Abstract
IntroductionInterleukin (IL)-27 is a novel member of the IL-6/IL-12 family cytokines that are produced early by antigen-presenting cells in T helper (Th)1-mediated inflammation. Elevated expression of IL-27 has been detected in the synovial membranes and fluid of rheumatoid arthritis (RA).MethodsWe investigated the in vitro effects of IL-27, alone or in combination with inflammatory cytokine tumor necrosis factor (TNF)-α or IL-1 β on the pro-inflammatory activation of human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects, and the underlying intracellular signaling molecules were determined by intracellular staining using flow cytometry.ResultsSignificantly higher plasma concentration of IL-27 was found in RA patients (n = 112) than control subjects (n = 46). Both control and RA-FLS constitutively express functional IL-27 receptor heterodimer, gp130 and WSX-1, with more potent IL-27-mediated activation of signal transducers and activators of transcription (STAT)1 in RA-FLS. IL-27 was found to induce significantly higher cell surface expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and release of inflammatory chemokine IL-6, CCL2, CXCL9, CXCL10 and matrix metalloproteinase-1 of RA-FLS than that of control FLS (all P < 0.05). Moreover, an additive or synergistic effect was observed in the combined treatment of IL-27 and TNF-α or IL-1 β on the surface expression of ICAM-1 and VCAM-1 and the release of CXCL9 and CXCL10 of RA-FLS. Further investigations showed that the expression of ICAM-1, VCAM-1 and chemokines stimulated by IL-27 was differentially regulated by intracellular activation of phosphatidylinositol 3-OH kinase-AKT, c-Jun amino-terminal kinase and Janus kinase pathways.ConclusionsOur results therefore provide a new insight into the IL-27-activated immunopathological mechanisms mediated by distinct intracellular signal transductions in joint inflammation of RA.
Highlights
Interleukin (IL)-27 is a novel member of the IL-6/IL-12 family cytokines that are produced early by antigen-presenting cells in T helper (Th)1-mediated inflammation
Quantitative real time PCR analysis showed that gp130 and WSX1 mRNA was highly expressed in control and rheumatoid arthritis (RA)-fibroblast-like synoviocytes (FLS), and PBMC (Figure 1A, B)
We found that IL-27 was able to induce significantly higher expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and to augment tumor necrosis factor (TNF)-α- and IL-1β-induced ICAM-1 and VCAM-1 on RA-FLS than that of control FLS (Figures 4 and 5), providing a novel immunopathological mechanism of IL-27 mediated joint inflammation in RA
Summary
Interleukin (IL)-27 is a novel member of the IL-6/IL-12 family cytokines that are produced early by antigen-presenting cells in T helper (Th)1-mediated inflammation. Rheumatoid arthritis (RA) is a chronic autoimmune disease with 1% prevalence in the industrialized countries, characterized by cytokine-mediated inflammation of the synovial lining of the diarthrodial joints and the destruction of cartilage and bone [1]. In RA, FLS respond to inflammatory cytokines including interleukin (IL)-1β, 6, 8, 12, 17, 18, 21, tumor necrosis factor (TNF)-α and interferon (IFN)-γ through the activation of multiple intracellular signaling pathways including extracellular signal-regulated protein kinase (ERK), c-Jun amino-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK), leading to the expression of multiple cytokines such as IL-1β, IL-6, and TNF-α, as well as the secretion of MMPs that contribute to tissue destruction [3,5,6,7,8]. Secretion of IL-15 from FLS, along with the other cytokines, activates T cells, neutrophils and macrophages [10]
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