Dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) is a monocyte-derived dendritic cell (MDDC)-specific lectin which participates in dendritic cell (DC) migration and DC-T lymphocyte interactions at the initiation of immune responses and enhances trans-infection of T cells through its HIV gp120-binding ability. The generation of a DC-SIGN-specific mAb has allowed us to determine that the acquisition of DC-SIGN expression during the monocyte-DC differentiation pathway is primarily induced by IL-4, and that GM-CSF cooperates with IL-4 to generate a high level of DC-SIGN mRNA and cell surface expression on immature MDDC. IL-4 was capable of inducing DC-SIGN expression on monocytes without affecting the expression of other MDDC differentiation markers. By contrast, IFN-α, IFN-γ, and TGF-β were identified as negative regulators of DC-SIGN expression, as they prevented the IL-4-dependent induction of DC-SIGN mRNA on monocytes, and a similar inhibitory effect was exerted by dexamethasone, an inhibitor of the monocyte-MDDC differentiation pathway. The relevance of the inhibitory action of dexamethasone, IFN, and TGF-β on DC-SIGN expression was emphasized by their ability to inhibit the DC-SIGN-dependent HIV-1 binding to differentiating MDDC. These results demonstrate that DC-SIGN, considered as a MDDC differentiation marker, is a molecule specifically expressed on IL-4-treated monocytes, and whose expression is subjected to a tight regulation by numerous cytokines and growth factors. This feature might help in the development of strategies to modulate the DC-SIGN-dependent cell surface attachment of HIV for therapeutic purposes.
HMGN1 is a novel alarmin that signals through TLR4 and is required for LPS-induced immune responses in vivo.
Neutrophils are the first major population of leukocyte to infiltrate infected or injured tissues and are crucial for initiating host innate defense and adaptive immunity. Although the contribution of neutrophils to innate immune defense is mediated predominantly by phagocytosis and killing of microorganisms, neutrophils also participate in the induction of adaptive immune responses. At sites of infection and/or injury, neutrophils release numerous mediators upon degranulation or death, among these are alarmins which have a characteristic dual capacity to mobilize and activate antigen-presenting cells. We describe here how alarmins released by neutrophil degranulation and/or death can link neutrophils to dendritic cells by promoting their recruitment and activation, resulting in the augmentation of innate and adaptive immune responses.
Acquisition of CCR7 expression is an important phenotype change during dendritic cell (DC) maturation that endows these cells with the capability to migrate to lymph nodes. We have analyzed the possible role of CCR7 on the regulation of the survival of DCs. Stimulation with CCR7 ligands CCL19 and CCL21 inhibits apoptotic hallmarks of serum-deprived DCs, including membrane phosphatidylserine exposure, loss of mitochondria membrane potential, increased membrane blebs, and nuclear changes. Both chemokines induced a rapid activation of phosphatidylinositol 3-kinase/Akt1 (PI3K/Akt1), with a prolonged and persistent activation of Akt1. Interference with PI3K, Gi, or G protein ␥ subunits abrogated the effects of the chemokines on Akt1 activation and on survival. In contrast, inhibition of extracellular signal-related kinase 1/2 (Erk1/2), p38, or c-Jun N-terminal kinase (JNK) was ineffective. Nuclear factor-B (NFB) was involved in the antiapoptotic effects of chemokines because inhibition of NFB blunted the effects of CCL19 and CCL21 on survival. Furthermore, chemokines induced down-regulation of the NFB inhibitor IB, an increase of NFB DNA-binding capability, and translocation of the NFB subunit p65 to the nucleus. In summary, in addition to its well-established role in chemotaxis, we show that CCR7 also induces antiapoptotic signaling in mature DCs. IntroductionApoptosis, or programmed cell death, is a physiologic process involved in the normal development and maintenance of tissue homeostasis. 1 The final stage of this process that leads to the demise of the cell is executed by proteases that degrade vital molecular components of the cell. 1 Hallmarks of cells undergoing apoptosis include disruption of mitochondria transmembrane potential, apparition of numerous blebs on the membrane, increased nuclear condensation, and increased appearance of phosphatidylserine (PS) in the outer leaflet of the cell membrane.Apoptosis is a programmed process that is regulated through a complex mechanism that involves multiple molecular intermediates. Surface receptors may inhibit apoptosis by relaying intracellular signals that either repress proapoptotic molecules and/or stimulate antiapoptotic ones. 1 Multiple pathways that inhibit apoptosis use as a common signaling intermediate phosphatidylinositol 3Ј-kinase (PI3K) and its downstream effector Akt1. 1-3 Akt1 phosphorylates and inhibits a variety of proapoptotic regulators and also regulates proteins that promote cell survival. [1][2][3] In this regard, it has been shown that Akt1 may activate IB kinase, which induces phosphorylation and subsequent degradation of IB, a molecule that binds and retains transcription factor nuclear factor-B (NFB) in the cytoplasm. 1-3 Upon IB degradation, NFB translocates to the nucleus and stimulates transcription from a variety of antiapoptotic genes. 2,4 Apart from PI3K/Akt1, in some cell settings, mitogen-activated protein kinase (MAPK) family members have also been shown to play an important role as regulators of apoptosis. [5][6][7] Dendritic ...
Granulysin (GNLY), IntroductionThe granulysin (GNLY) gene is located on chromosome 2 and consists of 6 exons. A major protein product of 15 kDa is translated, some of which is subsequently secreted or processed by proteolytic cleavage at both N and C termini to a 9-kDa protein stored in the granular compartment. 1 Whereas the 15-kDa protein is produced rapidly, has a shorter half-life, and is constitutively released, the secretory 9-kDa form is produced slowly and is relatively stable. The crystal structure of the human protein, elucidated in 2003 by Anderson et al, is predictive of its antimicrobial effects and clinical relevance in disease and pathogenesis. GNLY is highly cationic and folded as a 5-helix bundle stabilized by 2 highly conserved intramolecular disulfide bonds. 2 It belongs to the family of Saposin-like lipid binding proteins called SAPLIP and colocalizes in the granular compartments of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells along with granzymes and perforin. 3 GNLY has the highest sequence identity to NK-lysin (43% identity), a porcine protein with antibacterial activity that is also a member of the SAPLIP family. 3 No homologous protein has been identified to date in mice.GNLY is produced by human NK cells and activated CTLs, and the 9-kDa form is rapidly released upon degranulation. The kinetics of expression of GNLY by these 2 cell types differs. NK cells release GNLY very early in immune responses, whereas CTLs release it after 3-5 days of activation. 1 Elevation of GNLY expression and levels in tissue and serum has been reported in infections, autoimmune diseases, transplant rejection, and graft versus host reaction in patients with hematopoietic stem cell transplantation. [4][5][6][7][8][9][10] In leprosy, CD4 ϩ cells expressing GNLY were elevated (8%-15%) in the skin lesions of patients with the tuberculoid form compared with those with the disseminated lepromatous form of the disease. 7 Recent studies have demonstrated that in response to Mycobacterium tuberculosis-infected macrophages, human CD8 ϩ T cells were induced to express CCL5 and GNLY. 11 Recently, it was reported that blister fluids of patients suffering from Stevens Johnson syndrome and toxic epidermal necrolysis contained high levels of secretory 15-kDa GNLY, and the high concentration of GNLY, but not granzyme B or perforin, is responsible for the disseminated keratinocyte apoptosis in Stevens Johnson syndrome and toxic epidermal necrolysis. 12 By contrast, patients with severe immunodeficiencies have very low GNLY serum levels. 13 GNLY levels are also reduced in different cell types and even in serum of carcinoma patients and appear to be inversely correlated with tumor progression. 14-17 Consequently both forms of GNLY can be induced in the course of inflammation and have also been shown to be up-regulated by stimulation of lymphoid cells by proinflammatory mediators and pathogenassociated molecular patterns. 18,19 GNLY exhibits lytic activity against a variety of microorganisms and tumors. 3,14,[20][...
No abstract
Lactoferrin is an 80-kDa iron-binding protein present at high concentrations in milk and in the granules of neutrophils. It possesses multiple activities, including antibacterial, antiviral, antifungal, and even antitumor effects. Most of its antimicrobial effects are due to direct interaction with pathogens, but a few reports show that it has direct interactions with cells of the immune system. In this study, we show the ability of recombinant human lactoferrin (talactoferrin alfa (TLF)) to chemoattract monocytes. What is more, addition of TLF to human peripheral blood or monocyte-derived dendritic cell cultures resulted in cell maturation, as evidenced by up-regulated expression of CD80, CD83, and CD86, production of proinflammatory cytokines, and increased capacity to stimulate the proliferation of allogeneic lymphocytes. When injected into the mouse peritoneal cavity, lactoferrin also caused a marked recruitment of neutrophils and macrophages. Immunization of mice with OVA in the presence of TLF promoted Th1-polarized Ag-specific immune responses. These results suggest that lactoferrin contributes to the activation of both the innate and adaptive immune responses by promoting the recruitment of leukocytes and activation of dendritic cells.
Defensins are endogenous, small, cysteine-rich antimicrobial peptides that are produced by leukocytes and epithelial cells. Substantial evidence accumulated in recent years indicates that mammalian defensins are multifunctional and, by interacting with host cell receptor(s), participate in both the innate and adaptive antimicrobial immunity of the host. A better understanding of the function of defensins in immunity has implications for the development of potential clinical therapeutics for the treatment of infection or cancer. Here we will briefly outline the classification, genes, expression, and structure of mammalian defensins and focus on their roles in innate and adaptive immune response of the host.
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