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The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis,(More)
Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and(More)
It is recognized that there is molecular cross-talk between the inflammatory mediators NO and PGs that may regulate tissue homeostasis and contribute to pathophysiological processes. However, the literature is divided with respect to whether NO activates or inhibits PG production. In this study, we sought to determine whether conflicting observations could(More)
T cell receptor (TCR) dependent regulatory T cell (Treg) activity controls effector T cell (Teff) function and is inhibited by the inflammatory cytokine tumor necrosis factor (TNF)-α. Protein kinase C-θ (PKC-θ) recruitment to the immunological synapse is required for full Teff activation. In contrast, PKC-θ was sequestered away from the Treg immunological(More)
Osteoarthritis (OA) is a degenerative disease involving chondrocytes, cartilage and other joint tissues, and has a number of underlying causes, including both biochemical and mechanical factors. Although proinflammatory factors including nitric oxide (NO) are associated with OA, there is recent evidence suggesting that NO and its redox derivatives may also(More)
In these studies we provide conclusive evidence that (beta/gamma) actin present in human neutrophils is a substrate for nitric oxide (NO)-dependent ADP ribosylation and that this modification is associated with the inhibition of actin polymerization. A 43-kDa substrate for NO-dependent ADP ribosylation was identified as actin by four methods: (1)(More)
NF-kappaB transcription factors regulate inflammatory responses to cytokines such as IL-1beta and TNF-alpha. We tested whether PGE2 regulated nuclear localization of individual NF-kappaB subunits, p65 and p50, in synovial fibroblasts harvested from patients with rheumatoid arthritis (RA). IL-1beta/TNF-alpha stimulated the translocation of p65 and p50 from(More)
Osteoarthritis is often a progressive and disabling disease, which occurs in the setting of a variety of risk factors--such as advancing age, obesity, and trauma--that conspire to incite a cascade of pathophysiologic events within joint tissues. An important emerging theme in osteoarthritis is a broadening of focus from a disease of cartilage to one of the(More)
have reviewed the Draft document and provided-for each of the four topics subject to review (according to the Attachment #2 of Dr. Alexeeff)-determinations as to whether the scientific portions of the proposed [PHG] were based on sound scientific knowledge, methods, and practices. I thank you for the opportunity to review the 2009 Draft document, as well as(More)