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Immunomodulatory Cytokines (immunomodulatory + cytokine)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

Immunomodulatory cytokines determine the outcome of Japanese encephalitis virus infection in mice

JOURNAL OF MEDICAL VIROLOGY, Issue 2 2010
S.M. Biswas
Abstract Japanese encephalitis virus (JEV) induces an acute infection of the central nervous system, the pathogenic mechanism of which is not fully understood. To investigate host response to JEV infection, 14-day-old mice were infected via the extraneural route, which resulted in encephalitis and death. Mice that received JEV immune splenocyte transfer were protected from extraneural JEV infection. Pathology and gene expression profiles were then compared in brains of mice that either succumbed to JEV infection or were protected from infection by JEV immune cell transfer. Mice undergoing progressive JEV infection had increased expression of proinflammatory cytokines, chemokines, and signal transducers associated with the interferon (IFN) pathway. In contrast, mice receiving immune cell transfer had increased production of the Th2 cytokine IL-4, and of IL-10, with subdued expression of IFN-,. We observed IL-10 to be an important factor in determining clinical outcome in JEV infection. Data obtained by microarray analysis were further confirmed by quantitative RT-PCR. Together, these data suggest that JEV infection causes an unregulated inflammatory response that can be countered by the expression of immunomodulatory cytokines in mice that survive lethal infection. J. Med. Virol. 82:304,310, 2010. © 2009 Wiley-Liss, Inc. [source]

Regulation of IL-4 production in mast cells: a paradigm for cell-type-specific gene expression

IMMUNOLOGICAL REVIEWS, Issue 1 2001
Deborah L. Weiss
Summary: The role of interleukin (IL)-4 as an important immunomodulatory cytokine is well established. IL-4 exhibits a highly restricted pattern of expression by cells of distinct lineages. The cell types that produce IL-4 are located in anatomically distinct locations (e.g. circulating T cells vs. fixed tissue mast cells) and thus have access to different IL-4-responsive target cells. In addition, these cells appear to regulate IL-4 expression in cell-type-specific ways. These findings suggest that an understanding of IL-4 gene regulation in T and mast cells could provide the means to specifically control IL-4 release in a lineage- and site-specific manner. In this article we review the current knowledge regarding the cell-type specific regulation of IL-4 gene expression in mast cells and compare this to what has been defined in T cells. We show that there are distinct yet parallel events that control developmentally determined chromatin modifications, allowing accessibility of the locus, and provide the potential for transcription. In differentiated cells, a subset of unique cell activation signals initiates the cascade of events that lead to transcriptional activation of the IL-4 gene. This work was supported by the National Science Foundation (DLW), the National Institutes of Health and the Multiple Sclerosis Society (MAB). We appreciate the technical and intellectual contributions of many colleagues including Doris Powell, John Hural, Tammy Nachman, Ben Hock, David Tara, Greg Henkel, Susan Lee, Millie Kwan, Melanie Sherman and Ginny Secor. [source]

Histamine and prostaglandin E2 up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-,-induced CXCL10 production by immature human dendritic cells

IMMUNOLOGY, Issue 4 2006
Anne McIlroy
Summary Effector memory T helper 2 (Th2) cells that accumulate in target organs (i.e. skin or bronchial mucosa) have a central role in the pathogenesis of allergic disorders. To date, the factors that selectively trigger local production of Th2-attracting chemokines remain poorly understood. In mucosa, at the sites of allergen entry, immature dendritic cells (DC) are in close contact with mast cells. Histamine and prostaglandin E2 (PGE2) are two mediators released by allergen-activated mast cells that favour the polarization of maturing DC into Th2-polarizing cells. We analysed here the effects of histamine and PGE2 on the prototypic, Th2-(CCL17, CCL22) versus Th1-(CXCL10) chemokine production by human DC. We report that histamine and PGE2 dose-dependently up-regulate CCL17 and CCL22 by monocyte-derived immature DC. These effects were potentiated by tumour necrosis factor-,, still observed in the presence of the Th1-cytokine interferon-, (IFN-,) and abolished by the immunomodulatory cytokine interleukin-10. In addition, histamine and PGE2 down-regulated IFN-,-induced CXCL10 production by monocyte-derived DC. These properties of histamine and PGE2 were observed at the transcriptional level and were mediated mainly through H2 receptors for histamine and through EP2 and EP4 receptors for PGE2. Finally, histamine and PGE2 also up-regulated CCL17 and CCL22 and decreased IFN-,-induced CXCL10 production by purified human myeloid DC. In conclusion, these data show that, in addition to polarizing DC into mature cells that promote naïve T-cell differentiation into Th2 cells, histamine and PGE2 may act on immature DC to trigger local Th2 cell recruitment through a selective control of Th1/Th2-attracting chemokine production, thereby contributing to maintain a microenvironment favourable to persistent immunoglobulin E synthesis. [source]

Inhibition of p38 MAP kinase during cellular activation results in IFN-,-dependent augmentation of IL-12 production by human monocytes/macrophages

CLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 1 2001
J. B. Marriott
Interleukin-12 (IL-12) is a key immunomodulatory cytokine produced by antigen-presenting cells that promotes cellular immunity and enables the generation of protective immunity against intracellular pathogens and tumours. Therefore, modulation of IL-12 activity is a primary immunotherapeutic goal. However, little is known about its regulation. Signalling via p38 MAPK has been implicated in the control of inflammatory responses and is therefore a potential therapeutic target. We have used the highly selective p38 MAPK inhibitor (SB203580) to examine the effect of this pathway on the production of IL-12. Surprisingly, we found that SB203580 strongly up-regulated LPS induced IL-12p40 at the protein (intracellular and secreted) and mRNA levels in PBMC cultures. The effect on IL-12 was apparent using both T cell-independent and T cell-dependent stimuli but not in unstimulated cultures, indicating that activation signals are required. Furthermore, the production of IFN- , by T cells is crucial as production was not increased in LPS-stimulated, purified adherent monocytes/macrophages without the addition of exogenous IFN- ,. These results provide evidence that p38 MAPK has an unexpected suppressive effect on IL-12p40 gene transcription, and suggests interplay between p38 MAPK- and IFN- , -mediated signals in the regulation of IL-12 production by monocytes/macrophages. Furthermore, the importance of IL-12 as a key immunoregulatory cytokine suggests that the clinical application of pyrinidyl imidazole inhibitors, such as SB203580, may need to be reassessed. [source]

Immunomodulatory cytokines determine the outcome of Japanese encephalitis virus infection in mice

Quantitative Analysis of Inflammatory and Immune Responses in Dogs with Gastritis and Their Relationship to Helicobacter spp.

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2005
Infection
The present study sought to quantitatively examine mucosal inflammatory and immune responses in dogs with gastritis and the relationship of these responses to infection with Helicobacter. Gastric biopsies from 30 dogs were evaluated for B- and T-lymphocytes, neutrophils, eosinophils, macrophages, and mast cells. Mucosal atrophy, fibrosis, cellularity, and severity of gastritis were graded qualitatively. Messenger-RNA (mRNA) for actin, interleukin-1, (IL-1,), IL-4, IL-8, and IL-10, transforming growth factor beta (TGF-,), and interferon gamma (IFN-,) was quantified by polymerase chain reaction (PCR). The presence of Helicobacter spp. was determined by urease activity, histology, PCR, and enzyme-linked immunosorbent assay. mRNA for IL-1,, IL-8, IL-10, TGF-,, and IFN-, was detected in most dogs. IL-4 mRNA was detected in only 1 dog. Correlations were observed for IL-1, versus IL-8 and IL-10; IL-8 versus IL-10, IFN-,, and TGF-,; and IL-10 versus IFN-,. Mucosal pathology was related to cytokine mRNA expression (neutrophils to IL-8 and IFN-,, macrophages and lymphocytes to IFN-,, and fibrosis to IL-1,). Gastritis was categorized as lymphoplasmacytic in all dogs, and its histologic severity correlated with atrophy, infiltration with lymphocytes and macrophages, and expression of IL-10 and IFN-,. Of the dogs examined, 76.7% were infected with Helicobacter spp. Infection was associated with increased expression of TGF-, and fibrosis. Circulating anti- Helicobacter immunoglobulin G titers were higher in uninfected than infected dogs. We conclude that lymphoplasmacytic gastritis in dogs is characterized by concurrent activation of proinflammatory and immunomodulatory cytokines, with increased mRNA expression related to mucosal pathology. No significant associations between Helicobacter infection and proinflammatory cytokine expression, severity of gastritis, or differences in the pathogenicity of different Helicobacter spp. were found. [source]

Whole-body UVB (TL-01) or UVA-1 irradiation does not alter the levels of immunomodulatory cytokines in the serum of human volunteers

PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 2 2004
P. Mcloone
Background/Purpose: Ultraviolet (UV) exposure of mammalian skin induces local and systemic immunosuppression. In mice it has been proposed that systemic immunosuppression is mediated by an UV-induced cytokine cascade involving systemic interleukin (IL)-4 and IL-10 and a reduction in IL-12 activity. To investigate whether there was a parallel mechanism in humans we examined the effect of whole-body narrowband ultraviolet B (UVB) (311,313 nm; TL-01) and ultraviolet A (UVA)-1 (340,400 nm) on serum cytokine levels. Methods/Results: In a first study, five male psoriatic subjects were whole-body irradiated with three sessions of a standard UVB (TL-01) phototherapy regimen previously shown to cause downregulation of natural killer cell activity and T helper 1 (Th1) and Th2 cytokine production by peripheral blood mononuclear cells. Enzyme-linked immunoabsorbent assay (ELISA) of sera taken before and after the third session showed no effect of phototherapy on IL-10 and tumour necrosis factor-, (TNF-,). In a second study, five healthy subjects received three whole-body exposures of UVB (TL-01) and five other healthy subjects received three exposures of UVA-1 on alternate days (total 22 J/cm2). Blood samples were taken before the first irradiation and at 0, 4, 8, 12, 14, 24 and 48 h after the third irradiation. The sera were subsequently analysed for IL-10, IL-12, IL-8, IL-1, and TNF-,, by ELISA. The levels of IL-1, and TNF-, were below detection limits (<5 pg/ml), while no significant change in the levels of IL-10, IL-12 or IL-8 was detected as a result of either TL-01 or UVA-1. Conclusion: It seems unlikely that a modulation in these circulating cytokines assessed in this study accounts for systemic UV-induced immunosuppression in human subjects. [source]

Invariant natural killer T cells are natural regulators of murine spondylarthritis

ARTHRITIS & RHEUMATISM, Issue 4 2010
Peggy Jacques
Objective To investigate the role of invariant natural killer T (iNKT) cells in TNF,ARE/+ mice, an animal model of spondylarthritis (SpA) with both gut and joint inflammation. Methods The frequency and activation of iNKT cells were analyzed on mononuclear cells from the lymph nodes and livers of mice, using flow cytometry with ,-galactosylceramide/CD1d tetramers and quantitative polymerase chain reaction for the invariant V,14,J,18 rearrangement. Bone marrow,derived dendritic cells (DCs) were obtained by expansion of primary cells with granulocyte,macrophage colony-stimulating factor followed by coculture with iNKT cell hybridomas, and interleukin-2 release into the cocultures was then measured by enzyme-linked immunosorbent assay (ELISA). Cytokine levels were determined by ELISA or cytometric bead array analyses of freshly isolated DCs and iNKT cells in mixed cocultures. TNF,ARE/+ mice were backcrossed onto J,18,/, and CD1d,/, mice, and disease onset was evaluated by clinical scoring, positron emission tomography, and histology. CD1d levels were analyzed on mononuclear cells in paired blood and synovial fluid samples from patients with SpA compared with healthy control subjects. Results In the absence of iNKT cells, symptoms of gut and joint inflammation in TNF,ARE/+mice were aggravated. Invariant NKT cells were activated during the course of the disease. This was linked to an enrichment of inflammatory DCs, characterized by high levels of CD1d, particularly at draining sites of inflammation. A similar increase in CD1d levels was observed on DCs from patients with SpA. Inflammatory DCs from TNF,ARE/+ mice stimulated iNKT cells to produce immunomodulatory cytokines, in the absence of exogenous stimulation. Prolonged, continuous exposure, but not short-term exposure, to tumor necrosis factor (TNF) was found to be responsible for the enhanced DC,NKT cell crosstalk. Conclusion This mode of iNKT cell activation represents a natural counterregulatory mechanism for the dampening of TNF-driven inflammation. [source]

CD4+CD25+FoxP3+ regulatory T cells are increased whilst CD3+CD4,CD8,,,TCR+ Double Negative T cells are decreased in the peripheral blood of patients with multiple myeloma which correlates with disease burden

BRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2009
Sylvia Feyler
Summary Increased levels of naturally occurring regulatory T cells (TReg cells) have been found in a variety of solid tumours and haematological malignancies. In multiple myeloma (MM), evidence suggests that TReg cells are increased though controversy exists with regards to their function and no relationship to disease stage and treatment has been demonstrated. Here, we demonstrate significantly elevated levels of functional CD4+CD25+FoxP3+ TReg cells in a large cohort of patients with MM as well as monoclonal gammopathy of uncertain significance (MGUS) in comparison to age-matched, healthy controls. The frequency of Double Negative TReg cells was also evaluated, demonstrating that these cells were reduced in patients with MM. Furthermore, a characteristic profile of immunomodulatory cytokines in the peripheral blood and bone marrow of patients with MM and MGUS was demonstrated, compared with healthy controls. This data adds further evidence to the understanding of the role of TReg cell subsets in tumour immunology and the fundamentals of the host/tumour immune conflict. [source]

Gene therapy for posterior uveitis

ACTA OPHTHALMOLOGICA, Issue 2009
AD DICK
Purpose To investigate the role of gene therapy incorporating release of immunomodulatory cytokines in animal models of intraocular inflammation Methods By inoculating with either AAV or lente viruses incorporating genes for IL-1RA or IL-10 into either the anterior chamber or subretinally we onserved the ability to suppress either endotoxin induced uveitis (EIU) or experimental autoimmiune uveoretinitis (EAU). Results Anterior chamber inoculation with lente-IL-10 or IL-1RA successfully suppresses inflammation and protein exudation into the eye during the course of EIU. Subretinal injection of AAV-IL-10 suppresses EAU. The extent of local macrophage activation is also suppressed as there is marked reduction in nitrotyrosine expression within the retina. Conclusion Gene therapy with immunomodulatory cytokines offers a potential to suppress active inflammatory processes within the retina. Mechanisms will be discussed in the talk in relation to macrophage activation and restoring myeloid cell (microgolial) homeostasis within the retina. [source]