Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased blood-brain-barrier (BBB) permeability precedes any clinical or pathologic signs and is critical in the pathogenesis of multiple sclerosis (MS) and brain metastases. CD4+ TH1 cells mediate demyelination in MS, but how they get sensitized and enter the brain to induce brain inflammation remains obscure. TH2 cytokines associated with allergic disorders have recently been implicated in MS, while genes upregulated in MS plaques include the mast cell-specific tryptase, the IgE receptor (Fc-epsilon-RI) and the histamine-1 receptor. Mast cell specific tryptase is elevated in the CSF of MS patients, induces microvascular leakage and stimulates protease-activated receptors (PAR), leading to widespread inflammation. BBB permeability, MS and brain metastases appear to worsen in response to acute stress that leads to the local release of corticotropin-releasing hormone (CRH), which activates brain mast cells to selectively release IL-6, IL-8 and vascular endothelial growth factor (VEGF). Acute stress increases BBB permeability that is dependent on CRH and mast cells. Acute stress shortens the time of onset of experimental alleric encephalomyelitis (EAE) that does not develop in W/W mast cell deficient or CRH -/- mice. Brain mast cell inhibition and CRHR antagonists offer novel therapeutic possibilities.
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PMID:Corticotropin-releasing hormone and the blood-brain-barrier. 1712 8

The blood brain barrier (BBB) is composed of specialized endothelial cells tightly anastomosed to one another and surrounded by a thick extracellular matrix, the basement membrane. Together these components restrict the diffusion of cells and molecules from the periphery into the central nervous system (CNS), providing immune privilege and homeostasis. Dysregulation of the BBB and trans-endothelial migration of immune cells are amongst the earliest CNS changes partaking in lesion formation in multiple sclerosis (MS). Death receptors are members of the tumor necrosis factor receptor (TNFR) super-family. They are expressed on a variety of tissues including endothelium, but the consequence of their triggering appears to be cell type specific. In this study, we describe the expression of death receptors TNFR1, Fas and DR5 on primary cultures of human BBB-derived endothelial cells (ECs), as well as the effects of receptor activation on human brain endothelial cell (HBEC) function. We show that HBECs are resistant to cell death mediated via TNFalpha, FasL and TRAIL and that neither receptor ligation induces cellular proliferation of HBECs. TNFR1 ligation induces NFkappaB activation and the upregulation of chemokines MCP-1 and IL-8, as well as adhesion molecules ICAM-1 and VCAM-1, while Fas and DR5 triggering activate the extracellular signal regulated kinases-1 and -2 (Erk 1/2, p42/44 MAPK) inducing the release of matrix metalloproteinase 9 (MMP9) by BBB-derived ECs.
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PMID:Death receptor expression and function at the human blood brain barrier. 1739 9

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mainly mediated by Th1, but recent evidence indicates that Th2 T cells, mostly associated with allergic reactions, are also involved. Mast cells are involved in allergic and inflammatory reactions because they are located perivascularly and secrete numerous proinflammatory cytokines. Brain mast cells are critically placed around the blood-brain barrier (BBB) and can disrupt it, a finding preceding any clinical or pathological signs of MS. Moreover, mast cells are often found close to MS plaques, and the main MS antigen, myelin basic protein (MBP), can activate human cultured mast cells to release IL-8, TNF-alpha, tryptase, and histamine. Mast cells could also contribute to T cell activation since addition of mast cells to anti-CD3/anti-CD28 activated T cells increases T cell activation over 30-fold. This effect requires cell-to-cell contact and TNF, but not histamine or tryptase. Pretreatment with the flavone luteolin totally blocks mast cell stimulation and T cell activation. Mast cells could constitute a new unique therapeutic target for MS.
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PMID:Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. 1771 31

Neuropsychiatric disease in systemic lupus erythematosus (NPSLE) is a poorly understood, but potentially fatal, disease manifestation. A pathogenetic role for autoantibodies is suspected, but the mechanism is unclear. Since immune complexes in SLE can stimulate IFN-alpha and there is strong evidence in humans and in mice that IFN-alpha can cause neuropsychiatric manifestations, we asked whether NPSLE patient serum and/or cerebrospinal fluid (CSF) contain abnormally high IFN-alpha-inducing activity. In a bioassay containing plasmacytoid dendritic cells and a source of Ag, NPSLE CSF induced significantly higher IFN-alpha compared with CSF from patients with multiple sclerosis or other autoimmune disease controls. When normalized for IgG concentration, NPSLE CSF was 800-fold more potent at inducing IFN-alpha compared with paired serum due to inhibitors present in serum. Analysis of Ig-deficient patient serum, depletion of IgG from normal serum, as well as addition of purified IgG to NPSLE CSF and serum in the bioassays revealed that one inhibitor was contained within the IgG fraction itself. In addition to IFN-alpha, immune complexes formed by CSF autoantibodies produced significantly increased levels of IFN-gamma-inducible protein 10 (IP-10/CXCL), IL-8, and MCP-1, all of which have been reported to be elevated in CSF from NPSLE patients. Taken together, these findings are consistent with a two-step model of NPSLE whereby CSF autoantibodies bind to Ags released by neurocytotoxic Abs or other brain cell injury, and the resulting immune complexes stimulate IFN-alpha and proinflammatory cytokines and chemokines.
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PMID:Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. 1912 63

Leukocyte migration into the central nervous system (CNS) is mediated by chemokines expressed on CNS endothelial cell surfaces. This study investigated the production of chemokines and expression of chemokine receptors by human brain endothelial cells (HBECs) in vitro and in situ. Four chemokines (CCL2, CCL5, CXCL8, and CXCL10) were demonstrated by immunohistochemistry in endothelial cells in brain samples from patients with multiple sclerosis. CXCL8 and CCL2 were constitutively released and increased by primary HBECs and the brain endothelial cell line hCEMC/D3 in response to tumor necrosis factor and/or interferon gamma. CXCL10 and CCL5 were undetectable in resting endothelial cells but were secreted in response to these proinflammatory cytokines. Tumor necrosis factor strongly increased the production of CCL2, CCL5, and CXCL8; interferon gamma upregulated CXCL10 exclusively. CCL3 was not secreted by HBECs and seemed to be confined to astrocytes in situ. The chemokine receptors CXCR1 and CXCR3 were expressed by HBECs both in vitro and in situ; CXCR3 was upregulated in response to cytokine stimulation in vitro. In contrast, CXCR3 expression was reduced in noninflammatory (silent) multiple sclerosis lesions. The particularly high levels of CXCL10 and CXCL8 expressed by brain endothelium may contribute to the predominant TH1-type inflammatory response observed in chronic inflammatory conditions such as multiple sclerosis.
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PMID:Expression of chemokines and their receptors by human brain endothelium: implications for multiple sclerosis. 1922 13

Pregnancy has an ameliorating effect on multiple sclerosis (MS), but directly after delivery the risk of a relapse is increased. The pro-inflammatory chemokine interleukin 8 is associated with disease activity. We aimed to investigate whether pregnancy-induced fluctuations of interleukin 8 correlate with periods of enhanced and diminished disease activity. Thirty-six women with MS were prospectively studied before, during and after pregnancy. Serum levels of interleukin 8 were significantly decreased during the third trimester (p = 0.03). High first trimester serum levels of interleukin 8 were associated with a high risk of postpartum relapse (p = 0.007). These results help us to further understand the altered disease course during pregnancy.
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PMID:First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis. 1979 62

Despite its generalized use as drug therapy for multiple sclerosis (MS), the molecular mechanisms of action of interferon beta (IFNB) are still poorly understood. IFNB therapy is long-termed and clinical effects are not immediate, therefore reliable early biomarkers for IFNB activity should maintain a differential expression over time, but longitudinal studies at a transcriptional level have been rare. Microarrays were used to monitor 18 IFNB1b treated MS patients at four time points spanning a period of 1 year. Genes showing in the majority of patients the greatest and most consistent changes in their expression levels were studied. Interferon regulated genes were significantly overrepresented. Fifteen markers were differentially expressed during all three time points and followed a consistent time course pattern: EIF2AK2, IFI6, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, ISG15, MX1, OASL, RSAD2, SN, XAF1 and the marker 238704_at. Except for the last one, these biomarkers were all formerly identified as being indicative for IFNB activity. Expression changes were both early detectable and long lasting and could thus be optimal biomarkers for IFNB activity in long-term studies. Other known biomarkers of IFNB activity were found to be differentially expressed just for certain periods after therapy onset: Interleukin-8 was a short lasting marker and changes in STAT1 were detected with delay.
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PMID:Time course transcriptomics of IFNB1b drug therapy in multiple sclerosis. 1988 35

Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions. We will specifically focus on the involvement of two chemokine networks, namely CCL2/CCR2 and CXCL8/CXCR2, in promoting macrophage and neutrophil infiltration, respectively, into the lesioned parenchyma after focal traumatic brain injury. The constitutive brain expression of these chemokines and their receptors, including their recently identified roles in the modulation of neuroprotection, neurogenesis, and neurotransmission, will be discussed. In conclusion, the value of evidence obtained from the use of Ccl2- and Cxcr2-deficient mice will be reported, in the context of potential therapeutics inhibiting chemokine activity which are currently in clinical trial for various inflammatory diseases.
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PMID:Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. 1990 83

Multiple sclerosis (MS) is rare in Asians, but selective and severe involvement of the optic nerve and spinal cord is characteristic when it does occur. Recent epidemiological studies have demonstrated an increase in the prevalence of MS in Japan. Moreover, while there are two distinct phenotypes of MS in Asians, opticospinal (OSMS) and conventional (CMS), it is important to determine if MS phenotypes in Japanese are presently undergoing change. Four nationwide surveys of MS have been conducted in Japan: 1972, 1982, 1989, and 2004. The most recent survey demonstrated: (1) a four-fold increase in the estimated number of clinically definite MS patients in 2003 (9.900; crude MS prevalence. 7.7/100.000) compared to the numbers in 1972; (2) a shift in the peak age at onset from the early 30s in 1989 to the early 20s in 2003; (3) a successive proportional decrease in optic-spinal involvement; (4) a significant north-south gradient for the CMS/OSMS ratio: (5) after dividing the mainland (30-45 degrees North) into northern and southern parts at 37 degrees N, northern-born northern-residents (northern patients) showed a significantly higher CMS/OSMS ratio and higher frequency of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) than southern-born southern-residents; (6) among northern patients, the absolute numbers of CMS patients and those with Barkhof brain lesions rapidly increased with advancing birth year; (7) further classifications based on MRI findings demonstrated distinct demographic features with not only the CMS/OSMS phenotype but also the presence or absence of longitudinally extensive spinal cord lesions (LESCLs). In northern patients, the incidence of OSMS with LESCLs had decreased with advancing year of birth, while incidences of intermediate phenotypes, such as CMS with LESCLs and OSMS without LESCLs, had increased. Although phenotypic changes appeared to be mostly attributable to the increase in CMS patients with Barkhof brain lesions in younger northern populations, the emergence of such intermediate phenotypes may support the notion that CMS and OSMS represent opposite ends of a single spectrum of disease. These findings suggest that phenotype is drastically altered by environmental factors, such as latitude and "Westernization". The recent discovery of a specific IgG against neuromyelitis optica (NMO) suggests that NMO is a disease entity distinct from MS. NMO-IgG targeting aquaporin-4 (AQP4) is present in 30 to 60% of Japanese OSMS patients with LESCLs. MS patients with anti-AQP4 antibodies were not responsive to interferon beta-1b while those without anti-AQP4 antibody did respond. In CSF, IL-17, IFN-gamma, granulocyte-colony stimulating factor, and IL-8 were markedly upregulated in OSMS patients, irrespective of the presence or absence of the anti-AQP4 antibody. Pathological studies of autopsy specimens of OSMS patients disclose that there are two subtypes of OSMS, with or without showing a selective AQP4 loss; although both subtypes had severe necrotic spinal cord lesions. There are also OSMS cases showing both pathological patterns at different lesions. These findings indicate that both anti-AQP4 autoimmunity-related and -unrelated OSMS occur in Japanese. Th17/Th1 cells are involved in both conditions, while additional humoral factors also act in the former.
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PMID:[Recent advances of multiple sclerosis research in Japan]. 1992 84

Th17 cells are a recently described subset of T helper lymphocytes characterized by the production of IL-17 (IL-17A). Since their discovery in 2003, studies on Th17 cells have become increasingly popular among immunologists and they have emerged as key players in the pathogenesis of multiple sclerosis (MS) and other autoimmune disorders traditionally attributed to Th1 cells. Murine Th17 lymphocytes differentiate from naive CD4+ cells in a specific cytokine environment, which includes TGF-b and IL-6 or IL-21, whereas human Th17 cell development requires TGF-beta, IL-1b, and IL-2 in combination with IL-6, IL-21, or IL-23. Th17-related response is additionally enhanced by osteopontin, TNFalpha, and PGE2 and suppressed by IL-25, IL-27, IL-35, and IL-10. Apart from their main cytokine, Th17 cells can also express IL-17F, IL-21,IL-22, TNFalpha, CCL20, and, in humans, IL-26. All of these mediators may contribute to the proinflammatory action of Th17 cells both in the clearance of various pathogens and in autoimmunity. At least some of these functions are exerted through the induction of neutrophil-recruiting chemokines (CXCL1, CXCL2, CXCL8) by IL-17. Accumulating evidence from studies on mice and humans indicates an important role of Th17 cells in mediating autoimmune neuroinflammation. This has led some immunologists to question the previously exhibited importance of Th1 cells in MS pathology. However, more recent data suggest that both these T-cell subsets are capable of inducing and promoting the disease. Further investigation is required to clarify the role of Th17 cells in the pathogenesis of MS since some of the Th17-related molecules appear as attractive targets for future therapeutic strategies.
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PMID:[Th17 cells in the pathogenesis of multiple sclerosis]. 1994 Mar 28


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