Interleukin-18 as an in vivo mediator of monocyte recruitment in rodent models of rheumatoid arthritis

Abstract Introduction The function of interleukin-18 (IL-18) was investigated in pertinent animal models of rodent rheumatoid arthritis (RA) to determine its proinflammatory and monocyte recruitment properties. Methods We used a modified Boyden chemotaxis system to examine monocyte recruitment to recombinant human (rhu) IL-18 in vitro. Monocyte recruitment to rhuIL-18 was then tested in vivo by using an RA synovial tissue (ST) severe combined immunodeficient (SCID) mouse chimera. We defined monocyte-specific signal-transduction pathways induced by rhuIL-18 with Western blotting analysis and linked this to in vitro monocyte chemotactic activity. Finally, the ability of IL-18 to induce a cytokine cascade during acute joint inflammatory responses was examined by inducing wild-type (Wt) and IL-18 gene-knockout mice with zymosan-induced arthritis (ZIA). Results We found that intragraft injected rhuIL-18 was a robust monocyte recruitment factor to both human ST and regional (inguinal) murine lymph node (LN) tissue. IL-18 gene-knockout mice also showed pronounced reductions in joint inflammation during ZIA compared with Wt mice. Many proinflammatory cytokines were reduced in IL-18 gene-knockout mouse joint homogenates during ZIA, including macrophage inflammatory protein-3α (MIP-3α/CCL20), vascular endothelial cell growth factor (VEGF), and IL-17. Signal-transduction experiments revealed that IL-18 signals through p38 and ERK½ in monocytes, and that IL-18-mediated in vitro monocyte chemotaxis can be significantly inhibited by disruption of this pathway. Conclusions Our data suggest that IL-18 may be produced in acute inflammatory responses and support the notion that IL-18 may serve a hierarchic position for initiating joint inflammatory responses.http://deepblue.lib.umich.edu/bitstream/2027.42/112330/1/13075_2010_Article_2890.pd

CHIME/FRB Detection of Eight New Repeating Fast Radio Burst Sources

We report on the discovery of eight repeating fast radio burst (FRB) sources found using the Canadian Hydrogen Intensity Mapping Experiment (CHIME) telescope. These sources span a dispersion measure (DM) range of 103.5 to 1281 pc cm$^{-3}$. They display varying degrees of activity: six sources were detected twice, another three times, and one ten times. These eight repeating FRBs likely represent the bright and/or high-rate end of a distribution of infrequently repeating sources. For all sources, we determine sky coordinates with uncertainties of $\sim$10$^\prime$. FRB 180916.J0158+65 has a burst-averaged DM = $349.2 \pm 0.3$ pc cm$^{-3}$ and a low DM excess over the modelled Galactic maximum (as low as $\sim$20 pc cm$^{-3}$); this source also has a Faraday rotation measure (RM) of $-114.6 \pm 0.6$ rad m$^{-2}$, much lower than the RM measured for FRB 121102. FRB 181030.J1054+73 has the lowest DM for a repeater, $103.5 \pm 0.3$ pc cm$^{-3}$, with a DM excess of $\sim$ 70 pc cm$^{-3}$. Both sources are interesting targets for multi-wavelength follow-up due to their apparent proximity. The DM distribution of our repeater sample is statistically indistinguishable from that of the first 12 CHIME/FRB sources that have not repeated. We find, with 4$\sigma$ significance, that repeater bursts are generally wider than those of CHIME/FRB bursts that have not repeated, suggesting different emission mechanisms. Our repeater events show complex morphologies that are reminiscent of the first two discovered repeating FRBs. The repetitive behavior of these sources will enable interferometric localizations and subsequent host galaxy identifications.Comment: 40 pages, 11 figures; accepted by ApJL on 28 September 2019; added analysis of correlation between width and max. flux densit

Periodic activity from a fast radio burst source

Fast radio bursts (FRBs) are bright, millisecond-duration radio transients originating from extragalactic distances. Their origin is unknown. Some FRB sources emit repeat bursts, ruling out cataclysmic origins for those events. Despite searches for periodicity in repeat burst arrival times on time scales from milliseconds to many days, these bursts have hitherto been observed to appear sporadically, and though clustered, without a regular pattern. Here we report the detection of a $16.35\pm0.15$ day periodicity (or possibly a higher-frequency alias of that periodicity) from a repeating FRB 180916.J0158+65 detected by the Canadian Hydrogen Intensity Mapping Experiment Fast Radio Burst Project (CHIME/FRB). In 38 bursts recorded from September 16th, 2018 through February 4th, 2020, we find that all bursts arrive in a 5-day phase window, and 50% of the bursts arrive in a 0.6-day phase window. Our results suggest a mechanism for periodic modulation either of the burst emission itself, or through external amplification or absorption, and disfavour models invoking purely sporadic processes

Green tea extract inhibits chemokine production, but up-regulates chemokine receptor expression, in rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis

Objective. Evaluation of the efficacy of green tea extract (GTE) in regulating chemokine production and chemokine receptor expression in human RA synovial fibroblasts and rat adjuvant-induced arthritis (AIA). Methods. Fibroblasts isolated from human RA synovium were used in the study. Regulated upon activation normal T cell expressed and secreted (RANTES)/CCL5, monocyte chemoattractant protein (MCP)-1/CCL2, growth-regulated oncogene (GRO)a/CXCL1 and IL-8/CXCL8 production was measured by ELISA. Western blotting was used to study the phosphorylation of protein kinase C (PKC)d and c-Jun N-terminal kinases (JNK). Chemokine and chemokine receptor expression was determined by quantitative RT–PCR. The benefit of GTE administration in rat AIA was determined. Results. GTE (2.5–40 mg/ml) inhibited IL-1b-induced MCP-1/CCL2 (10 ng/ml), RANTES/CCL5, GROa/CXCL1 and IL-8/CXCL8 production in human RA synovial fibroblasts (P<0.05). However, GTE inhibited MCP-1/CCL2 and GROa/CXCL1 mRNA synthesis in RA synovial fibroblasts. Furthermore, GTE also inhibited IL-1b-induced phosphorylation of PKCd, the signalling pathway mediating IL-1b-induced chemokine production. Interestingly, GTE preincubation enhanced constitutive and IL-1b-induced CCR1, CCR2b, CCR5, CXCR1 and CXCR2 receptor expression. GTE administration (200 mg/kg/day p.o.) modestly ameliorated rat AIA, which was accompanied by a decrease in MCP-1/CCL2 and GROa/CXCL1 levels and enhanced CCR-1, -2, -5 and CXCR1 receptor expression in the joints of GTE administered rats. Conclusions. Chemokine receptor overexpression with reduced chemokine production by GTE may be one potential mechanism to limit the overall inflammation and joint destruction in RA.NIHPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77485/1/Marotte, et al. Green tea extract...Rheumatology 2010.pdf-