Regulation of TNFα and IL1β in rheumatoid arthritis synovial fibroblasts by leukotriene B4

Abstract

Arachidonic acid metabolites, such as leukotriene B4 (LTB4), are known to play an important role in pathogenesis of rheumatoid arthritis (RA). Apart from leukocytes, RA synovial fibroblasts (RASF) produce a broad array of inflammatory mediators to recruit, retain and activate immune cells and resident mesenchymal cells in the joints to promote ongoing inflammation and tissue destruction. To determine how LTB4 may contribute to this process, RASF was cultured from synovial tissues collected from RA patients undergoing total knee replacement. The level of LTB4 in culture medium was determined using ELISA, and expression of LTB4 receptors (BLT1 and BLT2) by RT-PCR. In the presence of exogenous LTB4, mRNA and protein levels of tumor necrosis factor-alpha (TNFalpha) and interleukin 1beta (IL1beta) were determined by real-time PCR and ELISA. Furthermore, we examined the effects of leukotrienes synthesis inhibitors, MK886 and bestatin, on mRNA and protein levels of TNFalpha and IL1beta in RASF. We found that LTB4 was present at a low concentration in the culture medium of RASF, and the major LTB4 receptor expressed in RASF was BLT2. LTB4 synthesis was activated by treatment with LIT (LPS, ionomycin and thapsogargin), and suppressed by MK886 and bestatin. Exogenous LTB4 remarkably increased the expression of TNFalpha and IL1beta at both the mRNA level and the protein level. In contrast, MK886 and bestatin significantly inhibited their expression. These data suggested that LTB4 contributed to RA by regulating the expression of TNFalpha and IL1beta in RASF. BLT2 was probably the major receptor mediating such effects.

5-Lipoxygenase Inhibitors Attenuate TNF-α-Induced Inflammation in Human Synovial Fibroblasts

“…Recent study has suggested that LTB4 is an essential and non-redundant role in both acute and chronic inflammation of rheumatoid arthritis [10]. In addition, exogenous LTB4 could increase the expression of cytokines like TNF-α and IL-1β in human synovial fibroblasts [26]. We thus investigated whether LTB4 is involved incytokines release in human synovial fibroblasts.…”

Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes

“…Under various disease states, leukocytes can be activated to locally produce LTs that initiate and amplify the inflammatory process [14,17,19]. For example, LTB 4 binds to BLT1, leading to activation of NF-B inflammatory cascades, generation of cytokines, and production of ROS [33][34][35][36]. Our previous studies have suggested a role for LTs in the development of early stages of DR [20,37].…”

Activated LTB4 pathway in muscle tissue of patients with polymyositis or dermatomyositis

“…It is rapidly formed by macrophages, neutrophils, mast cells and dendritic cells and is a powerful chemoattractant for myeloid leukocytes as well as for activated T cells, inducing their migration into inflamed tissue 7. LTB4 is also involved in the differentiation of naïve murine T cells by inhibiting the differentiation of regulatory T cells and promoting Th17 cells,8 and can also augment the cytokine production by activated T cells 9. Thus, LTB4 may have a role in chronic inflammatory processes such as muscle inflammation in PM/DM.…”