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In order to investigate the possible role of IL-1 receptor antagonist (IL-lra) in patients with rheumatoid arthritis (RA), this study was undertaken to measure the amounts of IL-lra and interleukin-1β (IL-1β) protein produced by mononuclear cells (MNC) and to investigate the relationship between production of these cytokines and clinical parameters. The MNC were cultured for 24 h and the supernatants were measured for IL-lra and IL-1β by ELISA kits. MNC from peripheral blood (PB) and synovial fluid of RA patients produced significantly higher amounts of IL-lra than normal PBMNC (P < 0.01 and P < 0.05, respectively). When the IL-1β/IL-lra ratio was calculated, IL-1β/IL-lra ratios of RA PBMNC were significantly lower than those of normal PBMNC (P < 0.001). The IL-1β/IL-lra ratio of RA PBMNC was significantly higher in active RA patients than in RA patients in remission (P < 0.02). The amounts of IL-lra produced by stimulated RA PBMNC positively correlated with the joint score (P < 0.05), serum CRP levels (P < 0.05) and the amounts of IL-1β produced (P < 0.01). The amounts of IL-lra produced by unstimulated RA PBMNC did not correlate with any of the clinical parameters studied. Gold sodium thiomalate (GST), but not auranofin, increased IL-lra production . These data suggest that increased IL-lra production in RA MNC is associated with IL-1β produced, thus protecting from IL-1β-mediated immune responses, and that enhanced IL-lra production by MNC cultured with GST is one of the mechanisms by which GST shows clinical efficacy. [ABSTRACT FROM PUBLISHER]

We examined the effect of TNF-α, IL-1β and IL-6 on alkaline phosphatase (ALP) and osteocalcin (OC) production, calcification and calcium (Ca) release in human osteoblastic cell cultures obtained from human periosteum. The cells were cultured with varying concentrations of cytokines for 3 days. TNF-α and IL-1β significantly inhibited ALP production, decreased cellular Ca content, and significantly enhanced Ca release in human osteoblastic cells. IL-6, on the other hand, significantly suppressed Ca release by osteoblastic cells. These cytokines did not influence the production of OC by osteoblastic cells. The results obtained suggest that TNF-α and IL-1β may inhibit bone formation and calcification and that the effects of IL-6 on osteoblastic cells may be different from those of TNF-α or IL-1β. These effects on osteoblastic cells may be one of the mechanisms by which bone loss occurs in patients with RA. [ABSTRACT FROM PUBLISHER]

We investigated the mechanisms of the marked increase of alkaline ribonuclease (RNase) in the sera of patients with rheumatoid arthritis associated with vasculitis. Among various tissues examined, blood vessels contained higher levels of alkaline RNase than acid RNase. Cultured human endothelial cells contained significantly higher amounts of alkaline RNase than acid RNase. In contrast, acid RNase was predominant in most other tissues and cells. Endothelial cells cultured with sera from patients with vasculitis released alkaline RNase into the extracellular medium. The phosphocellulose chromatographic profile of these sera differed from that of sera from healthy subjects. These results imply that the alkaline RNase in sera of patients with vasculitis is derived from blood vessels, probably from endothelial cells. [ABSTRACT FROM PUBLISHER]

Orexins (orexin-A and orexin-B) are neuropeptides that are reduced in narcolepsy, a sleep disorder that is characterized by excessive daytime sleepiness, sudden sleep attacks and cataplexy. However, it remains unclear how orexins in the brain and orexin neurons are reduced in narcolepsy. Orexin-A has two closely located intramolecular disulfide bonds and is prone to misfolding due to the formation of incorrect disulfide bonds. Protein disulfide isomerase (PDI) possesses disulfide interchange activity. PDI can modify misfolded orexin-A to its native form by rearrangement of two disulfide bonds. We have previously demonstrated that sleep deprivation and a high fat diet increase nitric oxide in the brain. This increase triggers S-nitrosation and inactivation of PDI, leading to aggregation of orexin-A and reduction of orexin neurons. However, the relationship between PDI inactivation and loss of orexin neurons has not yet been fully elucidated. In the present study, we used a PDI inhibitor, cystamine, to elucidate the precise molecular mechanism by which PDI inhibition reduces the number of orexin neurons. In rat hypothalamic slice cultures, cystamine induced selective depletion of orexin-A, but not orexin-B and melanin-concentrating hormone. Moreover, cystamine triggered aggregation of orexin-A, but not orexin-B in the Golgi apparatus of hypothalamic slice cultures and in vivo mouse brains. However, cystamine did not induce endoplasmic reticulum (ER) stress, and an ER stress inducer did not trigger aggregation of orexin-A in slice cultures. Finally, we demonstrated that cystamine significantly decreased extracellular secretion of orexin-A in AD293 cells overexpressing prepro-orexin. These findings suggest that cystamine-induced PDI inhibition induces selective depletion, aggregation in the Golgi apparatus and impaired secretion of orexin-A. These effects may represent an initial step in the pathogenesis of narcolepsy., (Copyright © 2017. Published by Elsevier Inc.)