Objective. To test the hypotheses that 1) proinflammatory cytokines affect osteoprotegerin (OPG) and soluble receptor activator of nuclear factor B ligand (sRANKL) production and therefore the OPG and sRANKL levels differ in rheumatoid arthritis (RA) patients in comparison with healthy individuals; and 2) anti-tumor necrosis factor ␣ (anti-TNF␣) therapy influences OPG and sRANKL levels.Methods. Sera were obtained from healthy individuals or RA patients receiving the combination of infliximab and methotrexate. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were isolated from RA patients. Fibroblast-like synoviocytes (FLS) were isolated from synovial tissue obtained at total knee replacement in RA patients. Supernatants from cells stimulated with cytokines were collected after culture in vitro. Concentrations of OPG and sRANKL were determined by enzymelinked immunosorbent assays.Results. A strong positive correlation between OPG concentration and age was observed in healthy individuals but not in RA patients. The OPG and sRANKL levels were higher in RA patients than in healthy controls. Cultured FLS spontaneously secreted much higher amounts of OPG than PBMCs or SFMCs. Proinflammatory cytokines enhanced OPG production. Anti-TNF␣ treatment resulted in the normalization of serum OPG and sRANKL levels in RA patients without influencing the OPG:sRANKL ratio.Conclusion. Although higher serum levels of OPG and sRANKL are present in RA patients than in healthy individuals, the ratio of OPG:sRANKL is similar. There is an age-dependent increase of OPG but not sRANKL levels in healthy subjects. Anti-TNF␣ treatment results in the normalization of elevated levels of OPG and sRANKL in RA patients.Bone remodeling and bone loss are controlled by a balance between tumor necrosis factor (TNF) superfamily molecules: osteoprotegerin/osteoclastogenesis inhibitory factor (OPG/OCIF), receptor activator of nuclear factor B ligand (RANKL), receptor activator of nuclear factor B (RANK), and TNF-related apoptosisinducing ligand (TRAIL) (1-4). RANKL plays a key role in the regulation of osteoclastogenesis, osteoclast activation, dendritic cell survival, lymphocyte development, and lymph node organogenesis (5). Recent data Presented in part at

This article describes the chemical modification of polyethylene terephthalate (PET) with a variety of compounds containing reactive glycidyl group(s). Four different modifiers, namely, diglycidyl ether of bisphenol‐A (DGEBA), N,N′‐bis[3(carbo‐2′,3′‐epoxypropoxy) phenyl] pyromellitimide (BGPM), triglycidyl glycerol (TGG), and triglycidyl isocyanurate (TGIC) were compared for their reactivity toward PET in the melt phase. It was found that the presence of tertiary nitrogen in the structure of the epoxide modifiers plays the role of in‐built catalyst for their reaction with the end groups of PET. TGIC as a modifier was selected for the detailed investigation of the simultaneously occurring degradation and chain extension/branching reactions in a batch‐melt mixer. The reactions were followed by torque changes, analyzing the products for residual carboxyl content, and by determining insoluble content. It is shown that the rate of the reactive modification of PET melt by TGIC depends upon stoichiometry, temperature, rate of shear, and the chemical composition and the molecular weight (MW) of the PET resin. In general, the results indicate an increase in melt viscosity and insoluble content, whereas an overall decrease in carboxyl content occurs, as defined by the choice of mixing conditions and stoichiometry. Analysis of the batch kinetic data can be useful to define the process requirements for carrying out the reactive modification in continuous extrusion equipment. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 643–652, 2003

The implication of select protein kinase C (PKC) isoenzymes in cytokine production by human monocytes was investigated using an isozymeselective inhibitor of PKC, rottlerin. We found that lipopolysaccharide (LPS) triggers cytosol-to-membrane translocation of PKC␣ and ␦ isoenzymes, whereas phorbol ester (

The most specific autoimmunity known for rheumatoid arthritis (RA) is reflected by generation of anti-citrullinated protein antibodies (ACPA). Presence of ACPA in established RA is associated with disease severity, while generation of ACPA at early developmental phases of RA can have a strong predictive value for progressing to the full-blown disease. Hence, development of ACPA may be of crucial importance to the pathogenesis of RA. Therefore, a lot of effort has been put recently to investigate the feature of ACPA at early developmental stages of RA (before disease onset) and functional activities of these autoantibodies. Results of these studies enlarged the knowledge about the nature of ACPA, which is essential for planning the therapeutic or preventive strategies interfering with their development and pathogenic functions. In this review we describe recent evidence for a role of ACPA in the etiopathogenesis of RA and indicate key unresolved issues regarding ACPA biology that need to be clarified in the future.

The hallmarks of rheumatoid arthritis (RA) are leukocytic infiltration of the synovium and expansiveness of fibroblast-like synoviocytes (FLS). The abnormal proliferation of FLS and their resistance to apoptosis is mediated, at least in part, by present in RA joints proinflammatory cytokines and growth factors. Because IL-15 exerts properties of antiapoptotic and growth factors, and is produced by RA FLS, we hypothesized that IL-15 participates in RA FLS activation. To test this hypothesis, we first examined whether RA FLS express chains required for high affinity functional IL-15R. Indeed, RA FLS express IL-15Rα at mRNA and protein levels. Moreover, we confirmed the presence of IL-2Rβ and common γ-chains. Interestingly, TNF-α or IL-1β triggered significant elevation of IL-15Rα chain at mRNA and protein levels. Next, we investigated the effects of exogenous or endogenous IL-15 on Bcl-2 and Bcl-xL expression, FLS proliferation, and apoptosis. Exogenous IL-15 enhanced RA FLS proliferation and increased the level of mRNA-encoding Bcl-xL. To test the role of endogenous IL-15 in the activation of RA FLS, an IL-15 mutant/Fcγ2a protein exerting properties of specific antagonist to the IL-15Rα chain was used. We found that blocking IL-15 biological activities using this protein substantially reduced endogenous expression of Bcl-2 and Bcl-xL, and RA FLS proliferation that was reflected by increased apoptosis. Thus, we have demonstrated that a distinctive phenotype of RA FLS, i.e., persistent activation, proliferation, and resistance to apoptosis, is related to the autocrine activation of IL-15Rs by FLS-derived IL-15.