Showing papers in "Journal of Leukocyte Biology in 2000"
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TL;DR: This article reviews recent developments in this field of research, with main emphasis on structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function ofCD40 on different cell types; and (4) in vivo functions of CD 40/CD40‐L interactions.
Abstract: CD40 is a cell surface receptor that belongs to the tumor necrosis factor-R (TNF-R) family, and that was first identified and functionally characterized on B lymphocytes. Its critical role in T cell-dependent humoral immune responses was demonstrated by patients with the hyper-IgM syndrome, as well as by gene targeting in mice. However, in recent years it has become clear that CD40 is expressed much more broadly, including expression on monocytes, dendritic cells, endothelial cells, and epithelial cells. In addition, the CD40-ligand (CD40-L/CD154), a member of the TNF family, is also expressed more widely than activated CD4+ T cells only. Therefore it is now thought that CD40-CD40-L interactions play a more general role in immune regulation. Collectively these studies have culminated in pre-clinical and clinical studies that are in progress. This article reviews recent developments in this field of research, with main emphasis on (1) structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function of CD40 on different cell types; and (4) in vivo functions of CD40/CD40-L interactions.
1,406 citations
TL;DR: The role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis is focused on.
Abstract: Leptin, the product of the ob gene, is a pleiotropic molecule that regulates food intake as well as metabolic and endocrine functions. Leptin also plays a regulatory role in immunity, inflammation, and hematopoiesis. Alterations in immune and inflammatory responses are present in leptin- or leptin-receptor-deficient animals, as well as during starvation and malnutrition, two conditions characterized by low levels of circulating leptin. Both leptin and its receptor share structural and functional similarities with the interleukin-6 family of cytokines. Leptin exerts proliferative and antiapoptotic activities in a variety of cell types, including T lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also affects cytokine production, the activation of monocytes/macrophages, wound healing, angiogenesis, and hematopoiesis. Moreover, leptin production is acutely increased during infection and inflammation. This review focuses on the role of leptin in the modulation of the innate immune response, inflammation, and hematopoiesis.
956 citations
TL;DR: In contrast, members that are inducible by interferons and lack the ELR motif (ELR−) are potent inhibitors of angiogenesis, a difference in angiogenic activity that may impact on the pathogenesis of a variety of disorders.
Abstract: A variety of factors have been identified that regulate angiogenesis, including the CXC chemokine family. The CXC chemokines are a unique family of cytokines for their ability to behave in a disparate manner in the regulation of angiogenesis. CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine amino acid residues separated by one non-conserved amino acid residue (i.e., CXC). A second structural domain within this family determines their angiogenic potential. The NH2 terminus of the majority of the CXC chemokines contains three amino acid residues (Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino acid residue of the primary structure of these cytokines. Members that contain the ELR motif (ELR+) are potent promoters of angiogenesis. In contrast, members that are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis. This difference in angiogenic activity may impact on the pathogenesis of a variety of disorders.
762 citations
TL;DR: The results demonstrate that CD163 expression in monocytes/macrophages is regulated by proinflammatory and antiinflammatory mediators, implying a functional role of CD163 in the antiinflammatory response of monocytes.
Abstract: CD163, also referred to as M130, a member of the scavenger receptor cysteine-rich family (SRCR) is exclusively expressed on cells of the monocyte lineage. In freshly isolated monocytes the CD14bright CD16+ monocyte subset revealed the highest expression of CD163 among all monocyte subsets. CD163 mRNA and protein expression is up-regulated during macrophage colony-stimulating factor (M-CSF)-dependent phagocytic differentiation of human blood monocytes. In contrast, monocytic cells treated with GM-CSF and interleukin-4 (IL-4) for dendritic differentiation down-regulate this antigen. CD163 expression is also suppressed by proinflammatory mediators like lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha, whereas IL-6 and the antiinflammatory cytokine interleukin-10 (IL-10) strongly up-regulate CD163 mRNA in monocytes and macrophages. The effects of the immunosuppressants dexamethasone, cyclosporin A (CA), and cortisol differ in their capacity to influence CD163 mRNA levels. Our results demonstrate that CD163 expression in monocytes/macrophages is regulated by proinflammatory and antiinflammatory mediators. This expression pattern implies a functional role of CD 163 in the antiinflammatory response of monocytes.
683 citations
TL;DR: The interleukin‐1 (IL‐1) receptor/Tolllike receptor (TLR) superfamily is a recently defined and expanding group of receptors that participate in host responses to injury and infection.
Abstract: The interleukin-1 (IL-1) receptor/Toll- like receptor (TLR) superfamily is a recently de- fined and expanding group of receptors that partici- pate in host responses to injury and infection. The superfamily is defined by the Toll/IL-1 receptor (TIR) domain, which occurs in the cytosolic region of family members, and is further subdivided into two groups based on homology to either the Type I IL-1 receptor or Drosophila Toll receptor extracel- lular domain. The former group includes the recep- tor for the important Th1 cytokine IL-18, and T1/ST2, which may have a role in Th2 cell func- tion. The latter group includes six mammalian TLRs, including TLR2 and TLR4, that largely mediate the host response to gram-positive and gram-negative bacteria, respectively. Whether bac- terial products are actual ligands for TLRs, or whether they generate ligands via as yet unidenti- fied pattern recognition receptors, has yet to be determined. Signaling pathways activated via the TIR domain trigger the activation of downstream kinases, and transcription factors such as NF-kB, and involve the adaptor protein MyD88, which itself contains a TIR domain. J. Leukoc. Biol. 67: 508-514; 2000.
503 citations
TL;DR: It is shown that human neutrophil defensins selectively induce the migration of human CD4+/CD45RA+ naive and CD8+, but not CD4/ CD45RO+ memory, T cells, suggesting that, in addition to their antimicrobial role, human neutrophic defensin also contribute to adaptive immunity by mobilizing T cells and dendritic cells.
Abstract: Defensins, a family of cationic, structurally related, antimicrobial peptides, contribute to host defense by disrupting the cytoplasmic membrane of microbes. Here we show that human neutrophil defensins selectively induce the migration of human CD4+/CD45RA+ naive and CD8+, but not CD4+/CD45RO+ memory, T cells. Moreover, human neutrophil defensins are chemotactic for immature human dendritic cells derived from either CD34+ progenitors or peripheral blood monocytes. Upon maturation induced by treatment with tumor necrosis factor alpha (TNF-alpha), dendritic cells lose their responsiveness to human neutrophil defensins. The chemotactic effect of human neutrophil defensins on both T and dendritic cells is pertussis toxin-sensitive, suggesting that a G(ialpha) protein-coupled receptor is responsible. Human neutrophil defensins are also chemotactic for immature murine dendritic cells. These data suggest that, in addition to their antimicrobial role, human neutrophil defensins also contribute to adaptive immunity by mobilizing T cells and dendritic cells.
489 citations
TL;DR: Flow cytometric analysis of isolated human monocytes recovered after transendothelial chemotaxis assays revealed that the percentage of CD14+CD16+ cells was dramatically reduced in the fraction migrating toward MCP‐1 compared with the fraction that did not migrate or the input, showing that polarized CCR2 expression was accompanied by a differential chemotactic responsiveness.
Abstract: The subset of human blood monocytes expressing low levels of CD14 and high levels of CD16 (CD14+CD16+) exhibits features resembling mature tissue macrophages and can be expanded in inflammatory conditions. We analyzed expression of CC chemokine receptors (CCR) in CD14+CD16+ versus CD14++ monocytes, which may be crucial for specific trafficking. Multicolor flow cytometric analysis of whole peripheral blood revealed that, as opposed to CD14++ monocytes, the CD14+CD16+ subset lacked surface expression of monocyte chemotactic protein-1 (MCP-1) receptor CCR2, however, it showed significantly higher surface expression of the macrophage inflammatory protein 1alpha (MIP-1alpha)/RANTES receptor CCR5. This was paralleled by differences in mRNA expression in the subsets, as shown by reverse transcriptase-polymerase chain reaction using sorted cells. In comparison to CD14++ monocytes, CD14+CD16+ cells expressed lower CCR2 but higher CCR5 transcript levels, whereas CCR1 levels were equivalent. Flow cytometric analysis of isolated human monocytes recovered after transendothelial chemotaxis assays revealed that the percentage of CD14+CD16+ cells was dramatically reduced in the fraction migrating toward MCP-1 compared with the fraction that did not migrate or the input, showing that polarized CCR2 expression was accompanied by a differential chemotactic responsiveness. Moreover, CD11b surface expression was preferentially up-regulated by MCP-1 in CD14++ cells but by MIP-1alpha in CD14+CD16+ monocytes, confirming the functional relevance of distinct CCR expression. The characteristics of CD14+CD16+ cells may reflect preactivation by cytokines and determine their predilective localization during specific inflammatory conditions or susceptibility to infection.
407 citations
TL;DR: It is suggested that increased intracellular calcium concentrations in resting neutrophils and/or a reduced hexose uptake result in reduced phagocytic ability and decreased bactericidal activity of neutrophil in the elderly.
Abstract: Neutrophil phagocytosis, reactive oxygen intermediate production (intra- and extracellular), neutrophil bactericidal activity, and chemotaxis/chemokinesis were assessed in three age groups: 21-36, 38-56, and 62-83 years. A significant age-dependent reduction in the number of phagocytized Escherichia coli per neutrophil (measured by acridine orange staining) and Staphylococcus aureus phagocytosis (measured by flow cytometry) was seen (r = 0.669 and r = 0.684, P<0.001 for both). These findings correlated with an age-dependent increase in intracellular calcium concentrations in resting neutrophils (r = 0.698, P<0.001) and a reduced hexose uptake (r = 0.591, P<0.01). In addition, a significant reduction in the intracellular reactive oxygen production was seen after stimulation with S. aureus (P<0.001) with increasing age. In contrast, no differences between the groups in reactive oxygen production was seen after stimulation with E. coli. The neutrophil bactericidal activity was impaired with increasing age (64+/-4% of the phagocytized bacteria were killed in group 1; 66+/-2 in group 2, and 59+/-6 in group 3; P<0.01). In addition, a trend toward a reduced neutrophil chemotaxis was seen with increasing age (P = 0.022). The findings suggest that increased intracellular calcium concentrations in resting neutrophils and/or a reduced hexose uptake result in reduced phagocytic ability and decreased bactericidal activity of neutrophils in the elderly.
385 citations
TL;DR: The response to S. typhimurium involves both T and B cell‐mediated immunity, and mechanisms mediated by both lymphocyte populations are important for control of primary infection and protection against secondary infection.
Abstract: Infection of mice with Salmonella typhimurium results in systemic infection and a disease similar to that seen in humans after infection with S. typhi. The innate immune system can restrict replication of S. typhimurium to a certain degree, but for effective control and eradication of bacteria, acquired immunity is essential. Salmonella infection induces the generation of specific CD4+ and CD8+ T cells, and both T cell populations are important for protection during primary and secondary responses, although the mechanisms underlying T cell-mediated protection are not yet completely understood. Infection with S. typhimurium also results in a strong antibody response to Salmonella antigens and, in contrast to most other intracellular bacteria, this antibody response participates in protection. In summary, the response to S. typhimurium involves both T and B cell-mediated immunity, and mechanisms mediated by both lymphocyte populations are important for control of primary infection and protection against secondary infection.
302 citations
TL;DR: This review focuses on the causes, the inflammatory processes involved, and possible strategies for decreasing vascular disease through regulation of the inflammatory response.
Abstract: When the body responds to an infectious insult, it initiates an immune response to eliminate the pathogen. The hallmark of the immune response is an inflammatory cascade that can also do extensive damage to host tissues. Inflammation is a major contributing factor to many vascular events, including atherosclerotic plaque development and rupture, aortic aneurysm formation, angiogenesis, and ischemia/reperfusion damage. The immune response is mediated by both circulating and resident leukocytes and the cells with which they interact (e.g., vascular endothelium and smooth muscle cells). The process is orchestrated by the activity of a changing series of released and displayed mediators. These include the expression of adhesion molecules on leukocytes and underlying vascular endothelium and the release of cytokines, chemokines, and tissue-destructive metalloproteases and reactive oxygen species. This review focuses on the causes, the inflammatory processes involved, and possible strategies for decreasing vascular disease through regulation of the inflammatory response.
275 citations
TL;DR: It is thought that “professional” antigen‐presenting cells play a dominant role in the induction of immunity by presenting vaccine peptides on MHC class I molecules, following direct transfection or “cross”‐presentation, and MHCclass II molecules after antigen capture and processing within the endocytic pathway.
Abstract: DNA vaccination, or genetic immunization, is a novel vaccine technology that has great potential for reducing infectious disease and cancer-induced morbidity and mortality worldwide. Since their inception, DNA vaccines have been used to stimulate protective immunity against many infectious pathogens, malignancies, and autoimmune disorders in animal models. Plasmid DNA encoding a polypeptide protein antigen is introduced into a host where it enters host cells and serves as an epigenetic template for the high-efficiency translation of its antigen. An immune response, which is mediated by the cellular and/or humoral arms of the immune system and is specific for the plasmid-encoded antigen, ensues. It is thought that "professional" antigen-presenting cells play a dominant role in the induction of immunity by presenting vaccine peptides on MHC class I molecules, following direct transfection or "cross"-presentation, and MHC class II molecules after antigen capture and processing within the endocytic pathway. The correlates of immunity can be manipulated according to many immunization parameters, including the method of vaccine delivery, presence of genetic adjuvants, and vaccine regimen. DNA vaccines first advanced to the clinic five years ago, and the initial picture of their utility in humans is emerging. However, further analysis is required to determine their ultimate efficacy and safety in human beings. This technology has acquired a strong foothold in the field of experimental immunotherapy, and it is hoped that it will eventually represent the next generation of prophylactic and therapeutic vaccines.
TL;DR: Findings that have elucidated the dynamic relationships among these factors and how they communicate with immune cells during inflammation are reviewed.
Abstract: Tissue injury caused by infection or physical damage evokes inflammatory reactions and events that are necessary for regaining homeostasis. Central to these events is the translocation of leukocytes, including monocytes, neutrophils, and T lymphocytes, from the vascular system, through endothelium, and into the extracellular matrix (ECM) surrounding the injured tissue. This transition from the vasculature into the site of inflammation elicits remarkable changes in leukocyte behavior as cells adhere to and migrate across ECM before carrying out their effector functions. Growing evidence suggests that, through its interactions with cytokines and degradative enzymes, the ECM microenvironment has a specialized role in providing intrinsic signals for coordinating leukocyte actions. Recent advances also reveal that enzymatic modifications to ECM moieties and cytokines induce distinctive cellular responses, and are likely part of the mechanism regulating the perpetuation or arrest of inflammation. This article reviews the findings that have elucidated the dynamic relationships among these factors and how they communicate with immune cells during inflammation.
TL;DR: Examination of the involvement of macrophage CSF and granulocyte CSF in collagen‐induced arthritis (CIA), a murine model of RA, shows that M‐CSF and G‐ CSF can be proinflammatory in CIA and provides evidence that macrophice‐ andgranulocyte‐lineage cells can exacerbate CIA.
Abstract: There is increasing evidence that the colony-stimulating factors (CSFs) may play a part in chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA). We examined the involvement of macrophage CSF (M-CSF or CSF-1) and granulocyte CSF (G-CSF) in collagen-induced arthritis (CIA), a murine model of RA. Daily injections of M-CSF or G-CSF, 20-24 days postprimary immunization with type II collagen, exacerbated disease symptoms in suboptimally immunized DBA/1 mice. Support for the involvement of endogenous M-CSF in CIA was obtained by studies in which neutralizing monoclonal antibody reduced the severity of established CIA and also by studies showing the resistance of M-CSF-deficient op/op mice to CIA induction. These studies show that M-CSF and G-CSF can be proinflammatory in CIA and provide evidence that macrophage- and granulocyte-lineage cells can exacerbate CIA. Our results also show that M-CSF-dependent cells are essential for CIA development, suggesting M-CSF may be a suitable target for therapeutic intervention in RA.
TL;DR: It is shown that mast cells release significant amounts of LTB4 and LTC4 in response to exposure to FimH‐expressing type 1 fimbriated Escherichia coli in vitro, which contributes to host defense by mediating early neutrophil influx and bacterial clearance at sites of infection.
Abstract: Stimulated mast cells release a variety of chemotactic factors such as tumor necrosis factor alpha (TNF-alpha) and leukotriene B4. Recent studies have shown that mast cell-derived TNF-alpha plays a critical role in host defense against Gram negative bacterial infections by the recruitment of neutrophils to the sites of infection. In the present study, we sought to investigate if mast cells release leukotriene (LT) B4 in response to bacteria and, if so, to establish its in vivo relevance. We show that mast cells release significant amounts of LTB4 and LTC4 in response to exposure to FimH-expressing type 1 fimbriated Escherichia coli in vitro. To test the functional significance of mast cell-derived LTs during an E. coli infection in vivo, we examined the effect of a LT-synthesis inhibitor, A-63162, on bacterial clearance and neutrophil influx in an infectious peritonitis model in mast cell-deficient mice (WBB6F1-W/WV) and their normal congenic control (WBB6F1-+/+) mice. Our results show that a treatment with A-63162 reduced neutrophil influx and bacterial clearance in the peritoneal cavities of mast cell-sufficient but not -deficient mice. Thus, mast cell-derived LTs contribute to host defense by mediating early neutrophil influx and bacterial clearance at sites of infection.
TL;DR: This review will concentrate on how macrophages in particular control the actin cytoskeleton to generate cell movement and the shape changes required for chemotaxis.
Abstract: Whereas most cells in adult tissues are fixed in place by cell junctions, leukocytes are motile and able to migrate actively through the walls of blood vessels into surrounding tissues. The actin cytoskeleton of these cells plays a central role in locomotion, phagocytosis, and the regulation of cell shape that are crucial elements of neutrophil and monocyte/macrophage function. This review will concentrate on how macrophages in particular control the actin cytoskeleton to generate cell movement and the shape changes required for chemotaxis. It has recently become evident that a complex of seven proteins known as the Arp2/3 complex regulates the assembly of new actin filament networks at the leading front of moving cells. Proteins of the Wiskott-Aldrich Syndrome Protein (WASP) family bind directly to the Arp2/3 complex and stimulate its ability to promote the nucleation of new actin filaments. Upstream of the WASP family proteins, receptor tyrosine kinases, G-protein-coupled receptors, phosphoinositide-3-OH kinase (PI 3-kinase), and the Rho family of GTPases receive and transduce the signals that lead to actin nucleation through WASP-Arp2/3 action. Although many gaps remain in our understanding, we are now in a position to consider completing signaling pathways that are initiated from outside the cell to the actin rearrangements that drive cell motility and chemotaxis.
TL;DR: Two pools of NADPH‐oxidase, one localized in the plasma membrane and the other in the granule membranes, are separately regulated and the signal transduction pathways leading to activation of these pools differ regarding involvement of PI 3‐kinase.
Abstract: The neutrophil NADPH-oxidase can be activated by protein kinase C (PKC) agonists such as phorbol myristate acetate (PMA), resulting in superoxide anion release. This superoxide release is independent of phosphatidylinositol 3-kinase (PI 3-kinase) because the inhibitor wortmannin does not affect the response. In this study, PMA is shown to also induce a wortmannin-sensitive NADPH-oxidase activation, however, not resulting in release of superoxide but in intracellular production of the radical. This indicates that two pools of NADPH-oxidase, one localized in the plasma membrane and the other in the granule membranes, are separately regulated and the signal transduction pathways leading to activation of these pools differ regarding involvement of PI 3-kinase. Activation of both pools was dependent on ERK/MAPK kinase (MEK) activity and protein phosphatase 1 and/or 2A. As the two oxidase responses were differently affected by the inhibitor Go-6850, different PKC isozymes are suggested to take part in the two signal transduction pathways.
TL;DR: A systematic approach has been used to determine whether different human leukocyte populations selectively or specifically expressed TLR mRNA, and whether the expression of a TLR in a single cell type may indicate a specific role for this molecule in a restricted setting.
Abstract: Toll is a Drosophila gene essential for ontogenesis and antimicrobial resistance. Several hortologues of Toll have been identified and cloned in vertebrates, namely Toll-like receptors (TLR). Human TLR are a growing family of molecules involved in innate immunity. TLR are structurally characterized by a cytoplasmic Toll/interleukin-1R (TIR) domain and by extracellular leucine-rich repeats. TLR characterized so far activate the MyD88/IRAK signaling cascade, which bifurcates and leads to NF-kappaB and c-Jun/ATF2/TCF activation. Genetic, gene transfer, and dominant-negative approaches have involved TLR family members (TLR2 and TLR4) in lipopolysaccharide recognition and signaling. Accumulating evidence suggests that some TLR molecules are also involved in signaling receptor complexes that recognize components of gram-positive bacteria and mycobacteria. However, the definitive role of other TLR is still lacking. A systematic approach has been used to determine whether different human leukocyte populations selectively or specifically expressed TLR mRNA. Based on expression pattern, TLR can be classified as ubiquitous (TLR1), restricted (TLR2, TLR4, and TLR5), and specific (TLR3). Expression and regulation of distinct though overlapping ligand recognition patterns may underlie the existence of a numerous, seemingly redundant, TLR family. Alternately, the expression of a TLR in a single cell type may indicate a specific role for this molecule in a restricted setting.
TL;DR: A model is proposed to assess the contribution by either of these chemokines to coordinated recruitment and activation of neutrophils in response to acute tissue injury and its major precursor connective tissue‐activating peptide III (CTAP‐III).
Abstract: The recruitment of neutrophil granulocytes to sites of tissue injury is one of the earliest events during host defense. Several chemotactic cytokines belonging to the CXC subfamily of chemokines are thought to be implicated in this kind of response. Especially those CXC chemokines that are stored in blood platelets and become immediately released upon activation are likely to dominate neutrophil-dependent host defense at the onset of inflammation. The major platelet-derived CXC chemokines are the beta-thromboglobulins and platelet factor 4 (PF-4), which are both released into the blood at micromolar concentrations. The availability as well as the functional activity of these mediators appear to be subject to tight control by diverse regulatory mechanisms. These include proteolytic processing of chemokine precursors, oligomer formation, and the differential usage of neutrophil-expressed receptors. Herein we review our work on early neutrophil regulation by PF-4, the beta-thromboglobulin neutrophil-activating peptide 2 (NAP-2) and its major precursor connective tissue-activating peptide III (CTAP-III). We moreover propose a model to assess the contribution by either of these chemokines to coordinated recruitment and activation of neutrophils in response to acute tissue injury.
TL;DR: Bacterial lipopolysaccharide activates multiple protein kinases such as p38, JNK, IKK‐β, and PKB/Akt via transforming growth factor β‐activated kinase‐1 (TAK1) and TAK1 plays an important role in similar activation pathways triggered by interleukin‐1.
Abstract: During inflammation the balance be- tween cell activation and cell death is determined by the tight regulation of multiple intracellular enzyme cascades. Key regulatory steps often involve protein kinases. We show that the prototypical pro-inflamma- tory molecule, bacterial lipopolysaccharide, activates multiple protein kinases such as p38, JNK, IKK-b, and PKB/Akt via transforming growth factor b-acti- vated kinase-1 (TAK1). We also show that TAK1 plays an important role in similar activation pathways triggered by interleukin-1. Thus TAK1 must be con- sidered as an important component of intracellular signaling pathways in cells involved in host responses to physiological and/or environmental stress signals during inflammation. J. Leukoc. Biol. 68: 909-915; 2000.
TL;DR: The results suggest that CXCR3 and CCR4, but not CCR5 or CCR3, appear to serve as the useful markers for identification of circulating Th1 and Th2 effector populations.
Abstract: The in vitro studies have proposed that human Th1 cells favor expression of CXCR3 or CCR5, whereas Th2 cells favor CCR3 and CCR4. In this study, the in vivo relevance of expression of these chemokine receptors on Th cells was investigated in patients with atopic dermatitis (AD) as the Th2-dominated disorder and nonatopic normal individuals. Flow-cytometric analysis using monoclonal antibodies against CXCR3, CCR5, CCR3, and CCR4 disclosed that a substantial proportion of memory (CD45RO+) CD4+ T cells in the blood of AD and normal patients expressed CXCR3, CCR5, or CCR4, but expression of CCR3 on these cells was negligible. Stimulation studies combined with intracellular cytokine staining revealed that the cells capable of producing Th2 cytokines, such as interleukin-4 (IL-4), IL-5, and IL-13, were restricted to the CCR4-expressing population within memory CD4+ T cells. Concerning Th1 cytokine production, interferon-gamma (IFN-gamma)-producing cells resided exclusively in CXCR3-expressing memory CD4+ T cells, although IFN-gamma production was found in both memory CD4+ T cells with and without CCR5 expression. We observed that CCR4-expressing memory CD4+ T cells in the blood were more increased in AD patients as compared with normal patients, whereas CXCR3-expressing memory CD4+ T cells were present in a lower frequency in AD than seen in normal patients. These results suggest that CXCR3 and CCR4, but not CCR5 or CCR3, appear to serve as the useful markers for identification of circulating Th1 and Th2 effector populations.
TL;DR: The molecular mechanisms underlying the synergistic gene induction discussed in this review involve cooperative activation of transcription factors that function synergistically with nuclear factor κB activated by LPS and TNF‐α.
Abstract: Generation of an inflammatory response is a complex process involving multiple factors acting in parallel and in concert. Viruses, parasites, and bacteria, particularly lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, act cooperatively with the cytokine interferon (IFN)-gamma to induce many of the genes involved in inflammation. In addition, these components synergistically induce secretion of tumor necrosis factor alpha (TNF-alpha), which also synergizes strongly with IFN-gamma. The molecular mechanisms underlying the synergistic gene induction discussed in this review involve cooperative activation of transcription factors. IFN-gamma-activated signal transducer and activator of transcription 1 and interferon regulatory factor-1 function synergistically with nuclear factor kappaB activated by LPS and TNF-alpha. In addition, cross-talk between the signal transduction pathways upstream of the activation of the transcription factors contributes to generation of the synergistic action. Cooperative activity of proinflammatory agents profoundly influences the immune response to infections and the efficiency of cellular clearance mechanisms.
TL;DR: The data suggest that continuous expression of MGSA/GRO proteins may facilitate tumor growth by stimulating the growth of microvessels into the tumor (paracrine) and by affecting melanocyte growth (autocrine).
Abstract: Continuous expression of the MGSA/GROalpha, beta, or gamma chemokine bestows tumor-forming capacity to the immortalized murine melanocyte cell line, melan-a. The mechanism for this transformation is unclear, although both autocrine and paracrine processes are possible because melan-a cells as well as endothelial cells express a low level of the receptor for this ligand. To further define the role of MGSA/GRO proteins in melanocyte transformation, two types of experiments were designed to neutralize the biological effects of MGSA/GRO in the transfected melan-a clones: (1) the effect of neutralizing antiserum to MGSA/GRO proteins on melan-a tumor growth was assessed; (2) the tumor-forming capacity of melan-a clones expressing ELR motif-mutated forms of MGSA/GRO with compromised receptor affinity was compared to the tumor-forming capacity of clones expressing wild-type MGSA/GRO. These experiments revealed that SCID mice inoculated with MGSA/GROalpha- or gamma-expressing melan-a cells and subsequently treated with antiserum to the respective chemokine exhibited decreased tumor growth. This reduction in tumor growth was accompanied by declining angiogenic activity in MGSA/GROgamma-expressing tumors. Moreover, athymic nude mice injected with melan-a cells expressing ELR-mutant forms of MGSA/GROalpha exhibited markedly impaired tumor-forming capacity compared with those mice injected with melan-a clones expressing wild-type MGSA/GRO. These data suggest that continuous expression of MGSA/GRO proteins may facilitate tumor growth by stimulating the growth of microvessels into the tumor (paracrine) and by affecting melanocyte growth (autocrine).
TL;DR: This work has shown that the toxicity mechanisms for many peptides consist of a rapid permeabilization of the target cell membrane, and some members of both families are multifunctional molecules, playing a modulating role in the inflammation and the antigen‐driven immune response.
Abstract: Antimicrobial peptides are effector molecules of innate immunity that provide a first line of defense against pathogens. In mammals, they are stored in granules of leukocytes and are present in those sites that are exposed to microbial invasion, such as mucosal surfaces and skin. In the last decade, biochemical investigations and recombinant DNA technology have allowed the identification and characterization of several antimicrobial peptides from various animal and vegetal species. Most of the mammalian peptides have been grouped in two broad families: defensins and cathelicidin-derived peptides. Functional studies have shown that the toxicity mechanisms for many peptides consist of a rapid permeabilization of the target cell membrane. In addition to their microbicidal activity, some members of both families are multifunctional molecules, playing a modulating role in the inflammation and the antigen-driven immune response.
TL;DR: Evidence is consistent with a role of this chemokine as an amplification loop of polarized type II responses, and emerging indications on the involvement of MDC in diverse pathologies, ranging from allergic reactions to HIV infection and neoplasia are discussed.
Abstract: Macrophage-derived chemokine (MDC) is a CC chemokine paradigmatic of emerging aspects of chemokine immunobiology. It is constitutively expressed, yet microbial products and cytokines regulate its expression with divergent effects of type II (IL-4 and IL-13) and type I (interferon) cytokines. Processing of the mature protein by dipeptidyl peptidase IV/CD26 provides a further level of regulation. It acts on diverse cellular targets including dendritic cells (DC), NK cells, and T cell subsets. Among these, MDC is a potent attractant for CCR4 expressing polarized Th2 and Tc2 cells, and evidence is consistent with a role of this chemokine as an amplification loop of polarized type II responses. Emerging indications on the involvement of MDC in diverse pathologies, ranging from allergic reactions to HIV infection and neoplasia, are discussed.
TL;DR: A better understanding of disease‐promoting and 'suppressing CD4+ T cells is providing insight into the mechanisms controlling immune responses within the intestinal compartment, fostering the design and evaluation of new therapeutic approaches that may eventually be applied to treat human inflammatory bowel disease.
Abstract: Emerging studies using mouse models of experimental colitis are defining the nature of the immunological disturbances that initiate inflammation and destruction of the intestine. A better understanding of disease-promoting and -suppressing CD4+ T cells is providing insight into the mechanisms controlling immune responses within the intestinal compartment. Moreover, a role for distinct T cell populations, including intraepithelial gammadelta T cells, in maintaining the physical integrity of the intestine was suggested by recent studies. Cytokine gene-knockout mice and anti-cytokine treatments remain important tools to define the pro- and anti-inflammatory functions of cytokines. These advances are fostering the design and evaluation of new therapeutic approaches that may eventually be applied to treat human inflammatory bowel disease.
TL;DR: The inhibition of fractalkine expression by sulfasalazine and sanguinarine further supported the central role of NF‐κB in fractalkin transcription regulation and suggested a novel therapeutic target aimed at modulating leukocyte endothelial cell interaction.
Abstract: Fractalkine is an endothelial cell-derived CX3C chemokine that is chemotactic mainly to mononuclear cells. Fractalkine was induced in rat aortic endothelial cells (RAEC) by interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and lipopolysaccharide (LPS) transcriptionally and translationally. This induction correlated with increased NF-kappaB DNA binding activity as determined by gel mobility shift assay. Supershift assays revealed that the NF-kappaB subunits p50 and p65 were responsible for kappaB binding. Accordingly, we examined the role of NF-kappaB in fractalkine induction in RAEC through the use of an adenovirus-mediated mutant IkappaB as a specific inhibitor. Delivery of a dominant-negative form of IkappaBalpha in RAEC dramatically reduced the induction of fractalkine by these stimuli, suggesting a role for NF-kappaB activation in fractalkine induction. The inhibition of fractalkine expression by two potent NF-kappaB inhibitors, sulfasalazine and sanguinarine, further supported the central role of NF-kappaB in fractalkine transcription regulation and suggested a novel therapeutic target aimed at modulating leukocyte endothelial cell interaction.
TL;DR: It is demonstrated that HIV‐1‐infected and immune‐activated MP (for example, microglia) and astrocytes produce β‐chemokines in abundance, as shown in both laboratory assays and within infected brain tissue.
Abstract: The neuropathogenesis of HIV-1 infec- tion revolves around the production of secretory factors from immune-activated brain mononuclear phagocytes (MP). MP-secreted chemokines may play several roles in HIV-1 encephalitis (HIVE). These can promote macrophage brain infiltration, blood-brain barrier (BBB) and neuronal dysfunc- tion during HIV-1-associated dementia. We inves- tigate how HIV-1-infected MP regulates the pro- duction of chemokines and how they influence HIV-1 neuropathogenesis. We demonstrate that HIV-1-infected and immune-activated MP (for ex- ample, microglia) and astrocytes produce b-che- mokines in abundance, as shown in both laboratory assays and within infected brain tissue. HIV-1-in- fected microglia significantly modulate monocyte migration in a BBB model system and in brains of SCID mice with HIVE. HIV-1-infected MP down- regulate tight junction protein and special polar- ized transport systems on brain microvascular en- dothelial cells as shown in human autopsy brain tissue and in SCID mice with HIVE. Chemokines can damage neurons directly. Toxicity caused by binding of stromal-derived factor-1a to its recep- tor on neurons exemplifies such mechanism. In toto, these works underscore the diverse roles of chemokines in HIV-1 neuropathogenesis and lay the foundation for future therapeutic interventions. J. Leukoc. Biol. 68: 413-422; 2000.
TL;DR: The data suggest a broad‐based innate host defense whereby potent antimicrobial peptides are present to prevent initial colonization by pathogenic microorganisms, and the recognition of bacteria coupled with a nascent inflammatory response can bolster this defense by a coordinated up‐regulation of the peptides.
Abstract: Antimicrobial peptides are a prevalent mechanism of host defense found throughout nature. In mammals, defensins are among the most abundant of these broad-spectrum antibiotics, and are expressed in epithelial and hematopoietic cells. The defensin peptides are especially abundant in neutrophils; however, gene expression is limited to the promyelocyte stage. In epithelial cells, defensin genes are found as both constitutively expressed and inducible. Induction has been observed in vitro by stimulation with bacterial lipopolysaccharide as well as inflammatory mediators. In vivo, up-regulation of several defensin genes occurs in both infectious and inflammatory states. Gene regulation occurs via signal transduction pathways common to other innate immune responses, utilizing transcription factors such as nuclear factor (NF)-kappaB and NF interleukin-6. Together, the data suggest a broad-based innate host defense whereby potent antimicrobial peptides are present to prevent initial colonization by pathogenic microorganisms. In addition, the recognition of bacteria coupled with a nascent inflammatory response can bolster this defense by a coordinated up-regulation of the peptides.
TL;DR: The presence of alpha-melanocyte-stimulating hormone (MSH) in barrier organs such as gut and skin suggests a role in the nonspecific (innate) host defense as discussed by the authors.
Abstract: The presence of the ancient anti-inflammatory peptide alpha-melanocyte-stimulating hormone [alpha-MSH (1-13), SYSMEHFRWGKPV] in barrier organs such as gut and skin suggests a role in the nonspecific (innate) host defense. alpha-MSH and and its carboxy-terminal tripeptide (11-13, KPV) were determined to have antimicrobial influences against two major and representative pathogens: Staphylococcus aureus and Candida albicans. alpha-MSH peptides significantly inhibited S. aureus colony formation and reversed the enhancing effect of urokinase on colony formation. Antimicrobial effects occurred over a broad range of concentrations including the physiological (picomolar) range. Small concentrations of alpha-MSH peptides likewise reduced viability and germ tube formation of the yeast C. albicans. Antimicrobial influences of alpha-MSH peptides could be mediated by their capacity to increase cellular cAMP. Indeed, this messenger was significantly augmented in peptide-treated yeast and the potent adenylyl cyclase inhibitor dideoxyadenosine (ddAdo) partly reversed the killing activity of alpha-MSH peptides. Reduced killing of pathogens is a detrimental consequence of therapy with anti-inflammatory drugs. Because alpha-MSH has potent anti-inflammatory effects we determined influences of alpha-MSH on C. albicans and S. aureus killing by human neutrophils. alpha-MSH peptides did not reduce killing but rather enhanced it, likely as a consequence of the direct antimicrobial activity. alpha-MSH peptides that combine antipyretic, anti-inflammatory, and antimicrobial effects could be useful in treatment of disorders in which infection and inflammation coexist.
TL;DR: Echinacea herb and root powders were found to stimulate murine macrophage cytokine secretion as well as to significantly enhance the viability and/or proliferation of human PBMCs in vitro.
Abstract: We have investigated the immunostimulatory, anti-inflammatory, and antioxidant activities of various Echinacea raw materials and commercially available products on murine macrophages and human peripheral blood mononuclear cells (PBMCs). To emulate oral dosing, a simulated digestion protocol was employed as a means of sample preparation. Echinacea-induced macrophage activation was used as a measure of immunostimulatory activity determined via quantitative assays for macrophage-derived factors including tumor necrosis factor alpha, interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, and nitric oxide. Echinacea herb and root powders were found to stimulate murine macrophage cytokine secretion as well as to significantly enhance the viability and/or proliferation of human PBMCs in vitro. In contrast, Echinacea extracts chemically standardized to phenolic acid or echinacoside content and fresh pressed juice preparations were found to be inactive as immunostimulatory agents but did display, to varying degrees, anti-inflammatory and antioxidant properties.