Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 3, Issue 1, 2003

An outstanding question of current immunology is to define the mechanisms by which microbial products influence the immunopathologic host response elements in the early stages of infection. Macrophages are now well recognized to have a critical role in both innate and acquired immunity. In order to adjust promptly to continuous changes in microenvironment and maintain the immunologic balance, macrophages adequately respond by activating one of the numerous immunologic programs. However, sustained macrophage activation and excessive production of inflammatory mediators can perpetuate the numerous pathological processes and contribute to induction of stress response and even apoptosis. Therefore, selective modulation of macrophage activity represents an important strategy for prevention and treatment of inappropriate inflammatory responses in order to minimize the unwanted side-effects of the immunity. Macrophages can be selectively reprogrammed for a specific phenotype of immune response, e.g. cytokine or nitric oxide (NO), by relatively short-term exposure of the cells to substimulatory concentrations of different microbial components, including LPS. These LPS-dependent reprogramming effects are mediated by IFNgamma- independent autocrine cytokine regulatory mechanisms that also controlled at the transcriptional level. Furthermore, LPS reprogrammed macrophages exhibit differential capacity to resist experimentally induced apoptosis and to produce heat shock proteins. Complete analysis of, and appreciation for, the immunoregulatory mechanisms implicated in LPS-dependent reprogramming of immune responses in macrophages can be expected to increase our understanding of the host innate response, as well as allow investigators to utilize emerging immunologic technologies in effective treatment of infections and chronic inflammatory diseases.

Lysophospholipids (LPLs), including glycerol- and sphingoid-based lipids, stimulate cell signaling and play important pathophysiological roles in humans and other animals. These LPLs include lysophosphatidic acid (LPA), lysophosphatidylinositol (LPI), lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), sphingosine-1-phosphate (S1P), and sphingosylphosphorylcholine (SPC). Analyses of LPLs in human body fluids from subjects with different pathophysiological conditions reveal not only the relevance of LPLs in human diseases, but also their potential application as biomarkers and / or therapeutic targets. In recent years, the identification and / or characterization of the plasma membrane receptors for LPLs and enzymes regulating the metabolism of LPLs have greatly facilitated our understanding of their role and signaling properties. In vitro and in vivo functional and signaling studies have revealed the broad and potent biological effects of LPLs and the mechanisms of LPL actions in different cellular systems. Development of specific antagonists for each of the LPL receptors will provide powerful tools for dissecting signaling pathways mediated by receptor subtypes. More importantly, these antagonists may serve as therapeutics for relevant diseases. Genetic depletion of LPL receptors in mice has provided and will continue to provide critical information on the pathophysiological roles of LPL receptors. It is important to further evaluate the significance of targeting these bioactive LPL receptors, their downstream signaling molecules, and / or metabolic enzymes in the treatment of cancers and other diseases.

Phagocytes are activated by several extracellular signals, including formylpeptides derived from bacterial proteins or disrupted cells. The most intensely studied member of the formylpeptide family is the synthetic tripeptide N-formyl-L-methionyl-L-leucyl-Lphenylalanine (fMLP), whose specific receptors have been identified on neutrophil plasma membrane and subsequently cloned. The fMLP-receptor interaction activates multiple transduction pathways responsible for various neutrophil functions such as adhesion, chemotaxis, exocytosis of secretory granules and superoxide anion production, which represent the physiological response to bacterial infection and tissue damage. An unresolved question is whether signaling requirements are identical or specific for each physiological function. The development of fMLP receptor agonists and antagonists has led to an improvement of our knowledge about the above issue. Of particular interest is the possibility that receptorial antagonists, able to transiently inhibit neutrophil responses to formylpeptides, could be therapeutic agents in the treatment of inflammation-related diseases.Aim of this review is, i) to summarise the current understanding of the series of events that begins at the level of formylpeptide-receptor interaction and is responsible for the activation of transduction pathways, which finally determine neutrophil response, ii) to define the state of art regarding the synthesis as well as the biological actions of fMLP receptor agonists and antagonists.

Vitamin D analogs have proven to be very valuable tools for the treatment of calcium-related diseases and certain hyperproliferative conditions such as renal osteodystrophy, psoriasis and cancer. In general, vitamin D analogs exploit the enzymic and receptor machinery of the 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) signal transduction pathway. Key proteins in this cascade include the vitamin D receptor (VDR), the vitamin D-binding protein (DBP) and three cytochrome P450s (CYP27A, CYP27B and CYP24) which effect the synthesis and breakdown of the natural hormone, 1α,25(OH)2D3. Analogs have been designed which reduce or enhance the importance of each of these proteins in the signal transduction pathway. Vitamin D prodrugs require one or more steps of activation and overcome congenital or acquired blocks in the 1α-hydroxylation step. By far the biggest class of vitamin D analogs are the VDR agonists which directly mimic 1α,25(OH)2D3 and trigger protein conformational changes in the receptor which lead to changes in the transcriptional machinery at vitamin D-responsive genes. Other emerging classes of molecules include the VDR antagonists and CYP24 inhibitors which target different events in the cascade. This review assesses the relative importance of each of the proteins of the vitamin D cascade, evaluates the success of these modifications in tailoring drugs in all classes for selected disease states and contemplates future directions for the field.

The primum movens in cholesterol gallstone formation is hypersecretion of hepatic cholesterol, chronic surpersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles.Associated events include biochemical defects (increased biliary mucin, and increased proportions of hydrophobic bile salts in the intestine and gallbladder), motility defects (gallbladder smooth muscle hypocontractility in vitro and gallbladder stasis in vivo, sluggish intestinal transit), and an abnormal genetic background.The study of physical-chemical factors and pathways leading to cholesterol crystallization in bile has clinical relevance and the task can be carried out in different ways. The lithogenicity of bile is investigated in artificial model biles made by three biliary lipids - cholesterol, bile salts and phospholipids - variably combined in systems plotting within the equilibrium ternary phase diagram; also, crystallization propensity of ex vivo incubated human bile is studied by biochemical analysis of precipitated crystals, polarizing quantitative light microscopy and turbidimetric methods.The present review will focus on the recent advances in the field of pathobiology of cholesterol gallstones, by underscoring the role of early events like water transport, lipid transport, crystallization phenomena - including a genetic background - in gallstone pathogenesis. Agents delaying or preventing precipitation of cholesterol crystals and gallstone formation in bile will also be discussed.

In the course of pregnancy amnion cells produce a number of factors which include cytokines and prostaglandins (PGs) produced in response to autocrine, paracrine and endocrine signals. Recent studies performed by several researchers contributed to elucidate the mechanism through which amnion tissue is involved in the triggering of physiological labor. However, there are other possible functions to be ascribed to amniotic cells, depending on the high number of factors that they produce as well as on the receptors that enable them to act in turn as target. For instance, it has been demonstrated that amnion cells are able to produce lecithin upon the regulation of several factors, such as glucocorticoids and epidermal growth factor, a finding that suggests a protective role of the tissue on fetal pulmonary function.As regards to triggering the uterine contractions, it is accepted that prostaglandin release by amnion cells represents a key event. It is under the control of hormones, growth factors, cytokines and probably PGs themselves. A striking analogy has been found between the mechanism of inflammation and the onset of myometrial activity in labor. In this context, it has been shown that for-Met-Leu-Phe (fMLP), the prototype of a series of formylated peptides traditionally considered chemotactic agents, is also involved in the regulation of amniotic PG release. The similitude between labor and inflammatory response is enforced by the antiprostaglandin action of some classes of antibiotics observed in amnion tissue, that enable them as effective tools against preterm labor, both in the absence and in the presence of infection.As for the mechanisms responsible for the regulation of PG synthesis, some agents act by influencing protein synthesis, while others exert their effects through the production of intracellular second messengers, mainly represented by phosphatidyl-inositol-4-5 bisphosphate and cyclic AMP. The mechanism whereby second messengers induce PG release is not clear, and a crosstalk between the two transduction pathways could be hypothesized. This interaction has extensively been analysed in “WISH” cells, a human amnion-derived cell line, which represent a model for the in vitro study of amnion functions.In the present review, we intend to report the results of the studies regarding the mechanisms through which the control of the above mentioned functions is executed.