Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis.

Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis.

Arthritis research & therapy (2010-07-08)

Chun K Wong, Da P Chen, Lai S Tam, Edmund K Li, Yi B Yin, Christopher W K Lam

PMID20604932

摘要

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. Elevated expression of IL-27 has been detected in the synovial membranes and fluid of rheumatoid arthritis (RA). We 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. Significantly 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. Our results therefore provide a new insight into the IL-27-activated immunopathological mechanisms mediated by distinct intracellular signal transductions in joint inflammation of RA.

材料

Product Number

品牌

产品描述

440202

Sigma-Aldrich

LY 294002, LY294002, CAS 154447-36-6, is a cell-permeable, potent, reversible, and specific inhibitor of PI 3-kinase ((IC₅₀ = 1.4 µM). Acts on the ATP-binding site.

559389

Sigma-Aldrich

SB 203580, SB 203580, CAS 152121-47-6, is a highly specific, potent, cell-permeable, selective, reversible, and ATP-competitive inhibitor of p38 MAP kinase (IC₅₀ = 34 nM in vitro, 600 nM in cells).

513000

Sigma-Aldrich

PD 98059, PD 98059, CAS 167869-21-8, is a cell-permeable, selective & reversible inhibitor of MAP Kinase Kinase (MEK). Inhibits MAP Kinase activation and subsequent phosphorylation of MAP Kinase substrates.

420119

Sigma-Aldrich

JNK抑制剂II, JNK Inhibitor II. SP600125, CAS 129-56-6, is a potent, cell-permeable, selective, and ATP competitive inhibitor of c-Jun N-terminal kinase (JNK; IC₅₀ = 40 nM for JNK-1 & JNK-2 & 90 nM for JNK-3).

658401

Sigma-Aldrich

AG 490, A cell-permeable, reversible, substrate competitive, and potent inhibitor of epidermal growth factor receptor kinase autophosphorylation (IC₅₀ = 100 nM).