Tumour necrosis factor-alpha (TNF-alpha)/cachectin is a multifunctional cytokine that has effects in inflammation, sepsis, lipid and protein metabolism, haematopoiesis, angiogenesis and host resistance to parasites and malignancy. TNF-alpha was first described in activated macrophages, but certain mouse or rat mast cell populations (reviewed in refs 4,5) and some in vitro-derived human cells with cytochemical features of mast cells-basophils may also contain products similar to TNF-alpha. Here we present evidence that resident mouse peritoneal mast cells constitutively contain large amounts of TNF-alpha bioactivity, whereas cultured, immature mast cells vary in their TNF-alpha content. IgE-dependent activation of cultured or peritoneal mast cells induces extracellular release of TNF-alpha and augments levels of TNF-alpha messenger RNA and bioactivity. These findings identify mouse mast cells as an important source of both preformed and immunologically inducible TNF-alpha, and suggest that release of TNF-alpha by mast cells may contribute to host defence, the pathophysiology of allergic diseases and other processes dependent on TNF-alpha.

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PMN are critical to innate immunity and are fundamental to antibacterial defense. To localize to sites of infection, PMN possess receptors that detect chemoattractant stimuli elicited at the site, such as chemokines, complement split products, or bioactive lipids. Signaling through these receptors stimulates chemotaxis toward the site of infection but also activates a number of biochemical processes, with the result that PMN kill invading bacteria. PMN possess two receptors, CXCR1 and CXCR2, for the N-terminal ELR motif-containing CXC chemokines, although only two chemokine members bind both receptors and the remainder binding only CXCR2. This peculiar pattern in receptor specificity has drawn considerable interest and investigation into whether signaling through each receptor might impart unique properties on the PMN. Indeed, at first glance, CXCR1 and CXCR2 appear to be functionally redundant; however, there are differences. Considering these proinflammatory activities of activating PMN through chemokine receptors, there has been great interest in the possibility that blocking CXCR1 and CXCR2 on PMN will provide a therapeutic benefit. The literature examining CXCR1 and CXCR2 in PMN function during human and modeled diseases will be reviewed, asking whether the functional differences can be perceived based on alterations in the role PMN play in these processes.

Mast cells (MC)l are widely distributed throughout vascularized tissues and certain epithelia. They represent a source ofpotent mediators ofinflammation (reviewed in references 1-4). These mediators are released after sensitization with IgE immunoglobulins, which are bound to IgE receptors (FceRI) on the MC, and crosslinking with specific multivalent antigen (4). Such activation causes MC to degranulate releasing histamine, heparin, and other sulphated proteoglycans and certain neutral proteases. Activated MC also elaborate newly synthesized mediators such as products of the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism (reviewed in references 2-4). MC are widely regarded as critical effector cells in the inflammatory reactions underlying disorders of IgE-dependent immediate hypersensitivity and in the expression ofprotective immunity involving IgE (reviewed in references 1-4).Studies in mice indicate that MC are derived from multipotential bone marrowderived hematopoietic precursors which complete their program of differentiation and maturation in vascularized tissues, epithelia, and serosal cavities (reviewed in references 1, 5). This process results in the generation ofmast cell populations which vary in multiple aspects of their phenotype, including morphology, mediator content, and sensitivity to regulation by cytokines affecting proliferation and maturation (reviewed in reference 1). One such population, referred to as "mucosal" mast cells (MMC) because they occur in the mucosal layer of gastrointestinal tissues, appears to be exquisitely sensitive to regulation by the T cell-associated cytokines IL-3 and IL-4 (1). IL-3 probably represents the major cytokine regulating proliferation ofthis subset (6, 7), whereas in vitro studies indicate that IL-4 can act as a costimulant of proliferation (8). Thus, the mouse MMC population is regulated by products I Abbreviations used in this paper: AbMuLV, Abelson murine leukemia virus; Ag, antigen; BMCMC, bone marrow-derived cultured mast cell ; DNP3o-40-HSA 2,4-dinitrophenyl-human serum albumin; FceRI, cell surface receptor for the Fc portion of IgE; GM-CSF, granulocyte/macrophage colony-stimulating factor ; MC, mast cell; MIP, macrophage inflammatory protein; MMC, mucosal mast cell ; PKC, protein kinase C. J. Exp. MED.

SummaryMast cell-associated mediators are generally classified into two groups: the preformed mediators, which are stored in the cells' cytoplasmic granules and are released upon exocytosis, and the newly synthesized mediators, which are not stored but are produced and secreted only after appropriate stimulation of the cell. We now report that tumor necrosis factor a (TNF-cr)/cachectin represents a new type of mast cell-associated mediator, in that IgE-dependent mast cell activation results in the rapid release ofpreformed stores of the cytokine followed by the synthesis and sustained release of large quantities of newly formed TNF-a. We also demonstrate that challenge with specific antigen induces higher levels ofTNF-a mRNA at skin sites sensitized with IgE in normal mice or mast cell-reconstituted genetically mast cell-deficient WBB6Fi-W/ W°mice than at identically treated sites in WBB6FvW/ W°mice that are devoid of mast cells . These findings identify mast cells as a biologically significant source of TNF-a/cachectin during IgE-dependent responses and define a mechanism whereby stimulation of mast cells via the FCERI can account for both the rapid and sustained release of this cytokine .T he biologically active mediators elaborated by mast cells are traditionally assigned to two groups (1, 2). One class of mediators, which includes histamine, serotonin, heparin, and other proteoglycans, and certain proteases, are stored in the cells' cytoplasmic granules. While extracellular release of these products is an energy-dependent process, expression of the bioactivities requires only exocytosis of cytoplasmic granules containing the preformed mediators . By contrast, another class of mediators, which includes products of the cyclooxygenase or lipoxygenase pathways of arachidonic acid metabolism and platelet activating factor, are not stored by mast cells, but are synthesized and released upon activation of the cells. However, several recent findings indicate that it may not be appropriate to classify all mast cell-associated mediators as either preformed or newly synthesized. It is now clear that in vitro derived mouse mast cells stimulated via the FCERI or by other mechanisms can express increased levels ofmRNA for a wide range o£multifunctional cytokines and, in some instances, release the products (3-6). In the case of one of these cytokines, TNF-a/cachectin, both in vitro derived and freshly purified mouse mast cells also constitutively store significant amounts of the bioactivity (6) . The presence of preformed stores of TNF-a in mast cells is of interest, in that other cell types that produce this cytokine, such as macrophages (7-9), T cells (10), and B cells (11), contain little or no detectable TNF-cr unless they are appropriately stimulated. We recently showed that stimulation of mouse mast cells via the FCERI resulted in both the release of TNF-a bioactivity and also increased levels ofTNF-a mRNA (6) . However, the extent to which the TNF-a bioactivity released by activated mast cells reflected the secreti...

Introduction

We recognize well the abilities of dendritic cells to activate effector T cell (Teff cell) responses to an array of antigens and think of these cells in this context as pre-eminent antigen-presenting cells, but dendritic cells are also critical to the induction of immunologic tolerance. Herein, we review our knowledge on the different kinds of tolerogenic or regulatory dendritic cells that are present or can be induced in experimental settings and humans, how they operate, and the diseases in which they are effective, from allergic to autoimmune diseases and transplant tolerance. The primary conclusions that arise from these cumulative studies clearly indicate that the agent(s) used to induce the tolerogenic phenotype and the status of the dendritic cell at the time of induction influence not only the phenotype of the dendritic cell, but also that of the regulatory T cell responses that they in turn mobilize. For example, while many, if not most, types of induced regulatory dendritic cells lead CD4+ naïve or Teff cells to adopt a CD25+Foxp3+ Treg phenotype, exposure of Langerhans cells or dermal dendritic cells to vitamin D leads in one case to the downstream induction of CD25+Foxp3+ regulatory T cell responses, while in the other to Foxp3− type 1 regulatory T cells (Tr1) responses. Similarly, exposure of human immature versus semi-mature dendritic cells to IL-10 leads to distinct regulatory T cell outcomes. Thus, it should be possible to shape our dendritic cell immunotherapy approaches for selective induction of different types of T cell tolerance or to simultaneously induce multiple types of regulatory T cell responses. This may prove to be an important option as we target diseases in different anatomic compartments or with divergent pathologies in the clinic. Finally, we provide an overview of the use and potential use of these cells clinically, highlighting their potential as tools in an array of settings.

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