Masanori Nakayama

IL-32-PAR2 axis is an innate immunity sensor providing alternative signaling for LPS-TRIF axis

Interleukin (IL)-32 is known to exert adujvant effects on innate immune response, however, receptors and downstream signaling pathways remain to be clarified. Here we found that IL-32γ upregulated serine protease activity of proteinase-3 (PR3), in turn triggering protease-activated receptor 2 (PAR2) signaling. Interestingly, silencing of PR3 or PAR2 using siRNA markedly diminished IL-32γ-induced TNFα and IFN-β mRNA expression. IL-32γ-PAR2 axis utilized TRIF and Ras-Raf-1 pathways. On stimulation with lipopolysaccharide (LPS), differential activation of protein kinase C isoforms modulated the balance between LPS-TLR4-TRIF and IL-32-PAR2-TRIF axes, because LPS was a strong inducer of IL-32γ. IL-32-PAR2-TRIF axis might serve not only as an extracellular sensor of bacterial and autologous proteases, but also as a modulator of innate and adaptive immunity during infection.

Enhanced susceptibility to lipopolysaccharide-induced arthritis and endotoxin shock in interleukin-32 alpha transgenic mice through induction of tumor necrosis factor alpha

IntroductionThe present study assessed the potential functions of interleukin (IL)-32α on inflammatory arthritis and endotoxin shock models using IL-32α transgenic (Tg) mice. The potential signaling pathway for the IL-32-tumor necrosis factor (TNF)α axis was analyzed in vitro.MethodsIL-32α Tg mice were generated under control of a ubiquitous promoter. Two disease models were used to examine in vivo effects of overexpressed IL-32α: Toll-like receptor (TLR) ligand-induced arthritis developed using a single injection of lipopolysaccharide (LPS) or zymosan into the knee joints; and endotoxin shock induced with intraperitoneal injection of LPS and D-galactosamine. TNFα antagonist etanercept was administered simultaneously with LPS in some mice. Using RAW264.7 cells, in vitro effects of exogenous IL-32α on TNFα, IL-6 or macrophage inflammatory protein 2 (MIP-2) production were assessed with or without inhibitors for nuclear factor kappa B (NFκB) or mitogen-activated protein kinase (MAPK).ResultsSingle injection of LPS, but not zymosan, resulted in development of severe synovitis with substantial articular cartilage degradation in knees of the Tg mice. The expression of TNFα mRNA in inflamed synovia was highly upregulated in the LPS-injected Tg mice. Moreover, the Tg mice were more susceptive to endotoxin-induced lethality than the wild-type control mice 48 hours after LPS challenge; but blockade of TNFα by etanercept protected from endotoxin lethality. In cultured bone marrow cells derived from the Tg mice, overexpressed IL-32α accelerated production of TNFα upon stimulation with LPS. Of note, exogenously added IL-32α alone stimulated RAW264.7 cells to express TNFα, IL-6, and MIP-2 mRNAs. Particularly, IL-32α -induced TNFα, but not IL-6 or MIP-2, was inhibited by dehydroxymethylepoxyquinomicin (DHMEQ) and U0126, which are specific inhibitors of nuclear factor kappa B (NFκB) and extracellular signal regulated kinase1/2 (ERK1/2), respectively.ConclusionsThese results show that IL-32α contributed to the development of inflammatory arthritis and endotoxin lethality. Stimulation of TLR signaling with LPS appeared indispensable for activating the IL-32α-TNFα axis in vivo. However, IL-32α alone induced TNFα production in RAW264.7 cells through phosphorylation of inhibitor kappa B (IκB) and ERK1/2 MAPK. Further studies on the potential involvement of IL-32α-TNFα axis will be beneficial in better understanding the pathology of autoimmune-related arthritis and infectious immunity.

Clinical significance of cartilage biomarkers for monitoring structural joint damage in rheumatoid arthritis patients treated with anti-TNF therapy.

Purpose With the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage. Methods Subjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated. Results Levels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p<0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ΔHA and ΔC2C/CPII from baseline to week 54 correlated significantly with not only ΔCRP, but also ΔDAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ΔHA to ΔDAS28 disappeared, whereas correlations of ΔC2C/CPII to ΔDAS28, ΔJNS, and ΔHAQ remained significant. These results suggest a role of ΔC2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation. Conclusion The temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ΔC2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3.

TimeTubes: visual fusion and validation for ameliorating uncertainties of blazar datasets from different observatories

Astronomers have been observing blazars to solve the mystery of the relativistic jet. A technique called TimeTubes uses a 3D volumetric tube to visualize the time-dependent multivariate observed datasets and allows astronomers to interactively analyze the dynamic behavior of and relationship among those variables. However, the observed datasets themselves exhibit uncertainty due to their errors and missing periods, whereas periods interpolated by TimeTubes result in a different type of uncertainty. In this paper, we present a technique for ameliorating such data- and mapping-inherent uncertainties: visual fusion of datasets for the same blazar from two different observatories. Visual data fusion with Time-Tubes enables astronomers to validate the datasets in a meticulous manner.

TimeTubes: Visual Exploration of Observed Blazar Datasets

Blazars are attractive objects for astronomers to observe in order to burrow into the magnetic field in the relativistic jet. This paper presents TimeTubes as a novel visualization scheme that allows astronomers to interactively explore characteristic temporal variation patterns in observed blazar datasets. In the TimeTubes spatialization, the two Stokes parameters and their errors with a common timestamp are transformed into an ellipse. A series of such ellipses are aligned in parallel along the timeline to form a 3D volumetric tube. The resulting tube is then colorized by the observed intensities and colors of the blazar, and finally volume-rendered. A designated user interface is provided with visual exploration functions according to Shneidermans Visual Information Seeking Mantra. In the latest version, an auxiliary mechanism, called visual data fusion, was incorporated to ameliorate data- and mapping-inherent uncertainties for more efficient and effective visual exploration.

Optical polarization variations in the blazar PKS 1749+096

We report on the variation in the optical polarization of the blazar PKS 1749+096 observed in 2008--2015. The degree of polarization (PD) tends to increase in short flares having a time-scale of a few days. The object favors a polarization angle (PA) of

FRI0026 Interleuikin-32 induces tnfalpha and type i interferon via proteinase 3 - protease activated receptor 2-tir-domain-containing adapter-inducing interferon-beta axis

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TimeTubes: Visualization of Polarization Variations in Blazars

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SeeGroove: Supporting Groove Learning through Visualization

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TimeTubes: Design of a Visualization Tool for Time-Dependent, Multivariate Blazar Datasets

at the flare maxima, which is close to the position angle of the jet (