Increased expression of caspase-1 and interleukin-18 in peripheral blood mononuclear cells in patients with multiple sclerosis.
ABSTRACT Multiple sclerosis (MS) is supposedly a T-cell mediated autoimmune disorder of the central nervous system. Cytokines and other molecules involved in the regulation of apoptosis are thought to be of importance for the pathogenesis of MS. In this study, the mRNA levels of interleukin 18 (IL-18), IL-1beta and their processing enzyme caspase-1 were quantified by a competitive RT-PCR method in unstimulated peripheral blood mononuclear cells (PBMCs) in MS patients never treated with disease modifying drugs. Western blot was used to support the expression pattern at the protein level. We found that the expression of caspase-1 and IL-18 was significantly increased in MS patients compared with healthy controls. Analysis of clinical subgroups revealed that caspase-1 was increased in all subgroups, whereas IL-18 was upregulated in chronic progression (P=0.001) and relapsing MS patients in remission (P=0.002) but not significantly during relapses (P=0.12). mRNA levels of IL-1beta were not significantly altered in MS except for a possible decrease in chronic progression (P=0.03). An increased IL-18 expression, potentially augmented at the mature protein level, may indicate a pathway worth considering in future therapeutic strategies in MS.
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ABSTRACT: Multiple sclerosis (MS) is a progressive immune‑ mediated disease caused by demyelination of the central nervous system. Cytokines and their receptors have an important role in the evolution of MS lesions, and pro‑ and anti‑inflammatory cytokine levels have been found to correlate with changes in MS disease activity. The aims of the present study were to evaluate the pro‑inflammatory [tumor necrosis factor (TNF)‑α and interleukin (IL) ‑1β, ‑6 and ‑12], T helper (Th) 1 [interferon (IFN)‑γ], Th17 (IL‑17) and Th2 (IL‑4 and ‑10) cytokine serum levels in relapsing‑remitting (RR)‑MS patients and to evaluate the association between the cytokine profile and the progression and activity of the disease. Serum cytokine levels were assessed using enzyme linked‑immunosorbent assays in 169 RR‑MS patients in the remission clinical phase and 132 healthy individuals who were age‑, gender‑, ethnicity‑ and body mass index‑matched. Disability and activity of the disease were evaluated using the Expanded Disability Status Scale and magnetic resonance imaging with gadolinium, respectively. IFN‑γ and IL‑6, ‑12 and ‑4 levels were higher in RR‑MS patients compared to controls (P=0.0009, 0.0114, 0.0297 and 0.0004, respectively). IL‑1 levels were higher in controls compared with RR‑MS patients. IL‑4 levels were higher in RR‑MS patients with mild disability compared to those with moderate and severe disability (P=0.0375). TNF‑α and IL‑10 levels were higher in RR‑MS patients with inactive disease compared with those with active disease. IL‑17 levels showed a trend towards being higher in RR‑MS patients with inactive disease compared to those with active disease (P=0.0631). Low TNF‑α and high IFN‑γ levels were independently associated with RR‑MS (P=0.0078 and 0.0056, respectively) and also with the activity of the disease (P=0.0348 and 0.0133, respectively). Results indicated that RR‑MS patients, even in the remission clinical phase, exhibit a complex system of inflammatory and anti‑inflammatory cytokines that may interact to modulate the progression and activity of the disease.Molecular Medicine Reports 01/2013; · 1.17 Impact Factor
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ABSTRACT: The NLRP3 inflammasome is a multiprotein complex consisting of three kinds of proteins, NLRP3, ASC, and pro-caspase-1, and plays a role in sensing pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, the mechanism by which the NLRP3 inflammasome induces EAE is not clear. In this study, we found that the NLRP3 inflammasome played a critical role in inducing T-helper cell migration into the CNS. To gain migratory ability, CD4(+) T cells need to be primed by NLRP3 inflammasome-sufficient antigen-presenting cells to up-regulate chemotaxis-related proteins, such as osteopontin, CCR2, and CXCR6. In the presence of the NLRP3 inflammasome, dendritic cells and macrophages also induce chemotactic ability and up-regulate chemotaxis-related proteins, such as α4β1 integrin, CCL7, CCL8, and CXCL16. On the other hand, reduced Th17 cell population size in immunized Nlrp3(-/-) and Asc(-/-) mice is not a determinative factor for their resistance to EAE. As currently applied in clinical interventions of MS, targeting immune cell migration molecules may be an effective approach in treating MS accompanied by NLRP3 inflammasome activation.Proceedings of the National Academy of Sciences 06/2012; 109(26):10480-5. · 9.74 Impact Factor
Article: NLRP3 Inflammasome and MS/EAE.[show abstract] [hide abstract]
ABSTRACT: Inflammasomes are cytosolic sensors that detect pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is currently the most fully characterized inflammasome and is known to detect a wide array of microbes and endogenous damage-associated molecules. Possible involvement of the NLRP3 inflammasome (or inflammasomes) in the development of multiple sclerosis (MS) was suggested in a number of studies. Recent studies showed that the NLRP3 inflammasome exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of MS, although EAE can also develop without the NLRP3 inflammasome. In this paper, we discuss the NLRP3 inflammasome in MS and EAE development.Autoimmune diseases. 01/2013; 2013:859145.