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Anti-inflammatory Molecules (anti-inflammatory + molecule)
Selected AbstractsTherapeutic benefit of pentostatin in severe IL-10,/, ColitisINFLAMMATORY BOWEL DISEASES, Issue 7 2008Jeffrey B. Brown MD Abstract Background: Pentostatin, an adenosine deaminase (ADA) inhibitor, is a purine antimetabolite used for the treatment of leukemias. ADA inhibition blunts expansion of proliferating lymphocytes and increases adenosine release, a potent anti-inflammatory molecule. Human inflammatory bowel disease (IBD) is driven by expansion of effector T cells (Teff) that overwhelm reulatory T cells (Treg) and propagate innate immune reponses. Here we study the therapeutic benefits of ADA inhibition to impair Teff cell expansion and reduce inflammatory cytokine release in IL-10-deficient (IL-10 -/- ) mice. Methods: Colitis was induced in IL-10 -/- mice by administering piroxicam for two weeks. Mice were treated with daily pentostatin or phosphate-buffered saline for 1 week and effects on tissue inflammation, lymphocyte numbers and cytokine production examined. Results: Pentostatin reduced inflammation by >50% and nearly normalized serum amyloid A levels. Lymphocyte expansions in the colon and mesenteric lymph node (MLN) (3.5-fold and >5-fold respectively) dropped by >50-90%. Pro-inflammatory factors in the colon and MLN (IL-1,, IFN-,, IL-6, CXCL10, TNF) dropped whereas FoxP3 and TGF-, were unchanged. Reductions in cytokine production from equivalent numbers of T cells from pentostatin-treated mice after in vitro (36h) or in vivo (3h) activation suggested anti-inflammatory effects of pentostatin independent of lymphodepletion contributed to its therapeutic benefit. Analysis of mucosal lymphocyte subsets suggested pentostatin reduced numbers of effector CD4+ CD69+ T cells, while sparing CD4+ CD62L+ T cells. Conclusions: Pentostatin dosages that avoid severe lymphocyte depletion effectively treat colitis by impairing Teff cell expansion and reducing pro-inflammatory cytokine production while preserving regulatory Treg populations and function. (Inflamm Bowel Dis 2008) [source] Copolymer effects on microglia and T,cells in the central nervous system of humanized miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2005Zsolt Illes The random amino acid copolymers FYAK and VWAK ameliorate EAE in a humanized mouse model expressing both a human transgenic myelin basic protein (MBP)85,99-specific T,cell receptor and HLA-DR2. Here we show that microglia isolated from the central nervous system (CNS) of humanized mice with EAE induced by MBP85,99 and treated with these copolymers had reduced expression of HLA-DR, and thus reduced capacity to present MBP85,99 and activate transgenic T,cells. In vitro microglia up-regulated empty HLA-DR2 upon activation with GM-CSF with or without LPS or IFN-,, but not with IL-4 or IL-10. Correspondingly, gene chip arrays showed that the CNS of untreated and YFAK-treated mice differentially expressed pro- and anti-inflammatory molecules during MBP85,99-induced EAE. Interestingly, microglia expressed the full-length ,,,and ,,,subunits of the tetrameric adaptor protein complexes AP-1 and AP-2 respectively, but after treatment with GM-CSF these complexes were cleaved, as had been found in immature dendritic cells derived from bone marrow. Strikingly, in vivo the perivascular lymphocyte infiltration seen in untreated mice immunized with MBP85,99 was composed of equal numbers of hV,2+ MPB85,99-specific transgenic and hV,2, endogenous T,cells, while the much smaller infiltration seen after treatment with YFAK was composed predominantly of hV,2, endogenous T,cells. [source] Analysis of peripheral blood T-cell subsets, natural killer cells and serum levels of cytokines in children with Down syndromeINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 4 2010S. Cetiner Summary The objective of this study was to evaluate the relationship between humoral and cell-mediated immune response parameters and impairment of immune functions in children with Down syndrome (DS). The patient group was consisted of cytogenetically documented 32 children with DS. Lymphocyte subsets and natural killer cells were counted by flow-cytometry system. Levels of interleukin (IL)-1,, IL-2, IL-4, IL-6, IL-8, IL-10 and tumour necrosis factor-alpha (TNF-,) were detected by enzyme-linked immunosorbent assay method. Serum IgG, IgM, IgA levels were measured by turbidimetric methods. The percentage of CD8+ lymphocytes and CD56+ cells of patients with DS were significantly higher, whereas CD20+ lymphocytes were lower than that of controls (P < 0.05). The percentage of CD2 and CD4 levels and CD4/CD8 ratio of patients with DS and normal controls were similar (P > 0.05). Levels of IL-4 and IL-10 were significantly increased, but IL-6 and TNF-, levels were decreased in children with DS (P < 0.05). Levels of other studied cytokines between patients with DS and controls were not statistically different (P > 0.05, for all). Serum IgG, IgM and IgA levels were found to be similar between the groups (P > 0.05). It has been known that IL-4 and IL-10 are anti-inflammatory molecules which inhibit the synthesis of proinflammatory cytokines such as IL-6 and TNF-,. In this study, levels of IL-4 and IL-10 were significantly increased, but IL-6 and TNF-, levels were decreased in children with DS. These results may suggest that continuing anti-inflammatory state in DS and this process may explain the cause of recurrent infection of the disease. On the other hand, in contrast to the low percentage of CD20+ cells, high percentage of CD8+ and CD56+ cells were found. Our findings may demonstrate that the cell-mediated and humoral immune system parameters in children with DS were altered according to healthy children. [source] Differential gene expression in LPS/IFN, activated microglia and macrophages: in vitro versus in vivoJOURNAL OF NEUROCHEMISTRY, Issue 2009Christoph D. Schmid Abstract Two different macrophage populations contribute to CNS neuroinflammation: CNS-resident microglia and CNS-infiltrating peripheral macrophages. Markers distinguishing these two populations in tissue sections have not been identified. Therefore, we compared gene expression between LPS (lipopolysaccharide)/interferon (IFN),-treated microglia from neonatal mixed glial cultures and similarly treated peritoneal macrophages. Fifteen molecules were identified by quantative PCR (qPCR) as being enriched from 2-fold to 250-fold in cultured neonatal microglia when compared with peritoneal macrophages. Only three of these molecules (C1qA, Trem2, and CXCL14) were found by qPCR to be also enriched in adult microglia isolated from LPS/IFN,-injected CNS when compared with infiltrating peripheral macrophages from the same CNS. The discrepancy between the in vitro and in vivo qPCR data sets was primarily because of induced expression of the ,microglial' molecules (such as the tolerance associated transcript, Tmem176b) in CNS-infiltrating macrophages. Bioinformatic analysis of the ,19000 mRNAs detected by TOGA gene profiling confirmed that LPS/IFN,-activated microglia isolated from adult CNS displayed greater similarity in total gene expression to CNS-infiltrating macrophages than to microglia isolated from unmanipulated healthy adult CNS. In situ hybridization analysis revealed that nearly all microglia expressed high levels of C1qA, while subsets of microglia expressed Trem2 and CXCL14. Expression of C1qA and Trem2 was limited to microglia, while large numbers of GABA+ neurons expressed CXCL14. These data suggest that (i) CNS-resident microglia are heterogeneous and thus a universal microglia-specific marker may not exist; (ii) the CNS micro-environment plays significant roles in determining the phenotypes of both CNS-resident microglia and CNS-infiltrating macrophages; (iii) the CNS microenvironment may contribute to immune privilege by inducing macrophage expression of anti-inflammatory molecules. [source] Noradrenergic depletion increases inflammatory responses in brain: effects on I,B and HSP70 expressionJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Michael T. Heneka Abstract The inflammatory responses in many cell types are reduced by noradrenaline (NA) binding to ,-adrenergic receptors. We previously demonstrated that cortical inflammatory responses to aggregated amyloid beta (A,) are increased if NA levels were first depleted by lesioning locus ceruleus (LC) noradrenergic neurons, which replicates the loss of LC occurring in Alzheimer's disease. To examine the molecular basis for increased responses, we used the selective neurotoxin DSP4 to lesion the LC, and then examined levels of putative anti-inflammatory molecules. Inflammatory responses were achieved by injection of aggregated A,1,42 peptide and IL-1, into frontal cortex, which induced neuronal inducible nitric oxide synthase (iNOS) and microglial IL-1, expression. DSP4-treatment reduced basal levels of nuclear factor kappa B (NF-,B) inhibitory I,B proteins, and of heat shock protein (HSP)70. Inflammatory responses were prevented by co-injection (ibuprofen or ciglitzaone) or oral administration (pioglitazone) of peroxisome proliferator-activated receptor gamma (PPAR,) agonists. Treatment with PPAR, agonists restored I,B,, I,B,, and HSP70 levels to values equal or above those observed in control animals, and reduced activation of cortical NF-,B. These results suggest that noradrenergic depletion reduces levels of anti-inflammatory molecules which normally limit cortical responses to A,, and that PPAR, agonists can reverse that effect. These findings suggest one mechanism by which PPAR, agonists could provide benefit in neurological diseases having an inflammatory component. [source] Novel role of TGF-, in differential astrocyte-TIMP-1 regulation: Implications for HIV-1-dementia and neuroinflammationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 7 2006Alok Dhar Abstract Astrocyte production of tissue inhibitor of metalloproteinase (TIMP)-1 is important in central nervous system (CNS) homeostasis and inflammatory diseases such as HIV-1-associated dementia (HAD). TIMPs and matrix metalloproteinases (MMPs) regulate the remodeling of the extracellular matrix. An imbalance between TIMPs and MMPs is associated with many pathologic conditions. Our recently published studies uniquely demonstrate that HAD patients have reduced levels of TIMP-1 in the brain. Astrocyte-TIMP-1 expression is differentially regulated in acute and chronic inflammatory conditions. In this and the adjoining report (Gardner et al., 2006), we investigate the mechanisms that may be involved in differential TIMP-1 regulation. One mechanism for TIMP-1 downregulation is the production of anti-inflammatory molecules, which can activate signaling pathways during chronic inflammation. We investigated the contribution of transforming growth factor (TGF)-signaling in astrocyte-MMP/TIMP-1-astrocyte regulation. TGF-,1 and ,2 levels were upregulated in HAD brain tissues. Co-stimulation of astrocytes with IL-1, and TGF-, mimicked the TIMP-1 downregulation observed with IL-1, chronic activation. Measurement of astrocyte-MMP protein levels showed that TGF-, combined with IL-1, increased MMP-2 and decreased proMMP-1 expression compared to IL-1, alone. We propose that one of the mechanisms involved in TIMP-1 downregulation may be through TGF-signaling in chronic immune activation. These studies show a novel extracellular regulatory loop in astrocyte-TIMP-1 regulation. © 2006 Wiley-Liss, Inc. [source] Glial reactions in Parkinson's diseaseMOVEMENT DISORDERS, Issue 4 2008Patrick L. McGeer MD Abstract Dopaminergic neurons of the substantia nigra are particularly vulnerable to oxidative and inflammatory attack. Such processes may play a crucial role in the etiology of Parkinson disease (PD). Since glia are the main generators of these processes, the possibility that PD may be caused by glial dysfunction needs to be considered. This review concentrates on glial reactions in PD. Reactive astrocytes and reactive microglia are abundant in the substantia nigra (SN) of PD cases indicating a robust inflammatory state. Glia normally serve neuroprotective roles but, given adverse stimulation, they may contribute to damaging chronic inflammation. Microglia, the phagocytes of brain, may be the main contributors since they can produce large numbers of superoxide anions and other neurotoxins. Their toxicity towards dopaminergic neurons has been demonstrated in tissue culture and various animal models of PD. The MPTP and ,-synuclein models are of particular interest. Years after exposure to MPTP, inflammation has been observed in the SN. This has established that an acute insult to the SN can result in a sustained local inflammation. The ,-synuclein model indicates that an endogenous protein can induce inflammation, and, when overexpressed, can lead to autosomal dominant PD. Less is known about the role of astrocytes than microglia, but they are known to secrete both inflammatory and anti-inflammatory molecules and may play a role in modulating microglial activity. Oligodendrocytes do not seem to play a role in promoting inflammation although, like neurons, they may be damaged by inflammatory processes. Further research concerning glial reactions in PD may lead to disease-modifying therapeutic approaches. © 2007 Movement Disorder Society [source] Structure of mouse IP-10, a chemokineACTA CRYSTALLOGRAPHICA SECTION D, Issue 6 2008Talat Jabeen Interferon-,-inducible protein (IP-10) belongs to the CXC class of chemokines and plays a significant role in the pathophysiology of various immune and inflammatory responses. It is also a potent angiostatic factor with antifibrotic properties. The biological activities of IP-10 are exerted by interactions with the G-protein-coupled receptor CXCR3 expressed on Th1 lymphocytes. IP-10 thus forms an attractive target for structure-based rational drug design of anti-inflammatory molecules. The crystal structure of mouse IP-10 has been determined and reveals a novel tetrameric association. In the tetramer, two conventional CXC chemokine dimers are associated through their N-terminal regions to form a 12-stranded elongated ,-sheet of ,90,Å in length. This association differs significantly from the previously studied tetramers of human IP-10, platelet factor 4 and neutrophil-activating peptide-2. In addition, heparin- and receptor-binding residues were mapped on the surface of IP-10 tetramer. Two heparin-binding sites were observed on the surface and were present at the interface of each of the two ,-sheet dimers. The structure supports the formation of higher order oligomers of IP-10, as observed in recent in vivo studies with mouse IP-10, which will have functional relevance. [source] Immune responses to gene therapy vectors in the context of corneal transplantationACTA OPHTHALMOLOGICA, Issue 2009T RITTER Purpose The genetic engineering of grafts or cells prior to transplantation is an attractive approach to protect the graft from allogeneic rejection. Virus vector-based gene therapy is a promising method for successful ex-vivo gene transfer however, the induction of an immune response against gene-modified tissues raises concern. Methods Different virus families (Adenovirus, Retrovirus, Adeno-associated virus, Herpesvirus) have been studied as gene therapy vehicles for the delivery of therapeutic molecules. Moreover, different serotypes or envelope proteins have been used to modulate transduction efficiencies of target cells or to evade pre-existing immunity. Results Here we review gene therapeutic applications using viral vectors in the context of cornea transplantation. Both local and systemic expression of immunomodulatory molecules have led to the prevention of corneal graft rejection. However, different results have been obtained with regard to the induction of immune responses after local or systemic expression of the gene therapy vector. Not surprisingly over-expression of anti-inflammatory molecules not only modulated allograft rejection but also influenced the immune response against the viral vector and virally transduced cells. Conclusion Recent clinical trials indicate that the application of viral vectors in ophthalmology is promising however, the generation of immune responses against the viral vector or virally transduced cells are still a serious obstacle for a broader application of gene therapy. Supported by Deutsche Forschungsgemeinschaft (DFG Pl 150/14-1 and Ri 764/10-1) and Science Foundation of Ireland (SFI 06/RFP/BIC056 and SFI 07/IN.1/B925) [source] | |||||||||||||