The JAK inhibitor baricitinib inhibits oncostatin M induction of proinflammatory mediators in ex-vivo synovial derived cells.

OBJECTIVES: To investigate the ex vivo effect of the JAK1/2 inhibitor baricitinib on expression of pro-inflammatory mediators in rheumatoid arthritis (RA) fibroblast like synoviocytes (FLS) stimulated with TNFα, IL-1ß and oncostatin M (OSM), and in RA synovial membrane cells (SMCs). METHODS: RA and osteoarthritis (OA) SMCs, were isolated from arthroplasty specimens of RA (n=8) and OA (n=8) patients, respectively, using enzymatic digestion followed by cell propagation to obtain RA (n=5) and OA (n=3) FLS. Normal FLS and normal human foreskin fibroblasts (HSF) were purchased from commercial sources. Fibroblasts were stimulated with cytokines with or without baricitinib. RA SMCs were cultured in the presence of baricitinib without stimulation. JAK/STAT activation and levels of mRNA and proteins of the various inflammatory cytokines (IL-6, IL-8, MCP-1, RANTES and IP-10) were determined by qPCR, ELISA and MSD. RESULTS: Baricitinib inhibited OSM-induced JAK signalling in RA synovial fibroblasts and effectively suppressed subsequent expression of the proinflammatory mediators IL-6, MCP-1 and IP-10. However, baricitinib was not effective in altering levels of spontaneously released TNFα, IL-6 and IL-8 in RA SMC. Although both TNFα and IL-1ß signal independently of the JAK/STAT pathway, in HSF, but not in RA FLS, baricitinib significantly inhibited TNFα- and IL-1ß-induced MCP-1 and IP-10 protein levels in a dose dependent manner. Furthermore, baricitinib did not inhibit TNFα- and IL-1ß-induced expression of IL-6, IL-8 and MCP-1 in RA FLS. CONCLUSIONS: These findings are consistent with known signalling pathways employed by OSM, TNFα and IL-1ß, but our data suggest that in HSF, baricitinib may have anti-inflammatory effects via downstream modulation of cytokines and chemokines produced in response to TNFα or IL-1ß.

The men of Nelson's navy: a comparative stable isotope dietary study of late 18th century and early 19th century servicemen from Royal Naval Hospital burial grounds at Plymouth and Gosport, England.

We present stable isotopic analyses of collagen from 80 servicemen excavated from the late 18th/early 19th century naval hospitals at Plymouth (50) and Haslar, Gosport (30) in southern England. Historical records suggest that, the diets of these two populations should be essentially identical. While δ(15) N of the rib collagen confirmed that naval servicemen were relatively well-catered for in terms of meat allowance (Plymouth average δ(15) N = 11.1‰, Gosport = 11.9‰), stable carbon isotope analysis produced average values for the two assemblages, which were significantly different (Plymouth average δ(13) C = -18.8‰, Gosport = -20.0‰). We postulate that these differences stem from divergent naval postings, with a greater proportion of Plymouth individuals serving in areas that entailed a greater input of C(4) foodstuffs. By comparison with published data from approximately contemporary burials at Snake Hill, Ontario, Canada and Chesapeake Bay, Virginia, we suggest that this area is the east coast of North America. For 15 of the 30 individuals from Gosport, we have data on ribs, femur, and dentine from the same skeleton, which appear to show that they came from a variety of locations in their preadolescence, but converged in dietary terms onto a "naval average," which is consistent with historical evidence for recruitment patterns into the Navy at the time. By comparison with published data from skeletons recovered from the wreck of the Mary Rose (sank 1545), we conclude that this naval diet was virtually unchanged from the 16th century to the end of the 18th century.