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ABSTRACT: IL-10 is an anti-inflammatory cytokine that plays a significant role in controlling inflammation and modulating adaptive immune responses that cause tissue damage. IL-10-producing lymphocytes contribute to the delicate balance between inflammation and immunoregulation, and are thus regarded as a kind of "regulatory cells." Dysregulation of these cells is linked with susceptibility to numerous inflammatory diseases. In this review, we summarized what is known about the regulatory effects of IL-10 produced by lymphocytes, including T cells, B cells and natural killer cells, in inflammatory diseases. We hope to augment immune responses or prevent immunopathology through making some small changes in the levels of IL-10 produced by lymphocytes, or in the cellular location where it is produced.
International Reviews Of Immunology 04/2013; · 3.43 Impact Factor
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ABSTRACT: Cigarette smoke exposure markedly compromises the ability of the immune system to protect against invading pathogens and tumorigenesis. Nicotine is a psychoactive component of tobacco products that acts as does the natural neurotransmitter, acetylcholine, on nicotinic receptors (nAChRs). Here we demonstrate that natural killer (NK) cells strongly express nAChR β2. Nicotine exposure impairs the ability of NK cells to kill target cells and release cytokines, a process that is largely abrogated by nAChR β2 deficiency. Further, nicotinic suppression of NF-κB-induced transcriptional activity in NK cells is dependent on nAChR β2. This nAChR subtype also plays a large role in the NK cell-mediated control of melanoma lung metastasis, in a murine lung metastasis model exposed to nicotine. Our findings suggest nAChR β2 as a prominent pathway for nicotine induced impairment of NK cell functions which contributes to the occurrence of smoking-related pathologies.
PLoS ONE 01/2013; 8(2):e57495. · 4.09 Impact Factor
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ABSTRACT: A prominent clinical symptom in multiple sclerosis (MS), a progressive disorder of the central nervous system (CNS) due to heightened neuro-inflammation, is learning and memory dysfunction. Here, we investigated the effects of a ketogenic diet (KD) on memory impairment and CNS-inflammation in a murine model of experimental autoimmune encephalomyelitis (EAE), using electrophysiological, behavioral, biochemical and in vivo imaging approaches. Behavioral spatial learning deficits were associated with motor disability in EAE mice, and were observed concurrently with brain inflammation. The KD improved motor disability in the EAE model, as well as CA1 hippocampal synaptic plasticity (long-term potentiation) and spatial learning and memory (assessed with the Morris Water Maze). Moreover, hippocampal atrophy and periventricular lesions in EAE mice were reversed in KD-treated EAE mice. Finally, we found that the increased expression of inflammatory cytokines and chemokines, as well as the production of reactive oxygen species (ROS), in our EAE model were both suppressed by the KD. Collectively, our findings indicate that brain inflammation in EAE mice is associated with impaired spatial learning and memory function, and that KD treatment can exert protective effects, likely via attenuation of the robust immune response and increased oxidative stress seen in these animals.
PLoS ONE 01/2012; 7(5):e35476. · 4.09 Impact Factor
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ABSTRACT: Genetic analyses indicate that HLA complex genes can be involved in susceptibility to autoimmune myasthenia gravis (MG). Various HLA alleles serve as genetic elements that either predispose to or protect against MG. This study investigates the probable relationship between HLA-DQ allele polymorphisms and MG cases in northern China. The HLA-DQA1 and DQB1 alleles were determined by polymerase chain reaction/sequence-specific primers (PCR-SSP) in 84 MG patients, and the results were compared to 293 healthy controls. Our findings indicate that DQ A1*0401(P=0.008, OR: 2.5, 95%CI: 1.24-3.07) and B1*0301(P=0.000, OR: 2.29, 95%CI: 1.48-3.54) were the most frequent allele; the frequencies of DQA1*0103(P=0.000, OR:0.24, 95%CI 0.13-0.49) and DQB1*0601(P=0.001, OR:0.40, 95%CI 0.22-0.50) were significantly decreased in MG patients compared with healthy controls. Patients with thymomatous MG were positively associated with DQA1 *0401(P=0.011, OR:4.57, 95% CI 1.40-14.90) and DQB1 *0604 (P=0.001, OR:4.01, 95% CI 1.65-9.73) as compared to MG patients without thymoma. Different genetic mechanisms may exist between MG patients with thymoma and those without thymoma. The HLA-DQ associations in MG subgroups suggest that disease heterogeneity may be influenced by different genes or alleles.
Journal of the neurological sciences 09/2011; 312(1-2):57-61. · 2.32 Impact Factor
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ABSTRACT: This study aims to investigate μ-calpain expression profiles in the anterior temporal neocortex in patients with intractable epilepsy, and to determine whether its pattern of expression is related to pathological changes seen in these patients.
The study subjects consisted of 30 patients with intractable epilepsy and a control group of 10 patients with brain trauma who underwent resection of the anterior temporal lobe. μ-Calpain expression in surgically resected anterior temporal cortices of patients with intractable epilepsy were analyzed using the RT-PCR, Western blot, immunohistochemistry and immunofluorescence staining. GFAP expression was detected by immunohistochemical staining. The related pro-inflammatory cytokines were quantified by elisa. Clinicopathological characteristics were evaluated by HE staining.
Analysis by Western blot and RT-PCR revealed that inactive μ-calpain expression and the calpain-cleaved spectrin fragment in surgically resected anterior temporal cortices of patients with intractable epilepsy were significantly increased compared to the tissues from corresponding regions of the control group. Immunohistological staining demonstrated that μ-calpain was overexpressed in the cell cytoplasm of neurons and glial cells in patients with intractable epilepsy and GFAP was overexpressed in the cell cytoplasm of glial cells in patients with intractable epilepsy. The level of pro-inflammatory cytokines, such as IL-1β, IL-6 and TGF-β1 were significantly increased in patients with intractable epilepsy. HE staining indicated μ-calpain overexpression is an independent prognostic factor for pathological changes such as neuronal loss, neuronal degeneration, gliosis and astrocytosis.
These data suggest that overexpression of μ-calpain is relationship with intractable epilepsy as well as the clinicopathological characteristics in these patients.
Seizure 02/2011; 20(5):395-401. · 1.80 Impact Factor
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Junwei Hao,
Denise Campagnolo,
Ruolan Liu,
Wenhua Piao,
Samuel Shi,
Baoyang Hu,
Rong Xiang,
Qinghua Zhou,
Timothy Vollmer,
Luc Van Kaer,
Antonio La Cava,
Fu-Dong Shi
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ABSTRACT: The role of natural killer (NK) cells in regulating multiple sclerosis (MS) is not well understood. Additional studies with NK cells might provide insight into the mechanism of action of MS therapies such as daclizumab, an antibody against the interleukin (IL)-2R α-chain, which induces expansion of CD56(bright) NK cells.
In a relapsing-remitting form of the experimental autoimmune encephalomyelitis (EAE) model of MS induced in SJL mice, we expanded NK cells with IL-2 coupled with an anti-IL-2 monoclonal antibody (mAb) and evaluated the effects of these NK cells on EAE. Further, we investigated the effect of the human version of IL-2/IL-2 mAb on NK cells from MS patients and its effect on central nervous system (CNS) inflammation and pathology in a human-mouse chimera model and assessed the underlying mechanisms.
IL-2/IL-2 mAb dramatically expands NK cells both in the peripheral lymphoid organs and in the CNS, and attenuates CNS inflammation and neurological deficits. Disease protection is conferred by CNS-resident NK cells. Importantly, the human version of IL-2/IL-2 mAb restored the defective CD56(+) NK cells from MS patients in a human-mouse chimera model. Both the CD56(bright) and CD56(dim) subpopulations were required to attenuate disease in this model.
These findings unveil the immunotherapeutic potential of NK cells, which can act as critical suppressor cells in target organs of autoimmunity. These results also have implications to better understand the mechanism of action of daclizumab in MS.
Annals of Neurology 11/2010; 69(4):721-34. · 11.09 Impact Factor
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ABSTRACT: A considerable number of in vivo studies have demonstrated that the cholinergic system can dampen the peripheral immune response, and it is thought that the α7-nicotinic acetylcholine receptor (nAChR) subtype is a key mediator of this process. The goal of the present study was to determine if nicotine modulates immunological mechanisms known to be involved in the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for CNS autoimmune disease, via α7-nAChRs. Here we show that nicotine exposure attenuates EAE severity and that this effect is largely abolished in nAChR α7 subunit knock-out mice. However, nicotine exposure partially retains the ability to reduce lymphocyte infiltration into the CNS, inhibit auto-reactive T cell proliferation and helper T cell cytokine production, down-regulate co-stimulatory protein expression on myeloid cells, and increase the differentiation and recruitment of regulatory T cells, even in the absence of α7-nAChRs. Diverse effects of nicotine on effector and regulatory T cells, as well as antigen-presenting cells, may be linked to differential expression patterns of nAChR subunits across these cell types. Taken together, our data show that although α7-nAChRs indeed seem to play an important role in nicotine-conferred reduction of the CNS inflammatory response and protection against EAE, other nAChR subtypes also are involved in the anti-inflammatory properties of the cholinergic system.
Experimental Neurology 10/2010; 227(1):110-9. · 4.70 Impact Factor
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ABSTRACT: Natural killer (NK) cells of the innate immune system can profoundly impact the development of adaptive immune responses. Inflammatory and autoimmune responses in anatomical locations such as the central nervous system (CNS) differ substantially from those found in peripheral organs. We show in a mouse model of multiple sclerosis that NK cell enrichment results in disease amelioration, whereas selective blockade of NK cell homing to the CNS results in disease exacerbation. Importantly, the effects of NK cells on CNS pathology were dependent on the activity of CNS-resident, but not peripheral, NK cells. This activity of CNS-resident NK cells involved interactions with microglia and suppression of myelin-reactive Th17 cells. Our studies suggest an organ-specific activity of NK cells on the magnitude of CNS inflammation, providing potential new targets for therapeutic intervention.
Journal of Experimental Medicine 08/2010; 207(9):1907-21. · 13.85 Impact Factor
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ABSTRACT: T-bet, a tissue-specific transcription factor, controls T helper 1 (Th1) cell differentiation and IFN-production. Given the reciprocal relationship between Th1 and other types of helper T cells, we hypothesized that T-bet impacts multiple helper and regulatory T (Treg) cells, thereby influencing the magnitude of autoimmune disease. We tested this hypothesis in an experimental model of autoimmune myasthenia gravis (EAMG) of mice. Myasthenia gravis (MG) and EAMG are T cell-driven, IgG autoantibody-mediated disorders that destroy muscles by attacking the target antigen acetylcholine receptor (AChR) or other antigens of skeletal muscle at neuromuscular junctions. We show that, compared to wild-type mice, AChR-primed T-bet(-/-) mice are less susceptible to EAMG. This phenotype is associated with a reduction of autoreactive Th1 cells and augmentation of Th2 and Th17 cells as well as an upregulation of Foxp3 expression by T-bet(-/-)CD4(+)CD25(+) Treg cells. Thus, in our model, T-bet not only specifies the Th1 lineage but also has a broad influence on autoreactive Th2, Th17 and Treg cells. These coordinated effects reduce the genesis of pathogenic antibodies and protect against B cell-mediated EAMG.
Experimental Neurology 10/2009; 220(2):366-73. · 4.70 Impact Factor
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ABSTRACT: The circulating estrogen concentration elevated gradually along with time after ovariectomy in rats. To explore the source of the increased circulation estrogen, the extragonadal aromatization as well as the synthesis of androgen in the adrenal cortex of the ovariectomized rats was evaluated.
Female rats were divided into twelve groups: 1 month after ovariectomy (OVX1M), OVX2M, OVX3M, OVX4M, OVX5M, OVX6M; intact 1 month (INT1M), INT2M, INT3M, INT4M, INT5M, INT6M. The blood concentration of testosterone (T) was measured by radioimmunoassay. The mRNA expressions of P450 aromatase in the liver and subcutaneous abdominal (SA) adipose as well as the adrenal cytochrome P450 17 alpha hydroxylase/lyase (P450c17) were semiquantified by RT-PCR. The P450 aromatase protein expressions in the liver and SA adipose were detected by Western blot.
The blood E2 concentrations increased gradually along with time after ovariectomy in the rats. The 58-kDa aromatase protein and mRNA expressions normalized to beta-actin in the OVX6M rats' SA adipose tissues showed higher levels than those from corresponding tissues in the INT6M (p < 0.05). And the ratios of aromatase mRNA and protein to beta-actin in the OVX6M rats' liver tissues increased significantly compared with those in the OVX1M rats (p < 0.05). The ratio of adrenal P450c17 to beta-actin in the OVX6M increased markedly, and was higher than OVX1M (p < 0.05), though the blood concentration of T decreased significantly in all the ovariectomized rats (p < 0.05).
Both the subcutaneous abdominal adipose tissues and the liver tissues contributed to the extragonadal aromatisation to promote the circulating E2 levels in the rats along with time after ovariectomy; the adrenal compensation might also be activated naturally.
Reproductive Biology and Endocrinology 02/2005; 3:6. · 2.05 Impact Factor
