Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

Increased levels of circulating acetylcholine receptor (AChR)-reactive IL-10-secreting cells are characteristic for myasthenia gravis (MG)

Antibodies to the nicotinic AChR are pivotal in the immunopathogenesis of MG. Cytokines produced by T-helper cells are important regulators of humoral immune responses. IL-10 is considered an anti-inflammatory cytokine, but it promotes B cell activation and worsens experimental autoimmune MG in Lewis rats, an experimental model of MG. To study IL-10 and, as a control, interferon-gamma (IFN-γ) in MG, we used an enzyme-linked immunospot (ELISPOT) assay, thereby assessing numbers of blood mononuclear cells (MNC) secreting IL-10 and IFN-γ spontaneously and after stimulation with AChR. Low numbers of IL-10-secreting cells were regularly found in peripheral blood from patients with MG as well as in controls with other neurological diseases and healthy subjects. However, only MG patients had elevated blood levels of AChR-reactive IL-10- and IFN-γ-secreting cells. The MG patients showed no responses to the control autoantigen myelin basic protein, underlining the specificity of the IL-10 and IFN-γ responses. Immunosuppressive treatment reduced numbers of AChR-reactive IFN-γ-secreting cells but increased the numbers of IL-10-secreting cells. The numbers of IL-10-secreting cells tended to be higher in patients with generalized versus ocular MG, further suggesting that the augmented IL-10 responses may be important in the pathogenesis and perpetuation of MG

Vortex tracking on visualized temperature fields in a rotating Rayleigh-Benard convection

We established a vortex detection method using instantaneous temperature fields that were visualized using thermochromic liquid crystals (TLCs) to investigate behaviors of vortical structures in a rotating Rayleigh-Benard convection. Experimental testing was performed at a fixed Rayleigh number in water containing encapsulated TLCs. Vortices were recognized as undulations that appear in the horizontal temperature fields, thus making vortex detection with high spatial resolution possible, and this enabled quantitative investigation of the dynamics of vortical structures. Standard template matching was used to detect individual vortices on visualized temperature fields, and two-dimensional curved surface fitting was adopted to remove erroneous detections and to evaluate shapes of local temperature fields corresponding to vortical structures. Additionally, vortex tracking clearly showed geometric advection pattern of vortical structures

Small Molecule 20S Proteasome Enhancer Regulates MYC Protein Stability and Exhibits Antitumor Activity in Multiple Myeloma

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM