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Excessive nutrient intake in obesity triggers the accumulation of various types of immune cells in adipose tissue, particularly visceral adipose tissue (VAT). This can result in chronic inflammation which disrupts insulin effects on adipocytes and muscle cells and culminates in development of insulin resistance. The interplay between immune cells and adipose tissue is a key event for the development of insulin resistance that precedes type 2 diabetes. CD40, a well-documented costimulatory receptor, is required for efficient systemic adaptive immune responses. However, we and other groups recently showed that CD40 unexpectedly ameliorates inflammation in VAT and accordingly attenuates obesity-induced insulin resistance. Specifically, although CD40 is typically considered to play its principal immune roles on B lymphocytes and myeloid cells, we found that CD40+CD8+T lymphocytes were major contributors to the protective effect. This unexpected inhibitory role of CD40 on CD8+T cell activation in VAT may reflect unique features of this microenvironment. Additional knowledge gaps include whether CD40 also plays roles in mucosal immunity that control the homeostasis of gut microbiota, and human metabolic diseases. Potential therapeutic approaches, including stimulating CD40 signaling and/or manipulating specific CD40 signaling pathways in the VAT microenvironment, may open new avenues for treatment of obesity-induced insulin resistance, and prevention of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Adipocytes not only store energy, but also secrete biologically active molecules called adipocytokines, which play a pivotal role in adipocyte-related pathological processes such as diabetes and cardiovascular disease. Recent studies have shown that preadipocyte/adipocyte expresses chemokines (e.g. monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha) which alter adipocyte function, indicating the involvement of chemokines in adipocyte-related pathologies. The current study investigated the potential of macrophage inflammatory protein-related protein-2 (MRP-2), a novel CC chemokine, to modulate preadipocyte trafficking and adipocyte differentiation. MRP-2 and its receptors were highly expressed in preadipocytes and differentiated adipocytes as well as in the mouse fat pad. Chemotaxis assays revealed that MRP-2 was a specific chemotactic regulator in preadipocyte migration. The levels of MRP-2 expression in adipose tissue were enhanced in obese mice compared to lean mice. MRP-2 secretion by preadipocytes was suppressed during differentiation. MRP-2 suppressed the expression of adipocyte differentiation markers such as adipocyte fatty acid-binding protein and glycerol-3 phosphate dehydrogenase. Taken together, our data suggest that MRP-2 plays a role in the regulation of preadipocyte migration and adipocyte differentiation during adipose tissue development. MRP-2 may be another adipocytokine, which can be involved in the adipocyte-related pathological process. [Copyright &y& Elsevier]

Activation of vascular endothelial cells (ECs) plays an important pathogenic role in the development of atherosclerosis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemoattractant of monocytes. Besides induction of monocyte recruitment, it has been suggested that MCP-1 can also affect the cellular responses of ECs. We investigated whether MCP-1 activated the three major mitogen activated protein (MAP)-kinases extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase (JNK) and p38 MAPK. Stimulation of ECs with MCP-1 induced a time- and concentration-dependent activation of all three MAP-kinases, concentrations as low as 0.1 ng/ml were sufficient for this mechanism. MCP-1 also induced secretion of matrix metalloproteinase (MMP)-2 which along with ERK activation was inhibited by PD098059. The results demonstrate that MCP-1 can lead to direct activation of MAP kinases together with induction of MMP2 in ECs. Our data thus propose a new mechanism for the proatherogenic effect of MCP-1. [Copyright &y& Elsevier]

This study was undertaken to demonstrate the unique specificity of the chemokine receptor CXCR4 antagonist AMD3100. Calcium flux assays with selected chemokine/cell combinations, affording distinct chemokine receptor specificities, revealed no interaction of AMD3100 with any of the chemokine receptors CXCR1 through CXCR3, or CCR1 through CCR9. In contrast, AMD3100 potently inhibited CXCR4-mediated calcium signaling and chemotaxis in a concentration-dependent manner in different cell types. Also, AMD3100 inhibited stromal cell-derived factor (SDF)-1-induced endocytosis of CXCR4, but did not affect phorbol ester-induced receptor internalization. Importantly, AMD3100 by itself was unable to elicit intracellular calcium fluxes, to induce chemotaxis, or to trigger CXCR4 internalization, indicating that the compound does not act as a CXCR4 agonist. Specific small-molecule CXCR4 antagonists such as AMD3100 may play an important role in the treatment of human immunodeficiency virus infections and many other pathological processes that are dependent on SDF-1/CXCR4 interactions (e.g. rheumatoid arthritis, atherosclerosis, asthma and breast cancer metastasis). [Copyright &y& Elsevier]

One of the major therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. However, a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. This review summarizes our current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion. Myocardial necrosis induces complement activation and free radical generation, triggering a cytokine cascade initiated by Tumor Necrosis Factor (TNF)-α release. If reperfusion of the infarcted area is initiated, it is attended by an intense inflammatory reaction. Interleukin (IL)-8 synthesis and C5a activation have a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium. Neutrophil infiltration is regulated through a complex sequence of molecular steps involving the selectins and the integrins, which mediate leukocyte rolling and adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. Despite this potential injury, substantial evidence suggests that reperfusion enhances cardiac repair improving patient survival; this effect may be in part related to the inflammatory response. Monocyte Chemoattractant Protein (MCP)-1 is also markedly upregulated in the infarcted myocardium inducing recruitment of mononuclear cells in the injured areas. Monocyte-derived macrophages and mast cells may produce cytokines and growth factors necessary for fibroblast proliferation and neovascularization, leading to effective repair and scar formation. At this stage expression of inhibitory cytokines such as IL-10 may have a role in suppressing the acute inflammatory response and in regulating extracellular matrix metabolism. Fibroblasts in the healing scar undergo phenotypic changes expressing smooth muscle cell markers. Our previous review in this journal focused almost exclusively on reduction of the inflammatory injury. The current update is prompted by the potential therapeutic opportunity that the open vessel offers. By promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling, that is the leading cause of heart failure and death. Elucidating the complex interactions and regulatory mechanisms responsible for cardiac repair may allow us to design effective inflammation-related interventions for the treatment of myocardial infarction. [ABSTRACT FROM PUBLISHER]

After birth two forms of vessel growth can be observed; angiogenesis and arteriogenesis. Angiogenesis refers to the formation of capillary networks. Arteriogenesis refers to the growth of preexistent collateral arterioles leading to formation of large conductance arteries that are well capable to compensate for the loss of function of occluded arteries. The process of arteriogenesis is initiated when shear stresses increase in the preexistent collateral pathways upon narrowing of a main artery. The increased shear stress leads to an upregulation of cell adhesion molecules for circulating monocytes, which accumulate subsequently around the proliferating arteries and provide the several required cytokines and growth factors. Several strategies are currently tested for their potential to stimulate the process of arteriogenesis. These strategies focus either at shear stress, at direct stimulation of endothelial and smooth muscle cell growth or at the monocytic pathway and promising results were obtained from experimental studies. However, some important questions remain to be answered before arteriogenesis can be brought from bench to bedside. [ABSTRACT FROM PUBLISHER]

The association of nitric oxide (NO) with cardiovascular disease has long been recognized and the extensive research on this topic has revealed both pro- and anti-atherosclerotic effects. While these contradictory findings were initially perplexing recent studies offer molecular mechanisms for the integration of these data in the context of our current understanding of the biochemistry of NO. The essential findings are that the biochemical properties of NO allow its exploitation as both a cell signaling molecule, through its interaction with redox centers in heme proteins, and an extremely rapid reaction with other biologically relevant free radicals. The direct reaction of NO with free radicals can have either pro- or antioxidant effects. In the cell, antioxidant properties of NO can be greatly amplified by the activation of signal transduction pathways that lead to the increased synthesis of endogenous antioxidants or down regulate responses to pro-inflammatory stimuli. These findings will be discussed in the context of atherosclerosis. [ABSTRACT FROM PUBLISHER]