Regulation of interleukin‐18 binding protein production by blood and synovial cells from patients with rheumatoid arthritis

Abstract

Objective. To study the regulation of interleukin-18 binding protein (IL-18BP) production by rheumatoid arthritis (RA) or control peripheral blood mononuclear cells (PBMCs) and by RA synovial tissue cells, and to compare the levels of IL-18BP messenger RNA (mRNA) expression in whole blood from RA patients and controls.Methods. Unstimulated or phytohemagglutinin and phorbol myristate acetate (PHA/PMA)-stimulated PBMCs from 10 RA patients and 12 healthy controls and unstimulated or PHA/PMA-stimulated synovial tissue cells from 8 RA patients were cultured with or without IL-12 (1 ng/ml) and IL-18 (5 ng/ml) alone or in combination. IL-18BP and interferon-␥ (IFN␥) levels in supernatants were measured by enzyme-linked immunosorbent assay. Levels of IL-18BP and IFN␥ mRNA expression in whole blood samples from 22 RA patients and 12 healthy controls were determined by quantitative reverse transcriptase-polymerase chain reaction.Results. IL-12 decreased the basal levels of IL-18BP production by freshly isolated RA or control PBMCs, but increased those of synovial cells or PHA/ PMA-stimulated PBMCs. IL-18 alone had no direct effect on IL-18BP production by PBMCs or RA synovial cells, with or without stimulation. Unstimulated whole blood samples from RA patients showed lower levels of IL-18BP mRNA expression than those from healthy controls. Conclusion.The production of IL-18BP in response to IL-12 and IL-18 was regulated differently in blood and synovial cells. The difference appears to be related to the level of cell activation.

HLA-DRB1⁎04 gene polymorphisms and expressions profiles of interleukin-18 and interleukin-18 binding protein following in vitro stimulation in human peripheral blood mononuclear cells of healthy individuals and patients with rheumatoid arthritis

“…The reduced IL-18BP mRNA expression in PBMCs from RA patients may in turn enhance the IL-18 bioactivity, leading to the proinflammatory profile characteristic of RA. In line with our results, Kawashima et al (2004) have reported recently that unstimulated whole blood samples from RA patients showed lower levels IL-18BP mRNA expression (by RT-PCR) than those from healthy controls. In our previous study, we have observed significant levels of IL-18 in the serum samples of RA patients.…”

“…Cytokines play important roles in various pathophysiological processes in human. Thus, quantification of cytokine mRNA levels are potentially useful as sensitive markers for determination of the state of immune cell activation (Kawashima et al, 2004). Moreover, the sequential determination of cytokine mRNA patterns could become a valuable tool for monitoring patients and improving therapy in a variety of clinical settings such as infectious diseases, autoimmune disorders or organ transplantation.…”

“…The PBMC preparations comprise different cell types with lymphocytes and monocytes representing the two major cell populations (Barth et al, 2000). Various stimuli may act through different signaling pathways (Kawashima et al, 2004;Gauchat et al, 1989) to modulate cytokine profile. In the present study, we used two different types of activators PHA (mitogen acting through the CD3 molecule, as well as the T-cell receptor), and LPS (antigen interacting with the CD14 cells) (Fan et al, 1998) to examine the time kinetics of the IL-18 and IL-18BP gene expressions.…”

Expression of interleukin-18, IL-18BP, and IL-18R in serum, synovial fluid, and synovial tissue in patients with rheumatoid arthritis

“…Here, we detected the levels of IL-18BP in synovial fluid, serum, and IL-18BP expression in synovial tissue. We found that IL-18BP decreased in serum, synovial fluid, and synovial tissue along with the increases of IL-18 and IFN-c. An in vitro study [34] indicated that production of IL-18BP did not increase without stimulation of IL-12 in the culture supernatants of PBMCs and synovial tissue from RA patients. As a constitutively secreted protein, IL-18BP is able to bind IL-18 with high affinity, providing a potential mechanism whereby IL-18 activity could be regulated.…”

Role of cytokines in the pathogenesis of rheumatoid arthritis

“…При РА ИЛ 18 обнаруживается в синовиальной обо-лочке сустава и синовиальной жидкости, причем высокий уровень в очаге воспаления ассоциируется со снижением его продукции мононуклеарными клетками перифериче-ской крови [40]. Повышение уровня ИЛ 18 коррелирует с активностью заболевания.…”