 integrins during initiation, progression, and regulation of chronic colitis.MethodsUsing the T-cell transfer model, we compared colitogenic potential between T cells lacking one or both of these molecules with wild-type T cells. To assess trafficking of cells to the secondary lymphoid tissue and the gut, we performed co-homing experiments.ResultsAdoptive transfer of wild-type, CD62L−/− or β7−/− single-deficient T cells induced moderate to severe disease with slightly different kinetics. However, transfer of CD62L−/− β7−/− double-deficient (DKO) T cells produced significantly attenuated gut inflammation, which correlated with fewer T cells and reduced levels of proinflammatory cytokines in the colon lamina propria. Our subsequent experiments established that lack of colitogenic potential of these cells was due to inability of DKO T cells to home to the secondary lymphoid tissue. Furthermore, homing of in vitro–generated effector DKO T cells to the inflamed intestine was significantly impaired. Lastly, DKO regulatory T cells were ineffective at suppressing colitis induced by wild-type T cells.ConclusionsWe established that T cells can use either CD62L or β7 integrins to induce chronic colitis, but lack of both abrogates their colitogenic potential. Effector T cells critically rely on β7 integrin during their recruitment to the inflamed intestinal mucosa. Finally, regulation of intestinal inflammation by regulatory T cells requires one or both of these adhesion molecules.

Tumor metastasis is a complex process involving the interaction between tumor cells and endothelial cells in which some adhesion molecules play an important role. It was our aim to investigate the role of the adhesion molecules, alpha v beta 3 and alpha v beta 5 and their ligands, developmental endothelial locus-1 (Del-1) and L1, in tumor cell adhesion to endothelial cells in vitro. In this study, the expression and regulation of alpha v beta 3, alpha v beta 5 and intercellular adhesion molecule -1 on liver sinusoidal endothelial cells and liver cancer endothelial cells (T3A) were analyzed by real-time PCR and fluorescent-activated cell sorter. The expression and regulation of the integrin ligands, Del-1 and L1, in six tumor cell lines were analyzed by real-time PCR and western blot. We found the expressions of alpha v beta 3 and alpha v beta 5 were higher on T3A than that on liver sinusoidal endothelial cells, whereas expression of intercellular adhesion molecule-1 was lower on T3A than that on liver sinusoidal endothelial cells. After 24 h hypoxia, the expressions of alpha v beta 3 and alpha v beta 5 were upregulated on T3A and liver sinusoidal endothelial cells; the expression of intercellular adhesion molecule-1 was increased on liver sinusoidal endothelial cells, but remained unchanged on T3A. Del-1 and L1 expression levels were obviously diverse in various tumor cell lines and differentially modulated after 12 h hypoxia. The adhesion of tumor cells with Del-1 and L1 expression was higher in T3A than that in liver sinusoidal endothelial cells, and was significantly increased under hypoxic conditions. Interestingly, the tumor cell adherence could be inhibited by antibodies against alpha v beta 5 and alpha v beta 5, but not by an antibody against intercellular adhesion molecule-1. The adhesion of tumor cells without Del-1 and L1 expression was also higher on T3A than that on liver sinusoidal endothelial cells, but the adhesion could not be inhibited by antibodies against alpha v beta 5, alpha v beta 5 or intercellular adhesion molecule-1, suggesting that other receptors are involved. In conclusion, alpha v beta 5, alpha v beta 5 and their ligands Del-1 and L1 play an important role in the process of tumor cells moving from the original place.

Tumor cells can show different malignant properties regarding their ability for organ-specific metastasis formation. Their adhesive and invasive characteristics mediated by various cell adhesion molecules appear to be crucial for this process. Using intravital fluorescence microscopy, we analyzed the adhesive and invasive interactions of circulating human colon carcinoma cells within the microvasculature of the liver in rats. The involvement of different cell adhesion molecules in specific tumor cell–host organ interactions was investigated. Single-cell suspensions of human colon carcinoma with low (HT-29P) and high (HT-29LMM) metastatic potential were fluorescence labeled with calcein-AM and intra-arterially injected into Sprague-Dawley rats. Initial interactions between different cell lines and the microvasculature of the liver were observed over 30 minutes and semiquantitatively analyzed. Different integrin subunits, carbohydrate ligands, and vascular cell adhesion molecule-1 were inhibited using function-blocking antibodies or by enzymatic removal. Inhibition of sialyl-Lewis a (sLe a) or enzymatic removal of selectin carbohydrate ligands significantly reduced metastatic cell adhesion. In addition, α6-, β1-, and β4-integrins can directly mediate cell adhesion within the hepatic microcirculation. Furthermore, α2-, α6-, β1-, and β4-integrins are involved in early tumor cell extravasation into the liver parenchyma. Organ-specific formation of colorectal metastases appears to be mainly mediated by specific interactions between circulating carcinoma cells and the vessel wall of target organs but not mechanical entrapment. Selectin–sLe a interactions with sinusoidal endothelial cells can play a key role in organ-specific targeting, but direct integrin-mediated cell adhesion to extracellular matrix components in the space of Disse appears to be required for the successful formation of liver metastases.

Cell-matrix adhesive interaction has an important role in the invasive process of tumor cells, and integrins are the major receptors mediating cell-matrix adhesion. The current study is to investigate the modulation of basement membrane (BM) proteins, especially collagen IV (C IV), laminin (LN), and fibronectin (FN) in the invasive processes of human hepatocellular carcinoma (HCC) cells in vitro, and to reveal the roles of beta1 integrins and RGD-containing oligopeptide in the cell-matrix interaction. Static adhesion assay was performed to study the rates of adhesion of MHCC97-H cells, treated or untreated with anti-beta1 (2 microg ml(-1)) and GRGDS, to C IV (50 microg ml(-1)), LN (50 microg ml(-1)) or FN (50 microg ml(-1)). Gelatin zymography was used to detect the secretion of MMPs in the conditioned medium of MHCC97-H cells incubated 24 h by C IV, LN or FN, and interactions with anti-beta1 and GRGDS. Transwell chamber assay was used to investigate the influence of C IV, LN or FN, interacting with anti-beta1 and GRGDS, on the cellular mobility of MHCC97-H cells. Compared with blank control group, MHCC97-H cells showed significantly higher rates of adhesion to C IV, LN, and FN. Pretreatment with anti-beta1 could suppress adhesion to C IV, LN or FN, but GRGDS inhibited adhesion to FN (P<0.05) only. LN and FN could stimulate the secretion of MMPs by MHCC97-H cells cultured in vitro, especially MMP-9 and its activated type. Treatment with anti-beta1 could partly counteract the effects of LN and FN. GRGDS could prominently induce the secretion of MMPs, but the effect could be inhibited by pretreatment of anti-beta1. The results of Transwell chamber assay showed that LN, FN, and GRGDS could increase the number of tumor cells penetrating the microporous membrane, but the data of C IV did not reach significance. The effects were partly counteracted by anti-beta1. BM proteins play an active role in the invasive process of human hepatocellular carcinoma cells. Integrin beta1 is an important molecule which mediates the cell-matrix adhesive interaction of tumor cells. RGD-containing peptides competitively combine with the binding site of integrin beta1, and the effects of FN are RGD sequence-dependent.