Chemokines and lymphocytes: the role of chemokines and their receptors in the immune system.

In the last few years. chemokines have emerged as an important superfamily where importance extends far beyond their most famous function as inflammatory mediators. Indeed, they are important molecules not only in inflammatory responses but also as immunoregulators. Chemokines ensure the continuous recirculation of immune cells among the various anatomical microenvironments, and are essential for maintaining immunological homeostasis. In addition, chemokines also have critical functions in lymphocyte development. In this article, we review the role of chemokines and their receptors in lymphopoiesis, lymphocyte's migration and immune response.     

The role of heat shock proteins and their receptors in the activation of the immune system

Heat shock proteins (HSPs) have been described as potent tumor vaccines in animal models and are currently studied in clinical trials. The underlying immune response relies on immunogenic peptides that the HSPs have acquired intracellularly by interfering with the classical antigen processing pathways. There have been numerous reports shedding light on how HSPs are able to gain this function and a number of important requirements for HSP-mediated specific immunity have been described: first, the ability of HSPs to bind immunogenic peptides. Second, the acquisition of HSPs by specialized antigen presenting cells with efficient antigen processing pathways capable of inducing cellular immune responses. Third, the existence of specific receptors on the surfaces of antigen presenting cells, allowing efficient and rapid uptake of HSP-peptide complexes from the extracellular fluid. And fourth, the ability of heat shock proteins to activate antigen presenting cells, enabling the latter to prime cytotoxic T cell responses against the peptides associated to HSPs.     

The role of scavenger receptors in the innate immune system

Akey aspect of the innate immune system is the ability to discriminate between self and infectious nonself. This is achieved through pattern recognition receptors which directly recognise molecular epitopes expressed by microbes. Scavenger receptors (SRs) have been studied primarily due to their ability to bind and internalise modified lipoproteins, suggesting an important role in foam cell formation and the pathogenesis of atherosclerosis. However, the ability of some SRs to function as pattern recognition receptors through their binding of a wide variety of pathogens indicates a potential role in host defence. This review will detail our current understanding of the function of SRs in innate immunity, and in the initiation of aquired immune responses.     

Effects of opioids on the immune system

Both therapeutic and chronic uses of opioids compromise the optimal functioning of the immune system. Overwhelming evidence suggests that opioid use affects both innate immunity and adaptive immunity. Chronic administration of opioids decreases the proliferative capacity of macrophage progenitor cells and lymphocytes. Additionally, the differentiated function of immune cells is significantly affected by opioids. These effects are mediated by either a direct action of opioids on the target cells or by indirect centrally mediated pathways. Molecular biological and biochemical characterization suggest that immune cells differentially express classical opioid receptors. Interestingly, these studies also reveal the presence of a novel class of opioid receptors in immune cells. We believe that this low affinity morphine binding site mediates the antiproliferative effects of morphine. Special issue dedicated to Dr. Eric J. Simon.     

Cannabinoid receptors and their endogenous ligands

Delta9-Tetrahydrocannabinol, a major psychoactive component of marijuana, has been shown to interact with specific cannabinoid receptors, thereby eliciting a variety of pharmacological responses in experimental animals and human. In 1990, the gene encoding a cannabinoid receptor (CB1) was cloned. This prompted the search for endogenous ligands. In 1992, N-arachidonoylethanolamine (anandamide) was isolated from pig brain as an endogenous ligand, and in 1995, 2-arachidonoylglycerol was isolated from rat brain and canine gut as another endogenous ligand. Both anandamide and 2-arachidonoylglycerol exhibit various cannabimimetic activities. The results of structure-activity relationship experiments, however, revealed that 2-arachidonoylglycerol, but not anandamide, is the intrinsic natural ligand for the cannabinoid receptor. 2-Arachidonoylglycerol is a degradation product of inositol phospholipids that links the function of cannabinoid receptors with the enhanced inositol phospholipid turnover in stimulated tissues and cells. The possible physiological roles of cannabinoid receptors and 2-arachidonoylglycerol in various mammalian tissues such as those of the nervous system are discussed.     

The role of SLAM family receptors in immune cell signaling.

The signaling lymphocyte-activating molecule (SLAM) family immunoreceptors are expressed in a wide array of immune cells, including both T and B lymphocytes. By virtue of their ability to transduce tyrosine phosphorylation signals through the so-called ITSM (immunoreceptor tyrosine-based switch motif) sequences, they play an important part in regulating both innate and adaptive immune responses. The critical role of the SLAM immunoreceptors in mediating normal immune reactions was highlighted in recent findings that SAP, a SLAM-associated protein, modulates the activities of various immune cells through interactions with different members of the SLAM family expressed in these cells. Importantly, mutations or deletions of the sap gene in humans result in the X-linked lymphoproliferative syndrome. In this review, we summarize current knowledge and survey the latest developments in signal transduction events triggered by the activation of SLAM family receptors in different cell types.     

阿片类物质在中枢神经系统的免疫调控作用

内源及外源性阿片具有调节神经元与胶质细胞的功能,这些调节具有保护或损伤脑功能的双重作用。吗啡具有促进受病毒复制及继发感染的作用。另一方面,阿片受体中的ｋａｐｐａ受体可能具有保护神经元的作用。更深层次的研究应是了解阿片通过什么机制作用在胶质细胞和神经元上,藉此以促进研制出具有明显疗效的新药。     

The role of the immune system in preeclampsia

Recent data demonstrate that an altered immune response may play a key role in the development of preeclampsia. Some epidemiological findings and animal models support this idea. In this article, we review the innate immune system and adaptive immune system in preeclampsia and discuss the pathophysiology of preeclampsia from an immunological viewpoint. The most characteristic immunological finding in preeclampsia is the activation of both the innate and adaptive immune system. Activated neutrophils, monocytes, and NK cells initiate inflammation which induce endothelial dysfunction, and activated T cells may support inadequate tolerance during pregnancy. The cytokine profile in preeclampsia shows that the production of type 1 cytokines, which induce inflammation, is dominant while the production of type 2 cytokines, which regulates inflammation, is suppressed. Furthermore, the immunoregulatory system is down-regulated in preeclampsia and persistent inflammation reduces regulatory T cell function. Therefore, systematical immunoactivation may be one cause of preeclampsia.     

Schistosomiasis: role of endogenous opioids in suppression of gonadal steroid secretion

1. Radioimmunoassay of the opiate, beta-endorphin, in mouse sera, indirect measurement of estrogen by examination of vaginal smears and indirect measurement of androgens by electrophoresis of major urinary proteins (MUP) revealed that beta-endorphin increases while estrogen and androgen levels decrease in mice with chronic Schistosoma mansoni infection. 2. Injections of the opiate antagonist, naltrexone, reversed the effects of schistosomiasis on estrogen and androgen levels. 3. Because opiates are known to inhibit the secretion of releasing hormones by the hypothalamus, the data suggest that the inhibition of hypothalamic-pituitary-gonadal function that occurs in chronically infected male and female mice results from excessive beta-endorphin. 4. It is also suggested that the excessive beta-endorphin may be secreted by T-lymphocytes and possibly macrophages involved in the cell-mediated immune response (CMIR) to the ova.     

Estrogen and endogenous opioids regulate CCK in reproductive circuits.

This review focuses on the interaction of estrogen with the cholecystokinin (CCK) and endogenous opioid peptide systems in the medial preoptic nucleus, and how these interactions result in alterations of a stereotypic female reproductive behavior--lordosis. The medial preoptic nucleus is an integral part of a circuit controlling lordosis that extends from the limbic system through the hypothalamus. Estrogen alters the integration of sensory information in the circuit that results in the display of sexually receptive behavior. Estrogen determines the activity of CCK and endogenous opioid peptide systems through regulation of expression, release and interaction with specific receptors. Studies of each system individually have indicated that they are pivotal to the expression of lordosis. Recent studies demonstrate an estrogen-dependent interaction between endogenous opioid and CCK systems that control reproductive behavior.     

The ErbB receptors and their role in cancer progression

The involvement of the ErbB receptor tyrosine kinases in human cancer, as well as their essential role in a variety of physiological events during normal development, have motivated the interest in this receptor family. Approaches taken to block the activity of ErbB receptors in cancer cells have not only proven that they drive in vitro tumor cell proliferation, but have also become clinically relevant for targeting tumors with deregulated ErbB signaling. The mechanisms and downstream effectors through which the ErbB receptors influence processes linked to malignant development, including proliferation, cell survival, angiogenesis, migration, and invasion, are, however, only now becoming apparent. Our particular emphasis in this review will be on how ErbB receptors, in particular ErbB1 and ErbB2, contribute to processes linked to cancer progression. Importantly, in keeping with the emerging theme that ErbB receptors do not function in isolation, we will focus on receptor cooperativity, i.e., ErbB1 cooperates with other classes of receptors, and the ligand-less ErbB2 functions as a heterodimer with other ErbBs.     

The role of endogenous opioids in the protective effects of local sublethal hyperthermia against the progression of burn injury

The aim of the present study was to evaluate the role of endogenous opioids in local sublethal hyperthermia-induced protection against burn injury.Second-degree burn wounds were induced on the back of Balb/c mice. Progression of burn injury and expression of heat shock protein (HSP)-70 were evaluated after 24 h.Both inhibition of HSP synthesis and blocking opioid receptors before applying local sublethal hyperthermia decreased the protective effects of sublethal hyperthermia against the progression of burn injury. Blocking opioid receptors attenuated induction of HSP-70 by sublethal hyperthermia.     

The endogenous cannabinoid system and its role in nociceptive behavior

The analgesic properties of exogenous cannabinoids have been recognized for many years and suggest a regulatory role for the endogenous cannabinoid ("endocannabinoid") system in mammalian nociceptive pathways. The endocannabinoid system includes: (1) at least two families of lipid signaling molecules, the N-acyl ethanolamines (e.g., anandamide) and the monoacylglycerols (e.g., 2-arachidonoyl glycerol); (2) multiple enzymes involved in the biosynthesis and degradation of these lipids, including the integral membrane enzyme fatty acid amide hydrolase; and (3) two G-protein coupled receptors, CB1 and CB2, which are primarily localized to the nervous system and immune system, respectively. Here, we review recent genetic, behavioral, and pharmacological studies that have tested the function of the endocannabinoid system in pain sensation. Collectively, these investigations support a role for endocannabinoids in modulating behavioral responses to acute, inflammatory, and neuropathic pain stimuli.     

The role of cystatins in cells of the immune system

The cystatins constitute a large group of evolutionary related proteins with diverse biological activities. Initially, they were characterized as inhibitors of lysosomal cysteine proteases - cathepsins. Cathepsins are involved in processing and presentation of antigens, as well as several pathological conditions such as inflammation and cancer. Recently, alternative functions of cystatins have been proposed: they also induce tumour necrosis factor and interleukin 10 synthesis and stimulate nitric oxide production. The aim of the present review was the analysis of data on cystatins from NCBI GEO database and the literature, and obtained in microarray and serial analysis of gene expression (SAGE) experiments. The expression of cystatins A, B, C, and F in macrophages, dendritic cells and natural killer cells of the immune system, during differentiation and activation is discussed.     

The role of atrial natriuretic peptide in the immune system

Atrial natriuretic peptide (ANP) is a hormone predominately produced by the heart atria which regulates the water and salt balance as well as blood pressure homeostasis. Being expressed in various parts of the immune system a link of the peptide to the immune system has been proposed. In fact, this review focus on effects of ANP in the immune system and reports about the role of the peptide in innate immune functions as well as in the adaptive immune response.     

The role of dendritic cells in the innate immune system

Dendritic cells (DCs) are bone-marrow-derived leucocytes that are specialised antigen-presenting cells capable of stimulating a primary T-lymphocyte response to specific antigen. In this chapter we discuss the role DCs play in the innate response acting as a critical link with the adaptive response and the influence of the innate response on dendritic cells.     

The role of innate immune receptors in the control of Brucella abortus infection: toll-like receptors and beyond

Research into intracellular sensing of microbial products is an up and coming field in innate immunity. Toll-like receptors (TLRs) recognize Brucella spp. and bacterial components and initiate mononuclear phagocyte responses that influence both innate and adaptive immunity. Recent studies have revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella infection. TLR2, TLR4 and TLR9 have been implicated in host interactions with Brucella; however, TLR9 has the most prominent role. Further, the relationship between specific Brucella molecules and various signal transduction pathways needs to be better understood. MyD88-dependent and TRIF-independent signaling pathways are involved in Brucella activation of innate immune cells through TLRs. We have recently reported the critical role of MyD88 molecule in dendritic cell maturation and interleukin-12 production during B. abortus infection. This article discusses recent studies on TLR signaling and also highlights the contribution of NOD and type I IFN receptors during Brucella infection. The better understanding of the role by such innate immune receptors in bacterial infection is critical in host-pathogen interactions.