347 research outputs found
Elevated aggrecan mRNA in early murine osteoarthritis
SummaryMale STR/ort mice develop osteoarthritis in the tibial articular cartilage. Low grade histological lesions first appear between 10β20 weeks of age. A previous study showed that the level of aggrecan, the major cartilage proteoglycan, is approximately twofold greater in the tibial cartilage of 16β19-week-old STR/ort mice compared with that in normal cartilage in control CBA mice. In the present investigation aggrecan gene transcription was investigated in 20-week-old STR/ort and CBA tibial cartilage using a quantitative reverse transcription-polymerase chain reaction (RT-PCR). The amount of aggrecan cDNA obtained from the STR/ort medial and lateral plateau was 2.8- and 4.6-fold greater per milligram of wet cartilage than that from the CBA tibial plateau. The difference was not due to differences in cellularity of tibial cartilage in the two strains and indicates that aggrecan gene transcription is elevated in early osteoarthritis
Altitude dependence of atmospheric temperature trends: Climate models versus observation
As a consequence of greenhouse forcing, all state of the art general
circulation models predict a positive temperature trend that is greater for the
troposphere than the surface. This predicted positive trend increases in value
with altitude until it reaches a maximum ratio with respect to the surface of
as much as 1.5 to 2.0 at about 200 to 400 hPa. However, the temperature trends
from several independent observational data sets show decreasing as well as
mostly negative values. This disparity indicates that the three models examined
here fail to account for the effects of greenhouse forcings.Comment: 9 pages, 3 figure
Evaluation of Tropospheric Water Vapor Simulations from the Atmospheric Model Intercomparison Project
T Cell Receptor-Independent, CD31/IL-17A-Driven Inflammatory Axis Shapes Synovitis in Juvenile Idiopathic Arthritis
T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of Ξ±Ξ²T cells that lacked both CD4 and CD8 co-receptors [herein called double negative (DN) T cells] and also lacked the CD28 costimulatory receptor. However, these synovial Ξ±Ξ²T cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28nullCD31+ DN Ξ±Ξ²T cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORΞ³T expression and trans-activation of the IL-17A promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFΞ±. Collectively, our data suggest that activation of a CD31-driven, Ξ±Ξ²TCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31+CD28null Ξ±Ξ²T cells and IL-17RA+CD38+ FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis
Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection.
Innate immune cells quickly infiltrate the site of pathogen entry and not only stave off infection but also initiate antigen presentation and promote adaptive immunity. The recruitment of innate leukocytes has been well studied in the context of extracellular bacterial and fungal infection but less during viral infections. We have recently shown that the understudied cytokine Interleukin (IL)-17D can mediate neutrophil, natural killer (NK) cell and monocyte infiltration in sterile inflammation and cancer. Herein, we show that early immune cell accumulation at the peritoneal site of infection by mouse cytomegalovirus (MCMV) is mediated by IL-17D. Mice deficient in IL-17D or the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of IL-17D, featured an early decreased number of innate immune cells at the point of viral entry and were more susceptible to MCMV infection. Interestingly, we were able to artificially induce innate leukocyte infiltration by applying the Nrf2 activator tert-butylhydroquinone (tBHQ), which rendered mice less susceptible to MCMV infection. Our results implicate the Nrf2/IL-17D axis as a sensor of viral infection and suggest therapeutic benefit in boosting this pathway to promote innate antiviral responses
Oral epithelial IL-22/STAT3 signaling licenses IL-17-mediated immunity to oral mucosal candidiasis
Neutrophils in cancer: neutral no more
Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets
IL-17RA Signaling Amplifies Antibody-Induced Arthritis
Objective: To investigate the role of IL-17RA signaling in the effector phase of inflammatory arthritis using the K/BxN serumtransfer model. Methods: Wild-type and Il17ra 2/2 mice were injected with serum isolated from arthritic K/BxN mice and their clinical score was recorded daily. Mice were also harvested on days 12 and 21 and ankles were analyzed for cytokine and chemokine mRNA expression by qPCR on day 12 and for bone and cartilage erosions by histology on day 21, respectively. The induction of cytokine and chemokine expression levels by IL-17A in synovial-like fibroblasts was also analyzed using qPCR. Results: Il17ra 2/2 mice were partially protected from clinical signs of arthritis and had markedly fewer cartilage and bone erosions. The expression of several pro-inflammatory mediators, including the chemokines KC/CXCL1, MIP-2/CXCL2, LIX/ CXCL5 MIP-1c/CCL9, MCP-3/CCL7, MIP-3a/CCL20, the cytokines IL-1b, IL-6, RANKL and the matrix metalloproteinases MMP2, MMP3, and MMP13 were decreased in the ankles of Il17ra 2/2 mice compared to wild-type mice. Many of these proinflammatory genes attenuated in the ankles of Il17ra 2/2 mice were shown to be directly induced by IL-17A in synovial fibroblasts in vitro. Conclusions: IL-17RA signaling plays a role as an amplifier of the effector phase of inflammatory arthritis. This effect is likel
Porphyromonas gingivalis suppresses adaptive immunity in periodontitis, atherosclerosis and Alzheimerβs disease
Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis, has been found to associate with remote body organ inflammatory pathologies including atherosclerosis and Alzheimerβs disease (AD). Although P. gingivalis has a plethora of virulence factors, much of its pathogenicity is surprisingly related to the overall immunosuppression of the host. This review focuses on P. gingivalis aiding suppression of the hostβs adaptive immune system involving manipulation of cellular immunological responses specifically T- and B-cells in periodontitis and related conditions. In periodontitis this bacterium inhibits the synthesis of IL-2 and increases humoral responses. This reduces inflammatory responses related to T- and B-cell activation, and subsequent IFN-Ι€ secretion by a subset of T cells. The T cells further suppresses upregulation of programmed cell death-1 (PD-1)-receptor on CD+-cells and its ligand PD-L1 on CD11b+- subset of T-cells. IL-2 down-regulates immune response-regulated genes, induces a cytokine pattern in which the Th17 lineage is favored thereby modulating the Th17/ T-regulatory cell (Treg) imbalance. The suppression of IFN-Ι€ stimulated release of interferon-inducible protein-10 (IP-10) chemokine ligands [ITAC (CXCL11) and Mig (CXCL9)] by P. gingivalis capsular serotypes, triggers distinct T-cell responses, and contributes to local immune evasion by release of its outer membrane vesicles. In atherosclerosis P. gingivalis reduces Tregs and transforming growth factor beta-1 (TGF-1) and causes imbalance in the Th17 lineage of the Treg population. In Alzheimerβs disease P. gingivalis may affect the blood-brain barrier permeability, and inhibit local IFN-Ι€ response by preventing entry of immune cells into the brain. The scarcity of adaptive immune cells in Alzheimerβs disease neuropathology implies P. gingivalis infection of the brain likely causes impaired clearance of insoluble amyloid and induces immunosuppression. By the effective manipulation of the armory of adaptive immune suppression through a plethora of virulence factors P. gingivalis may act as a keystone organism in periodontitis and in related systemic diseases and other remote body inflammatory pathologies
Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression
The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naΓ―ve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy
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