Proinflammatory Effector Cells Research Articles

Adaptive Immunity in Neurodegenerative and Neuropsychological Disorders.

Neurodegenerative and neuropsychological disorders are becoming a greater proportion of the global disease burden; however the pathogenic mechanisms by which these disorders originate and contribute to disease progression are not well-described. Increasing evidence supports neuroinflammation as a common underlying component associated with the neuropathological processes that effect disease progression. This collection of articles explores the role of adaptive immunity in autoimmunity, neurodegeneration, neurotrauma, and psychological disorders. The section emphasizes the interactions of T cells with innate cellular responses within the CNS and the effects on neurological functions. One recurrent theme is that modified and aggregated self-proteins upregulate innate-mediated inflammation and provide a permissive environment for polarization of T cells to proinflammatory effector cells. Moreover, infiltration and reactivation of those T effector cells exacerbate neuroinflammation and oxidative stress to greater neurotoxic levels. Another recurrent themein these disorders promotes diminished regulatory functions that reduce control over activated T effector cells and microglia, and ultimately augment proinflammatory conditions. Augmentation of regulatory control is discussed as therapeutic strategies to attenuate neuroinflammation, mitigate neurodegeneration or neuronal dysfunction, and lessen disease progression.

Eosinophil-specific deletion of IκBα in mice reveals a critical role of NF-κB–induced Bcl-xL for inhibition of apoptosis

AbstractEosinophils are associated with type 2 immune responses to allergens and helminths. They release various proinflammatory mediators and toxic proteins on activation and are therefore considered proinflammatory effector cells. Eosinophilia is promoted by the cytokines interleukin (IL)-3, IL-5, and granulocyte macrophage–colony-stimulating factor (GM-CSF) and can result from enhanced de novo production or reduced apoptosis. In this study, we show that only IL-5 induces differentiation of eosinophils from bone marrow precursors, whereas IL-5, GM-CSF, and to a lesser extent IL-3 promote survival of mature eosinophils. The receptors for these cytokines use the common β chain, which serves as the main signaling unit linked to signal transducer and activator of transcription 5, p38 mitogen-activated protein kinase, and nuclear factor (NF)-κB pathways. Inhibition of NF-κB induced apoptosis of in vitro cultured eosinophils. Selective deletion of IκBα in vivo resulted in enhanced expression of Bcl-xL and reduced apoptosis during helminth infection. Retroviral overexpression of Bcl-xL promoted survival, whereas pharmacologic inhibition of Bcl-xL in murine or human eosinophils induced rapid apoptosis. These results suggest that therapeutic strategies targeting Bcl-xL in eosinophils could improve health conditions in allergic inflammatory diseases.

Secretory Phospholipases A2 Are Secreted From Ciliated Cells and Increase Mucin and Eicosanoid Secretion From Goblet Cells

Secretory phospholipases A2 (sPLA2) initiate the biosynthesis of eicosanoids, are increased in the airways of people with severe asthma, and induce mucin hypersecretion. We used IL-13-transformed, highly enriched goblet cells and differentiated (ciliary cell-enriched) human bronchial epithelial cell culture to evaluate the relative contribution of ciliated and goblet cells to airway sPLA2 generation and response. We wished to determine the primary source(s) of sPLA2 and leukotrienes in human airway epithelial cells. Human bronchial epithelial cells from subjects without lung disease were differentiated to a ciliated-enriched or goblet-enriched cell phenotype. Synthesis of sPLA2, cysteinyl leukotrienes (cysLTs), and airway mucin messenger RNA and protein was measured by real-time-polymerase chain reaction and an enzyme-linked immunosorbent assay, and the localization of mucin and sPLA2 to specific cells types was confirmed by confocal microscopy. sPLA2 group IIa, V, and X messenger RNA expression was increased in ciliated-enriched cells (P < .001) but not in goblet-enriched cells. sPLA2 were secreted from the apical (air) side of ciliated-enriched cells but not goblet-enriched cells (P < .001). Immunostaining of sPLA2 V was strongly positive in ciliated-enriched cells but not in goblet-enriched cells. sPLA2 released cysLTs from goblet-enriched cells but not from ciliated-enriched cells, and this result was greatest with sPLA2 V (P < .05). sPLA2 V increased goblet-enriched cell mucin secretion, which was inhibited by inhibitors of lipoxygenase or cyclooxygenase (P < .02). sPLA2 are secreted from ciliated cells and appear to induce mucin and cysLT secretion from goblet cells, strongly suggesting that airway goblet cells are proinflammatory effector cells.

Tumor-induced CD11b(+) Gr-1(+) myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner.

Immunosuppressive CD11b(+) Gr-1(+) myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or α-galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Con A induced liver damage. Hepatic CD11b(+) Gr-1(+) cells revealed a polarized proinflammatory gene signature after Con A treatment. An IFN-γ-dependent upregulation of CD40 on hepatic CD11b(+) Gr-1(+) cells along with an upregulation of CD80, CD86, and CD1d after Con A treatment was observed. Con A treatment resulted in a loss of suppressor function by tumor-induced CD11b(+) Gr-1(+) MDSCs as well as enhanced reactive oxygen species (ROS)-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Con A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40(-/-) tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased ROS production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as proinflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner.

Proinflammatory human 6-sulfo LacNAc-positive dendritic cells accumulate in intestinal acute graft-versus-host disease

Proinflammatory human 6-sulfo LacNAc-positive dendritic cells accumulate in intestinal acute graft-versus-host disease

Abstract T P71: Meningeal-Derived IL-6 Exacerbates Post-Stroke Inflammation and Pathology

Background: Inflammation critically contributes to post-stroke brain damage and consequently there is much interest in factors that influence stroke-induced brain inflammation. Interleukin 6 (IL-6) has been heralded as an important predictor of stroke outcome, however there are conflicting reports describing detrimental, beneficial and even no effects of IL-6 on stroke pathology. This has led to the suggestion that the post-stroke effects of IL-6 may be dependent on its cellular location. We report that IL-6 produced by meningeal resident mast cells (pro-inflammatory effector cells) significantly exacerbates brain inflammation and pathology after stroke. These are the first data to identify the role in stroke pathology of IL-6 derived from a specific cell type in a particular anatomic location in vivo. Methods: A mast cell (MC) ‘knock-in’ mouse model was used where MC-deficient mice (KitW/W-v) were repaired of their MC deficiency by engraftment of in-vitro-derived MCs. MCs from wild-type (WT) or IL-6 knock-out mice were engrafted into the meninges. Mice were subjected to 30 min middle cerebral artery occlusion. Brain swelling and infarct size were assessed by T2-weighted MRI and histology. The immune response was quantified by flow cytometry. Results: CNS distribution analysis of MCs in wild-type and MC-engrafted mice revealed equivalent numbers of MCs in meninges in all groups but almost no MCs in brain parenchyma of the MC-engrafted groups. At 3d post-stroke, wild-type mice and MC-deficient mice engrafted with WT MCs exhibited significantly greater brain swelling, larger infarcts, and more brain granulocytes and activated macrophages than MC-deficient mice. These findings indicate that meningeal MCs exacerbate stroke outcome. In contrast, the pathology in IL6-KO MC-engrafted mice resembled that in MC-deficient mice, with significantly less brain swelling, smaller infarcts and fewer granulocytes and activated macrophages than in the WT MC-engrafted mice. This indicates that MC-secreted IL-6 contributes importantly to the detrimental effects of MCs. Conclusions: IL-6 produced by mast cells in the meninges is detrimental to stroke outcome. Thus, intrathecal targeting of meningeal inflammation may offer a novel therapeutic strategy for stroke.

Ly6Chi Monocytes in the Inflamed Colon Give Rise to Proinflammatory Effector Cells and Migratory Antigen-Presenting Cells

Ly6C(hi) monocytes seed the healthy intestinal lamina propria to give rise to resident CX(3)CR1(+) macrophages that contribute to the maintenance of gut homeostasis. Here we report on two alternative monocyte fates in the inflamed colon. We showed that CCR2 expression is essential to the recruitment of Ly6C(hi) monocytes to the inflamed gut to become the dominant mononuclear cell type in the lamina propria during settings of acute colitis. In the inflammatory microenvironment, monocytes upregulated TLR2 and NOD2, rendering them responsive to bacterial products to become proinflammatory effector cells. Ablation of Ly6C(hi) monocytes ameliorated acute gut inflammation. With time, monocytes differentiated into migratory antigen-presenting cells capable of priming naive Tcells, thus acquiring hallmarks reminiscent of dendritic cells. Collectively, our results highlight cellular dynamics in the inflamed colon and the plasticity of Ly6C(hi) monocytes, marking them as potential targets for inflammatory bowel disease (IBD) therapy.

Activation-induced silencing of Thpok defines a new type of CD4 effector T lymphocytes

CD4 T helper lineage-commitment is initially determined during thymic selection and is driven by the key transcription factor ThPOK. Continuous expression of ThPOK is required to maintain mature MHC class II restricted CD4 T lymphocytes as T helper cells. Here we identify an activation induced differentiation process in vivo that is characterized by the silencing of Thpok and the generation of a new type of antigen-experienced CD4 T cells. This alternative differentiation also prevents activated CD4 T cells from becoming pro-inflammatory effector cells that could damage tissues. Therefore, the data show an unexpected plasticity in mature CD4 T lymphocytes, and define a new subtype of activated CD4 T cells characterized by the loss of the ThPOK-controlled T helper phenotype and the gain of cytotoxic and regulatory competence.

Cancer Vaccination Reprograms Regulatory T Cells into Helper CD4 T Cells to Promote Antitumor CD8 T-Cell Responses

Evaluation of: Sharma MD, Hou DY, Baban B et al. : Reprogrammed Foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33, 942-954 (2010). It has been recognized that natural CD4(+)Foxp3(+) Tregs could display a phenotypic and functional plasticity in an inflammatory microenvironment. Following the loss of key transcription factor, Foxp3 and core inhibitory molecules associated with suppression, Tregs are reprogrammed into proinflammatory effector cells in vivo. However, the biological significance of this conversion is elusive. Sharma et al. demonstrate that in response to vaccines containing antigens, IFA and CpG, a large proportion of Tregs are dedifferentiated into Th1-like effector cells, which coexpress CD40L - a key molecule for CD8 help by licensing dendritic cells. Under certain experimental conditions, these reprogrammed Tregs are absolutely essential in helping the differentiation of CD8 T cells primed by antigen cross-presentation pathways. Treg conversion is diminished by tumor-induced indoleamine 2,3-dioxygenase in tumor-bearing mice, and blockade of indoleamine 2,3-dioxygenase activity in vivo is able to rescue Treg reprogramming. Collectively, in response to signaling from innate immune cells, Tregs are rapidly reprogrammed into Th1-like effector cells, which are also capable of providing timely help for antigen-specific CD8 T cells in the early phase of activation, when the traditional cognate help from conventional CD4 T cells has not yet became available.

Column-free isolation of untouched CD4+CD127lowCD49d- human regulatory T cells in 45 minutes (168.4)

Abstract Regulatory T cells (Tregs) are a subset of lymphocytes that play a key role in maintaining immune homeostasis. The isolation of highly purified Tregs is essential for advancing this exciting field of research. FOXP3 remains the best marker for the identification of Tregs, but its intracellular localization currently precludes its use for the isolation of viable human Tregs. To overcome these technical difficulties, researchers have exploited the expression of other surface markers to isolate Treg populations. Typically, the expression of CD127 inversely correlates with FOXP3 expression, while CD49d, is expressed on the majority of pro-inflammatory effector cells but is absent on Tregs. Removal of CD127high cells from the CD4+ T-cell population enriches for Tregs with high levels of FOXP3 expression. Additional depletion of CD49d expressing cells further removes contaminating IFNγ and IL-17 secreting cells. Together this strategy permits selective isolation of highly enriched Tregs. We have developed a new kit for the negative enrichment of highly purified human Tregs. Our new EasySep™ CD4+CD127lowCD49d- kit isolates untouched Tregs by by column-free magnetic separation in only 45 minutes. Mean CD4+ T-cell purity is 94.3% +/- 5.5% of which 65.5% +/- 11.7% express high levels of FOXP3 (n=7). This new product will add to the array of powerful yet convenient tools available for the isolation of functional highly purified human Tregs.

Early Aged T-Cells in Immune-Mediated Diseases

Early loss of thymic function may be crucial for the development of immune-mediated diseases. According to this concept premature collapse of thymic output is compensated by homeostatic proliferation of peripheral T-cells, driven by recognition of self antigens and finally resulting in the expansion of autoreactive, senescent T-cell clones. Such senescent T-cells are characterized by the loss of the co-stimulatory receptor CD28 and the gain of new immunomodulatory molecules such as natural killer cell receptors and toll-like receptors. The immune system may compensate for these changes by regulatory mechanisms, including the evolvement of regulatory T-cells. However, the aging process may also affect these regulatory T-cells leading to a second “hit” of the immune system. Current therapeutic approaches in patients with immune-mediated diseases target common end pathways of inflammation, driven by proinflammatory cytokines and effector cells. Future directions will include the aim to reset the immune system, by restoring the ability to repopulate the immune system with young and adaptable lymphocytes as well as by strengthening the effect of regulatory T-cells. Keywords: CD28, aging, regulatory T-lymphocyte, cellular senescence, thymus, autoimmune disease, T-Cells, natural killer cell, toll-like receptors, immune system, inflammation, cytokines, homeostasis, rheumatoid arthritis, innate immune system, thymopoesis, autoimmune regulator, juvenile idiopathic arthritis, haematopoietic progenitor cells, major histocompatibility complex M, MHC II, HLA-DR4, thymic atrophy, autoimmune diseases, Epstein Barr Virus, EBV, CD4, CD8, CD27, IFN, perforin, granzyme B, CCR-5, CCR-7, Ankylosing spondylitis, Dermatomyositis, 50

Combined Administration of a Mutant TGF-β1/Fc and Rapamycin Promotes Induction of Regulatory T Cells and Islet Allograft Tolerance

The critical roles of TGF-β in the reciprocal differentiation of tolerance-promoting CD4(+)Foxp3(+) regulatory T cells (Tregs) and proinflammatory Th17 effector cells affect alloimmune reactivity and transplant outcome. We reasoned that a strategy to harness TGF-β and block proinflammatory cytokines would inhibit the differentiation of Th17 cells and strengthen the cadre of Tregs to promote tolerance induction and long-term allograft survival. In this study, we report the development of a long-lasting autoactive human mutant TGF-β1/Fc fusion protein that acts in conjunction with rapamycin to inhibit T cell proliferation and induce the de novo generation of Foxp3(+) Treg in the periphery, while at the same time inhibiting IL-6-mediated Th17 cell differentiation. Short-term combined treatment with TGF-β1/Fc and rapamycin achieved long-term pancreatic islet allograft survival and donor-specific tolerance in a mouse model. This effect was accompanied by expansion of Foxp3(+) Tregs, enhanced alloantigen-specific Treg function, and modulation of transcript levels of Foxp3, IL-6, and IL-17. Our strategy of combined TGF-β1/Fc and rapamycin to target the IL-6-related Tregs and Th17 signaling pathways provides a promising approach for inducing transplant tolerance and its clinical application.

Adiponectin‐mediated changes in effector cells involved in the pathophysiology of rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with increased production of adipokines, which are cytokine-like mediators that are produced mainly in adipose tissue but also in synovial cells. Since RA synovial fibroblasts (RASFs), lymphocytes, endothelial cells, and chondrocytes are key players in the pathophysiology of RA, this study was undertaken to analyze the effects of the key adipokine adiponectin on proinflammatory and prodestructive synovial effector cells. Lymphocytes were activated in part prior to stimulation. All cells were stimulated with adiponectin, and changes in gene and protein expression were determined by Affymetrix and protein arrays. Messenger RNA and protein levels were confirmed using semiquantitative reverse transcription-polymerase chain reaction (PCR), real-time PCR, and immunoassays. Intracellular signal transduction was evaluated using chemical signaling inhibitors. Adiponectin stimulation of human RASFs predominantly induced the secretion of chemokines, as well as proinflammatory cytokines, prostaglandin synthases, growth factors, and factors of bone metabolism and matrix remodeling. Lymphocytes, endothelial cells, and chondrocytes responded to adiponectin stimulation with enhanced synthesis of cytokines and various chemokines. Additionally, chondrocytes released increased amounts of matrix metalloproteinases. In RASFs, adiponectin-mediated effects were p38 MAPK and protein kinase C dependent. Our previous findings indicated that adiponectin was present in inflamed synovium, at sites of cartilage invasion, in lymphocyte infiltrates, and in perivascular areas. The findings of the present study indicate that adiponectin induces gene expression and protein synthesis in human RASFs, lymphocytes, endothelial cells, and chondrocytes, supporting the concept of adiponectin being involved in the pathophysiologic modulation of RA effector cells. Adiponectin promotes inflammation through cytokine synthesis, attraction of inflammatory cells to the synovium, and recruitment of prodestructive cells via chemokines, thus promoting matrix destruction at sites of cartilage invasion.

Mast cells in atherogenesis: Actions and reactions

Mast cells (better known as allergy cells) are proinflammatory effector cells present in the human arterial intima and in evolving atherosclerotic lesions. Experiments in vitro, in vivo experiments in animals, and immunohistologic studies of human coronary samples have uncovered mechanisms by which activated mast cells could participate in the development of the lesions. When activated, mast cells acutely expel a fraction of their cytoplasmic granules, which are filled with a wide selection of heparin-bound preformed mediators. These include histamine, neutral proteases, growth factors, and proinflammatory cytokines. The microenvironmental targets of these effector molecules are various lipoprotein particles in the intimal fluid, components of the extracellular matrix, and intimal cells neighboring the activated mast cells. Importantly, sustained selective release of proinflammatory mediators without degranulation may also occur at sites of chronic inflammation. The activities of the various mediators are suggested to contribute to fatty streak formation and to the generation of unstable plaques susceptible to rupture. Thus, mast cells appear to provide a novel link between inflammation and atherogenesis.

CD34 + hemopoietic progenitor cells are potent effectors of allergic inflammation

In steady state, hemopoietic progenitors constantly egress from the bone marrow (BM) into the blood and circulate through the peripheral tissues. In allergic diseases, the BM releases increased numbers of CD34(+) progenitor cells that migrate to the site of allergic inflammation, where they differentiate into tissue-dwelling and classic effector cells of allergy, such as mast cells, eosinophils, and basophils. To examine whether peripheral blood CD34(+) cells in addition to being progenitors may also directly function as inflammatory effector cells. Highly purified neonatal or adult blood CD34(+) cells were examined for the expression of thymic stromal lymphopoietin (TSLP) and IL-33 receptors and for their response to these cytokines as well as to supernatants of primary small airway epithelial cells and nasal explants from rhinosinusitis and control subjects. Sputum of patients with asthma was examined before and after allergen inhalation for the presence of IL-5 and IL-13-containing CD34(+) cells. Circulating CD34(+) cells expressed receptors for TSLP and IL-33 and responded to these cytokines by rapidly releasing high levels of proinflammatory T(H)2-like cytokines and chemokines. These cells were activated in a TSLP-dependent manner by the supernatant fluids from activated primary human small airway epithelial cells and from nasal explants of patients with chronic rhinosinusitis. Moreover, activated CD34(+) cells containing IL-5 and IL-13 could be detected in the sputum of individuals with allergic asthma, with numbers increasing in response to specific allergen inhalation challenge. Blood CD34(+) cells, in addition to being progenitors, may act as proinflammatory effector cells by themselves and directly contribute to the allergic inflammation.

Chemokine receptor expression on infiltrating lymphocytes from abdominal aortic aneurysms: Role of CXCR4–CXCL12 in lymphoid recruitment

This is a study to define the profile of chemokine receptors expressed on isolated infiltrating lymphocytes in human abdominal aortic aneurysms (AAAs), and to examine their role in lymphoid recruitment. AAA T-lymphocytes were CXCR4-positive, CCR7-negative and partially CXCR3 and CCR5-positive. Functionally, AAA T-cells were proinflammatory effector cells, as they produced IFN-γ and granzyme A. AAA B-lymphocytes were CXCR4-positive and exhibited low CXCR5 expression. A relevant feature of infiltrating T- and B-lymphocytes was the high intensity of CXCR4 expression and the capability to migrate to CXCL12. CXCL12-producing cells were found in the adventitia of AAA. These cells were CD45-negative and partially VCAM-1 and DR-positive. In summary, the present results suggest that CXCR4, expressed on infiltrating lymphocytes, and CXCL12, expressed on stromal cells, is involved in the recruitment of lymphocytes within the arterial wall in AAA.

Type I IFN-Producing CD4 Vα14i NKT Cells Facilitate Priming of IL-10-Producing CD8 T Cells by Hepatocytes

Upon entering the liver CD8 T cells encounter large numbers of NKT cells patrolling the hepatocyte (HC) surface facing the perisinusoidal space. We asked whether hepatic NKT cells modulate the priming of CD8 T cells by HC. Hepatic (alpha-galactosyl-ceramide-loaded CD1d dimer binding) NKT cells produce predominantly IL-4 when stimulated with glycolipid-presenting HC but predominantly IFN-gamma when stimulated with glycolipid-presenting dendritic cells. These NKT cells prime naive CD8 T cells to a (K(b)-presented) peptide ligand if they simultaneously recognize a CD1d-binding glycolipid presented to them on the surface of the responding CD8 T cells that they prime. No IL-10-producing CD8 T cells are detected if these T cells are primed by either HC or NKT cells. In contrast, IL-10 is produced by HC-primed CD8 T cells if IFN-beta-producing NKT cells are coactivated by the same HC presenting a glycolipid (in the context of CD1d) and an antigenic peptide (in the context of K(b)). Hence, IL-10-producing CD8 T cells are generated in a type I IFN-dependent manner if the three cell types (CD8 T cells, NKT cells, and ligand-presenting HC) specifically and closely interact. IL-10-producing CD8 T cells generated under these conditions down-modulate IL-2 (and proliferative) responses of naive CD4 or CD8 T cells primed by DC. If in close proximity, NKT cells can thus locally modulate the phenotype of CD8 T cells during their priming by HC thereby limiting the local activation of proinflammatory immune effector cells and protecting the liver against immune injury.

THE EFFECT OF ROFLUMILAST ON HUMAN INFLAMMATORY CELLS RELEVANT TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND ASTHMA

PURPOSE: Chronic airway inflammation is the key characteristic common to COPD and asthma. However, different cellular mechanisms are involved in the pathophysiology of both airway diseases. In COPD, prominent pro-inflammatory effector cells are CD8+ T-cells, neutrophils, and macrophages, whereas in asthma, CD4+ T-cells, eosinophils, and dendritic cells are relevant to the inflammatory process. Phosphodiesterase 4 (PDE4) is expressed in all inflammatory cells and degrades cAMP, an intracellular modulator of various pro-inflammatory responses. Thus, PDE4 inhibition represents a key target for anti-inflammatory therapies. We examined the in vitro effects of roflumilast, an investigational PDE4 inhibitor, on human inflammatory cells.

MAST CELLS AS “TUNABLE” EFFECTOR AND IMMUNOREGULATORY CELLS: Recent Advances

This review focuses on recent progress in our understanding of how mast cells can contribute to the initiation, development, expression, and regulation of acquired immune responses, both those associated with IgE and those that are apparently expressed independently of this class of Ig. We emphasize findings derived from in vivo studies in mice, particularly those employing genetic approaches to influence mast cell numbers and/or to alter or delete components of pathways that can regulate mast cell development, signaling, or function. We advance the hypothesis that mast cells not only can function as proinflammatory effector cells and drivers of tissue remodeling in established acquired immune responses, but also may contribute to the initiation and regulation of such responses. That is, we propose that mast cells can also function as immunoregulatory cells. Finally, we show that the notion that mast cells have primarily two functional configurations, off (or resting) or on (or activated for extensive mediator release), markedly oversimplifies reality. Instead, we propose that mast cells are "tunable," by both genetic and environmental factors, such that, depending on the circumstances, the cell can be positioned phenotypically to express a wide spectrum of variation in the types, kinetics, and/or magnitude of its secretory functions.

Cerivastatin and atorvastatin inhibit IL-3-dependent differentiation and IgE-mediated histamine release in human basophils and downmodulate expression of the basophil-activation antigen CD203c/E-NPP3.

Recent data suggest that the statins, apart from their lipid-lowering activity, exhibit profound anti-inflammatory effects. Basophils are major proinflammatory effector cells in diverse pathologic reactions. We have examined the in vitro effects of five different statins on primary human basophils, their progenitors, and the basophil cell line KU-812. Preincubation of blood basophils with cerivastatin or atorvastatin (0.1-100 microM) for 24 h reduced their capacity to release histamine on immunoglobulin E (IgE)-dependent stimulation in a dose-dependent manner. These statins also inhibited IgE-dependent up-regulation of the basophil-activation antigen CD203c. Moreover, both statins suppressed interleukin-3-induced differentiation of basophils from their progenitors as well as (3)H-thymidine uptake in KU-812 cells. All inhibitory effects of cerivastatin and atorvastatin were reversed by mevalonic acid (200 microM). The other statins tested (lovastatin, simvastatin, pravastatin) did not show significant inhibitory effects on basophils. Together, these data identify cerivastatin and atorvastatin as novel inhibitors of growth and activation of human basophils.