Induction Of Adhesion Molecules Research Articles

A Convenient Protocol for Selective Cleavage of 2‐Hydroxy Acid Amides. Application to Semisynthesis of the Cyclic Heptapeptide Aza HUN‐7293.

A two-step protocol for the first chemoselective cleavage of 2-hydroxy acid amides has been developed. Mesylation of the model substrate 2-(hydroxypropionylamino)-4-methylpentanoic acid methyl ester (11) followed by treatment with N-ethylthiourea (13) allows cleavage of 2-hydroxy acid amides under smooth conditions. Successful application of this methodology to the open-chain transesterification product 15 (methylester) of the cyclic heptadepsipeptide HUN-7293, a potent inhibitor of inducible cell adhesion molecule expression, delivered the corresponding hexapeptide 18 with unprotected N-terminus in 70−75% yield. This result demonstrates that the protocol developed even works in the presence of an ester and several methylated and unmethylated amide bonds. Finally, a sequence of ligation of methyl d-dehydroglutaminate (20) to the C-terminus of the saponification product 21, followed by the degradation protocol and ring closure, allowed chemical “point mutation” at the DGCN site affording the aza analogue o...

Suppression of endothelial adhesion molecule up-regulation with cyclopentenone prostaglandins is dissociated from IkappaB-alpha kinase inhibition and cell death induction.

The cyclopentenone prostaglandins (cPG) 15-deoxy-Delta12,14-prostaglandin J2 (dPGJ2) and PGA1 can inhibit multiple steps in nuclear factor (NF)-kappaB signaling and can induce cell death. Here we characterized the effects of dPGJ2 and PGA1 on the inflammatory induction of endothelial cell adhesion molecules (CAM). Pretreatment of endothelial cells with dPGJ2 or PGA1 at low concentrations dose dependently inhibited the up-regulation of CAM expression and monocyte arrest by tumor necrosis factor (TNF)-alpha but not expression of inhibitor of apoptosis proteins. Only at high concentrations, cPG enhanced TNF-alpha-induced cell death and inhibited TNF-alpha-induced IkappaB-alpha kinase (IKK) activation, IkappaB-alpha degradation, and NF-kappaB/p65 translocation, while promoting AP-1/c-jun phosphorylation. Expression of an IKK-beta mutant (C179A) resistant to interaction with cPG impaired cell death induction but not inhibition of CAM up-regulation by cPG. Gel shift and reporter gene analysis revealed that cPG at low concentrations directly impaired DNA binding of NF-kappaB and NF-kappaB-dependent transactivation. The synthetic analogs dPGA1 or dPGA2 were ineffective, indicating structural specificity of cPG. Thus, the suppression of endothelial CAM up-regulation with cPG is dissociated from cell death sensitization and IKK inhibition above threshold concentrations and related to interference with NF-kappaB binding. Our findings define distinct mechanisms for anti-inflammatory and proapoptotic effects of cPG in endothelial cells.

Different phenotypes of colon carcinoma cells interacting with endothelial cells: role of E-selectin and ultrastructural data.

Adhesion molecules are intimately involved in the process of tumour progression. Among them, E-selectin is an inducible endothelial cell adhesion molecule that plays a role in the interactions of neoplastic cells with the endothelium. These interactions are required for the trans-endothelial migration of tumour cells that leads to the growth at the new sites. Since the detailed events in the early phase of metastasis still remain poorly defined, our study has undertaken an electron-microscopic analysis of the interactions of human colon carcinoma cells with endothelial cells as well as an analysis of the effect of recombinant purified E-selectin in the cell signalling involved in colon cancer cell malignant phenotype. Results revealed that SW480 and T84 colon cancer cell lines show different features, different adhesion kinetics, a different cytoskeletal organization, and a different tyrosine phosphorylation pattern when seeded on an endothelial cell monolayer or recombinant E-selectin. In particular T84 cancer cells adhere more efficiently to the E-selectin and this interaction is associated with pronounced morphological changes, actin redistribution and filopodial processes, and an increase in tyrosine phosphorylation of different proteins. These data support the hypothesis that E-selectin ligand is not only a cell-cell adhesion molecule but also initiates a signalling transduction pathway inside the cells.

The contribution of interleukin-1 and tumor necrosis factor to periodontal tissue destruction.

Interleukin (IL)-1 and tumor necrosis factor (TNF) represent proinflammatory cytokines that stimulate a number of events which occur during periodontal disease. These include the induction of adhesion molecules and other mediators that facilitate and amplify the inflammatory response, the stimulation of matrix metalloproteinase, and bone resorption. The activity of these cytokines coincides with the critical events that occur during periodontal disease, namely, loss of attachment and bone resorption. The use of antagonists to IL-1 and TNF in experimental periodontitis have demonstrated a cause-and-effect relationship between the activity of these cytokines and the spread of an inflammatory front to deeper areas in the connective tissue, loss of connective tissue attachment, osteoclast formation, and loss of alveolar bone. In addition, the loss of fibroblasts that occurs during infection with periodontal pathogens is, in part, mediated by TNF. Thus, much of the damage that occurs during periodontal tissue destruction can be attributed to IL-1 and TNF activity. This destruction may very well represent an overreaction of the host response to periodontal pathogens caused by excessive production of IL-1 and TNF.

The same endothelial receptor controls lymphocyte traffic both in vascular and lymphatic vessels.

The mechanisms controlling the exit of lymphocytes from tissues via lymphatics are practically unknown. We have now identified a 270-300-kDa molecule designated common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) on human lymphatic endothelium and high endothelial venules. We show that it mediates binding of lymphocytes both to high endothelial venules and to lymphatic vessels. Moreover, blocking of the function of CLEVER-1 results in significant reduction of lymphocyte traffic in vivo. Notably, CLEVER-1 is also an inducible vascular adhesion molecule for other classes of leukocytes at sites of inflammation in peripheral tissues. These findings suggest that CLEVER-1 is involved in regulation of lymphocyte recirculation and migration of leukocytes to sites of inflammation and is a potential new target to control inflammation.

Interleukin-3, -5, and granulocyte macrophage colony-stimulating factor-induced adhesion molecule expression on eosinophils by p38 mitogen-activated protein kinase and nuclear factor-[kappa] B.

We investigated the intracellular signaling mechanisms for cytokine interleukin (IL)-3, IL-5, or granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced expression of adhesion molecules including very late antigen 4 (CD49 d), macrophage antigen-1 (CD11b), leukocyte function-associated antigen-1 (CD11a/CD18), intercellular adhesion molecule (ICAM)-1, and ICAM-3 on eosinophils. The expression of adhesion molecules and nuclear factor (NF)-kappaB pathway was measured by flow cytometry and cDNA expression array, respectively. The phosphorylation of inhibitor kappaB-alpha and p38 mitogen-activated protein kinase (MAPK) was detected by Western blot, whereas NF-kappaB activity was measured by electrophoretic mobility shift assay. IL-3, IL-5, and GM-CSF could enhance p38 MAPK and NF-kappaB activity and induce ICAM-1, CD11b, and CD18 expressions on eosinophils. They could suppress ICAM-3 expression, but had no effect on CD49 d expression. Either SB 203580 or MG-132 was able to offset the cytokine-induced expression of ICAM-1. Only SB 203580 could reverse the effect on CD11b, CD18, and ICAM-3 expressions. Therefore, the expression of ICAM-1 might involve both p38 MAPK and NF-kappaB activities, whereas the regulation of CD11b, CD18, and ICAM-3 expressions might be mediated through p38 MAPK but not NF-kappaB. These cytokines therefore play a crucial role, via the p38 MAPK and NF-kappaB pathways, in the expression of important adhesion molecules on eosinophils in allergic inflammation.

Adhesion molecules, catecholamines and leucocyte redistribution during and following exercise.

The circulating blood normally contains no more than 1-2% of the body's population of leucocytes. The numbers and phenotypes of circulating leucocyte subsets can change dramatically during and immediately following exercise. The surface expression of adhesion molecules makes an important contribution to such responses by changing patterns of cell trafficking. Alterations in the surface expression of adhesion molecules could reflect a shedding of molecules, selective apoptosis or differential trafficking of cells with a particular phenotype, effects from mechanical deformation of the cytoplasm, active biochemical processes involving cytokines, catecholamines, glucocorticoids or other hormones, or changes in the induction of adhesion molecules. The expression of adhesion molecules changes with maturation and activation of leucocytes. Typically, mature cells express lower densities of L-selectin (CD62L), the homing receptor for secondary lymphoid organs, and higher densities of LFA-1 (CD11a), the molecule associated with trafficking to non-lymphoid reservoir sites. The neutrophils and natural killer cells that are mobilised during exercise also express high levels of Mac-1 (CD11b), a marker associated with cellular activation. Possibly, exercise demarginates older cells that are awaiting destruction in the spleen. Plasma concentrations of catecholamines rise dramatically with exercise, and there is growing evidence that catecholamines, acting through a cyclic adenosine monophosphate second messenger system, play an important role in modifying the surface expression of adhesion molecules. Analogous changes can be induced by other forms of stress that release catecholamines or by catecholamine infusion, and responses are blocked by beta(2)-blocking agents. Catecholamines also modify adherence and expression of adhesion molecules in vitro. Cell trafficking is modified by genetic deficiencies in the expression of adhesion molecules, but leucocyte responses to exercise and catecholamines are generally unaffected by splenectomy. A number of clinical conditions including atherogenesis and metaplasia are marked by an altered expression of adhesion molecules. The effects of exercise on these molecules could thus have important health implications.

857 IFN-γ/STAT1 acts as a pro-inflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1

857 IFN-γ/STAT1 acts as a pro-inflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1

Statin inhibits interferon-gamma-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Pathogenesis of atherosclerosis is multistep processes where transendothelial migration of various leukocytes including monocytes is a crucial step. Interferon-gamma (IFN-gamma) contributes in this process by activating macrophages and T-lymphocytes, and by inducing adhesion molecules in vascular endothelial and smooth muscle cells. In this study we investigated the expression of intercellular cell adhesion molecule-1 (ICAM-1) in transformed endothelial cell line ECV304 cells as influenced by lovastatin, tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma. Results show that lovastatin suppresses expression of ICAM-1 by inhibiting the IFN-gamma-induced extracellular signal-regulated kinase (ERK) p44/p42-STAT1 signaling pathway. In cells treated with lovastatin and IFN-gamma, ICAM-1 was expressed at a lower level than in cells treated with IFN-gamma alone. However, lovastatin does not reduce TNF-alpha induced expression of ICAM-1. A similar result was observed in cells treated with the MEKK inhibitor PD98059 and IFN-gamma. Cis-acting DNA sequence elements were identified in the 5'-flanking region of the ICAM-1 promoter that mediate inhibition by lovastatin; these sequences map to the IFN-gamma activated site which also binds the STAT1 homodimer. However, lovastatin did not inhibit IFN-gamma-mediated induction of the Y701 phosphorylated form of STAT1. But lovastatin does inhibit the IFN-gamma-mediated phosphorylation of ERK1/ERK2 (T202/Y204) and S727 phosphorylation of STAT1. TNF-alpha does not induce phosphorylation of ERK1/ERK2 and S727 in ECV304 and smooth muscle cells. The results provide the evidences that statins may have beneficial effects by inhibiting IFN-gamma action in atherosclerotic process

New strategy for preventing ischemia/reperfusion-induced organ injury and promoting regeneration: a novel trial for improving transplant organ function by targeted regulation of cellular signals

ISCHEMIA/reperfusion(I/R)-induced graft injury is still a serious concern in organ transplantation. Reperfusion of ischemic tissue results in generation of reactive oxygen species (ROS). The oxidant stress represents a major cause of injury associated with reperfusion. Parenchymal and endothelial cells within the ischemic tissue contribute to the oxidant stress through intracellular ROS generation early after reperfusion. The ROS both initiate and propagate lipid peroxidative reactions, including cellular components of polyunsaturated fatty acids, and also permeate into the nucleus, directly injuring DNA. In addition to this tissue damage, ROS produced early after reperfusion also function as signaling intermediaries that up-regulate a variety of pro-inflammatory molecules, many of which serve as redox-sensitive transcription factors such as NFB. The inflammatory reaction then compounds and perpetuates the early reperfusion injury, leading to cellular apoptosis/necrosis and initiation of rejection episodes. Cellular ROS induced early after reperfusion may also signal induction of adhesion molecules, such as ICAM-1, which are expressed on the endothelial cell surfaces during the subacute phase, for neutrophilic infiltration. The secondary damage produced neutrophil infiltration occurs in a later phase after reperfusion that is more injurious than the early phase. In order to suppress secondary damage induced by neutrophil infiltration, numerous trials have sought to block the postischemic injury. Our primary goal was to suppress the ischemic and I/R-induced injury, and to promote regeneration of the transplanted organ, especially in poor-conditioned grafts. We have successfully transferred specific genes to overexpress proteins using replication-deficient adenoviral vectors, thereby reducing I/R-induced liver injury. Our main strategy to protect against I/R injury was to modulate specific cellular signals that lead to postischemic cell death in the liver parenchyma, thereby promoting liver regeneration after the transplantation. Cellular ROS as a signal transducer early after reperfusion is the site of our special interest. The ROS are known to send signals for cell proliferation at low concentrations (physiological conditions), but also have been shown to trigger apoptosis at higher concentrations (pathological conditions such as hypoxia/reoxygenation [H/R]). To counteract ROS, host defense systems include anti-oxidants and enzymes, including catalase SOD. . . In the pathological conditions, these enzymes quench harmful newly generated ROS in cells/ tissues. However, these defense enzymes may be even more advantageous to scavenge ROS-signal intermediaries before they send messages of harmful and/or misleading signals downstream.

The chemokine system: tuning and shaping by regulation of receptor expression and coupling in polarized responses.

The chemokine system: tuning and shaping by regulation of receptor expression and coupling in polarized responses.

Heterogeneous expression of cell adhesion molecules by endothelial cells in ARDS.

ARDS (acute respiratory distress syndrome) can be associated with septic shock and multiple organ failure caused by an uncontrolled systemic inflammatory response to Gram-negative bacterial infection. While in animal models the key role of the endothelial adhesion molecules ICAM-1, E-selectin, and VCAM in ARDS has been extensively studied, there are scarcely any corresponding pathomorphological studies of human lung tissue. Hence, little is known about whether there is a comparable, or even heterogeneous, expression pattern of these molecules in the human pulmonary vasculature. This study was therefore undertaken to investigate the immunohistochemical expression of the constitutively expressed PECAM (CD31) and the inducible molecules ICAM-1, E-selectin, and VCAM in ARDS lungs from patients who had died in septic shock induced by Gram-negative bacteria. While in all specimens (ARDS and normal lungs) there was homogeneous strong expression of PECAM in all vessels, ICAM-1 was clearly up-regulated in ARDS lungs. E-selectin and VCAM were not expressed by endothelial cells (ECs) in normal lungs, but in ARDS lungs there was strong expression of both molecules in larger vessels, while in the capillaries there was only mosaic-like weak expression of a few ECs. This immunohistochemical investigation demonstrates the induction and up-regulation of adhesion molecules in human ARDS lungs, comparable to that described in animal models. There is also markedly heterogeneous expression of E-selectin and VCAM, indicating toporegional differences in the function of pulmonary ECs.

Novel Expression of Vascular Cell Adhesion Molecule-1 (CD106) by Squamous Epithelium in Experimental Acute Graft- versus-Host Disease

Vascular cell adhesion molecule-1 (VCAM-1; CD106), the receptor for VLA-4, is an important mediator of adhesive and co-stimulatory interactions that govern cutaneous immune responses. Initial studies designed to elucidate temporal aspects of endothelial adhesion molecule induction in murine acute graft-versus-host disease (aGVHD) revealed unexpected and novel VCAM-1 expression by cutaneous and mucosal epithelial cells. Immunohistochemical techniques confirmed VCAM-1 staining as early as 7 days after transplantation in a distinctive subpopulation of squamous epithelial cells that normally occupy focal domains within the epidermal basal cell layer, the follicular infundibulum, and the dorsal lingual epithelium. Specifically, VCAM-1 expression was intimately associated with rete ridge-like prominences in footpad epidermis and in dorsal lingual epithelium. VCAM-1, as evaluated by serial section-labeling techniques, was preferentially expressed at sites of early epithelial infiltration by CD4(+) T cells. Western blot analysis confirmed expression of the 110-kd isoform of VCAM-1 in epithelium isolated from aGVHD animals, and immunoelectron microscopy demonstrated VCAM-1 reactivity restricted exclusively to epithelial cell plasma membranes. It is concluded that VCAM-1 is selectively expressed by discrete squamous epithelial subpopulations in murine aGVHD. As such, VCAM-1 may play a previously unrecognized role in mediating interactions between donor effector T lymphocytes and host epithelial cell targets.

Human herpesvirus-6 infection is associated with adhesion molecule induction and lymphocyte infiltration in liver allografts

Background/Aims: Human herpesvirus-6 (HHV-6) infection has been recently described in liver transplants. HHV-6 may infect the transplant and cause graft dysfunction. Some association between HHV-6 and rejection has also been recorded. We have now investigated the possible involvement of HHV-6 in the intragraft immunological processes, adhesion molecules induction and lymphocyte activation. Methods: HHV-6 was detected in liver biopsies of 19 patients transplanted in the period from 1996 to 2000. Patients with other infections or rejection were excluded from the study. Finally, 19 biopsies of eight allografts with pure HHV-6 infection were available. Adhesion molecules (ICAM-1, VCAM-1, ELAM-1) and their ligands (LFA-1, VLA-4, sLeX) and lymphoid activation markers (MHC class II, IL-2R) were demonstrated in liver biopsies by immunohistochemistry. Five biopsies from patients with normal graft function and without rejection or infection were used as controls for immune staining, and ten biopsies with acute rejection but without infection were used as positive controls. Results: Biopsy histology demonstrated mild to moderate lymphocyte infiltration associated with HHV-6 infection. HHV-6 significantly ( P≤0.05) increased the vascular expression of ICAM-1 and VCAM-1, and the number of graft infiltrating lymphocytes positive for LFA-1, VLA-4 and class II antigens. A total of 3/8 grafts developed chronic rejection. Conclusions: HHV-6 infection increased adhesion molecule expression and lymphocyte infiltration in liver allografts.

Effect of Pro-inflammatory Stimuli on Tumor Cell-Mediated Induction of Endothelial Cell Adhesion Molecules in Vitro

The object of our study was the question about the relevance of the tumor surrounding inflammatory cells with respect to the metastatic potential of the tumor cells. To imitate the role of inflammatory cells, three colon carcinoma (HT-29, HRT-18, and SW-620), one breast carcinoma (MCF-7), and one melanoma (ST-ML-12) cell lines were treated with pro-inflammatory stimuli, LPS, TNF-α, or IL-1β. HUVEC monolayers were then stimulated by the collected supernatants (SN) of the tumor cells, following washing out of the applied stimuli. Analysis of CAM expression on HUVEC was performed using cell enzyme immunoassay. E-selectin, VCAM-1, and, in part, ICAM-1 were significantly up-regulated on HUVEC by exposure to SN of all LPS-stimulated tumor cells. This was especially the case for the colon carcinoma cell lines. A minimal increase of expression of VCAM-1 was observed after exposure to SN from TNF-α-stimulated HT-29 and MCF-7 cells. IL-1β stimulation had no effect on endothelial CAM expression. These observations indicate that LPS could play a crucial role in tumor metastasis by inducing the release of soluble factors from different tumor cell lines capable of up-regulating CAM expression. This might be of special significance in colon carcinomas, where a large source of bacterial LPS is available in the intestinal lumen.

Tumor necrosis factor modulates apoptosis of monocytes in areas of developmentally regulated bone remodeling.

Tooth eruption is characterized by spatially segregated bone resorption along the path of eruption and bone formation in the opposite direction. Monocyte recruitment occurs in two distinct peaks in both areas of resorption and formation. Without such recruitment tooth eruption does not occur. The signals that regulate this recruitment are thought to involve the expression of cytokines and chemokines. One such cytokine is tumor necrosis factor (TNF), which can affect monocyte recruitment through the induction of chemokines and adhesion molecules and increase their lifespan by acting as antiapoptotic cell survival signals. We examined the latter by studying mice with targeted deletions of TNF receptors p55 and p75 (TNFRp55/p75). The results indicate that mice that lack functional TNF receptors have a significantly reduced number of monocytes in the apical area associated with bone formation. The reduced number of monocytes in this area can be accounted for by an increase in apoptosis in TNFRp55-/-/p75-/-. In contrast, the number of monocytes, the rate of monocyte apoptosis, and the formation of osteoclasts in the occlusal area associated with bone resorption occurred independently of TNF activity. These results suggest that TNF receptor signaling can affect tooth eruption by acting as a monocyte survival signal in some but not all areas of bone undergoing developmentally regulated remodeling.

The Pathogenesis of Rheumatoid Arthritis: A Guide to Therapy

The cause of rheumatoid arthritis (RA) is unknown; however, extensive research has yielded great insight into its pathogenesis. Lymphocytes play a significant role, but a lesser role in the perpetuation of late disease. The rheumatoid synovium is composed primarily of fibroblasts and monocytes that produce inflammatory cytokines, of which interleukin-1 and tumor necrosis factor are of key importance. Potential regulatory mechanisms balancing the effects of these cytokines are inadequate to prevent joint damage and subsequent disability. These cytokines seem responsible for stimulating destructive processes in the joint via induction of prostaglandins, angiogenesis, chemokines, adhesion molecules, osteoclastogenesis, and matrix metalloproteinases. This review discusses recent research findings in the immunopathogenesis of RA with respect to potential targets for therapy.

Chemokines in ischemia/reperfusion injury

Ischemia/reperfusion injury is an unavoidable consequence of organ transplantation that results in the generation of reactive oxygen species and the initiation of an inflammatory response. The characteristic features of ischemia/reperfusion injury involve the activation of endothelium by reactive oxygen species and inflammatory cytokines, induction of adhesion molecules (for example, P-selectin and E-selectin), adherence of platelets, and infiltration by leukocytes consisting initially of neutrophils with subsequent infiltration by monocytes, macrophages, and T lymphocytes. In this review, we consider the current evidence for involvement of chemokines during the period after ischemia/reperfusion injury and examine the temporal relation between chemokine expression and leukocyte infiltration. Changes in the profile of chemokines after ischemia/reperfusion injury, in association with upregulation of endothelial adhesion molecules, may contribute to the immunogenicity of a transplanted organ by increasing its ability to recruit particular leukocyte subsets at specific time points after ischemia/reperfusion injury.

Induction of α-Catenin, Integrin α3, Integrin β6, and PDGF-B by 2,8-Dihydroxyadenine Crystals in Cultured Kidney Epithelial Cells

Background: Homozygous adenine phosphoribosyltransferase (APRT) deficiency is associated with 2,8-dihydroxyadenine (DHA) nephrolithiasis. Using whole kidney RNA from Aprt knockout mice, we previously showed that the renal deposition of DHA leads to changes in the expression of genes involved in tissue injury. To determine the cellular basis for these changes, we investigated gene expression in cultured human kidney (NHK-C) and African green monkey (BSC-1) epithelial cells exposed to DHA or calcium oxalate monohydrate (COM) crystals. Methods: First-strand cDNAs, synthesized from mRNA isolated from treated and untreated cells, were hybridized to membrane-bound cDNA arrays containing 588 genes associated with various physiological and pathological processes. Changes in gene expression were confirmed by reverse transcription PCR. Results: Twenty-seven percent of the array cDNAs were expressed in untreated NHK-C cells at varying levels relative to a housekeeping gene. The expression of three adhesion molecules (α-catenin, integrin α3, and integrin β6) and platelet-derived growth factor B (PDGF-B) was elevated following exposure of NHK-C cells to DHA. Increased expression of the adhesion molecules was also observed in BSC-1 cells, but PDGF-B expression could not be detected. COM crystals also stimulated the expression of these four genes in NHK-C cells, but the expression profile was quantitatively different compared with DHA. Conclusions: These findings suggest that DHA crystals stimulate the expression of specific genes in kidney epithelial cells and that the pathways for DHA-induced cell injury may be similar to those for COM crystals. The induction of adhesion molecules and PDGF-B may affect cell-cell or cell-matrix interactions and/or alter the actin cytoskeleton. These alterations may ultimately contribute to crystal-induced renal injury.

Endothelial activation: intracellular signaling pathways

Chapter summaryTumor necrosis factor (TNF) is the prototypic proinflammatory cytokine and endothelial cells are the principal cellular targets of its actions. Here I review the responses of endothelial cells to TNF, with emphasis on the induction of endothelial leukocyte adhesion molecules. I focus on the biochemistry and cell biology of signal transduction in TNF-treated endothelial cells that lead to the expression of adhesion molecules.