Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

Harigai, Masayoshi; Hara, Masako; Kawamoto, Manabu; Kawaguchi, Yasushi; Sugiura, Tomoko; Tanaka, Michi; Nakagawa, Minoru; Ichida, Hisae; Takagi, Kae; Higami-Ohsako, Satomi; Shimada, Kaoru; Kamatani, Naoyuki

doi:10.1002/art.20340

Cited by 31 publications

(23 citation statements)

References 57 publications

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“…The reduction in TNF␣ and IL-6 expression is likely to be a direct consequence of CD40 down-regulation. T cells from patients with RA express abundant CD40L (37), and CD40-CD40L interactions have been shown to regulate macrophage activation and production of inflammatory cytokines such as TNF␣ and IL-6 locally in the joints (38)(39)(40). Moreover, Nov038 delivers CD40-ASO to myeloid DCs, major regulators of the immune system processes leading to immunity or tolerance.…”

Section: Discussionmentioning

confidence: 99%

Amphoteric liposomes enable systemic antigen‐presenting cell–directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis

Andreakos¹,

Rauchhaus²,

Stavropoulos³

et al. 2009

Arthritis & Rheumatism

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Objective. Mediation of RNA interference by oligonucleotides constitutes a powerful approach for the silencing of genes involved in the pathogenesis of inflammatory disease, but in vivo application of this technique requires effective delivery to immune cells and/or sites of inflammation. The aim of the present study was to develop a new carrier system to mediate systemic administration of oligonucleotides to rheumatoid arthritis (RA) joints, and to develop an antisense oligonucleotide (ASO)-based approach to interfere with CD40-CD154 interactions in an experimental model of RA.Methods. A novel liposomal carrier with amphoteric properties, termed Nov038, was developed and assessed for its ability to systemically deliver an ASO directed against CD40 (CD40-ASO). Male DBA/1 mice with collagen-induced arthritis were treated with Nov038-encapsulated CD40-ASO, and the effects of treatment on various parameters of disease activity, including clinical score, paw swelling, lymph node responses, and inflammatory cytokine production in the joints, were assessed. Results. Nov038 was well tolerated, devoid of immune-stimulatory effects, and efficacious in mediating systemic oligonucleotide delivery to sites of inflammation. In mice with collagen-induced arthritis, Nov038 enabled the therapeutic administration of CD40-ASO and improved established disease, while unassisted CD40-ASO was ineffective, and anti-tumor necrosis factor ␣ (anti-TNF␣) treatment was less effective in this model. Nov038/CD40-ASO efficacy was attributed to its tropism for monocyte/macrophages and myeloid dendritic cells (DCs), resulting in rapid downregulation of CD40, inhibition of DC antigen presentation, and reduction in collagen-specific T cell responses, as well as decreased levels of TNF␣, interleukin-6 (IL-6), and IL-17 in arthritic joints.Conclusion. Amphoteric liposomes represent a novel carrier concept for systemic and antigen-presenting cell-targeted oligonucleotide delivery with clinical applicability and numerous potential applications, including target validation in vivo and inflammatory disease therapeutics. Moreover, Nov038/CD40-ASO constitutes a potent alternative to monoclonal antibodybased approaches for interfering with CD40-CD40L interactions.Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology that is characterized

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Section: Discussionmentioning

confidence: 99%

Amphoteric liposomes enable systemic antigen‐presenting cell–directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis

Andreakos¹,

Rauchhaus²,

Stavropoulos³

et al. 2009

Arthritis & Rheumatism

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“…Proinflammatory cytokine/chemokine synthesis and secretion require the activation of MEK/ERK and NF-B pathways. The importance of CD40 signaling through MEK/ERK MAPK family members in inflammatory responses of monocytes and macrophages (28), synovial cells (20), and human proximal tubule cells (21) is well recognized. To study CD40-mediated activation of this pathway in ␤-cells, we began our experiments using NIT-1 cells (29) because these are an acceptable surrogate of primary ␤-cells, given the limited availability and cost of human or NHP islets for research.…”

Section: Diabetes Vol 55 September 2006mentioning

confidence: 99%

“…Previous reports have shown that a significant number of genes are induced by CD40 in nonimmune cells, including genes associated with costimulation signals (42), cytokine secretion (10,20,43), apoptosis induction (44), cell survival (45), and inflammation (46). Earlier studies showed that CD40 signaling results in the activation of the MEK/NF-B pathways in monocytes/macrophages (28,43,47) and synovial (20) and epithelial (46) cells.…”

Section: Cd40 Triggers Inflammatory Pathways In Isletmentioning

confidence: 99%

“…Earlier studies showed that CD40 signaling results in the activation of the MEK/NF-B pathways in monocytes/macrophages (28,43,47) and synovial (20) and epithelial (46) cells. Here, we show that the same pathways are activated in pancreatic ␤-cells.…”

Section: Cd40 Triggers Inflammatory Pathways In Isletmentioning

confidence: 99%

“…In vitro studies indicate that CD40 activation in duct cells induces secretion of IL-1␤ and TNF-␣ (10), which in turn activates dendritic cells and triggers apoptosis in neighboring ␤-cells (19). Moreover, it has been reported that CD40 signaling activates mitogenactivated protein kinase (MAPK), pathways frequently involved in inflammatory responses in other cell types such as synovial cells (20) and human proximal tubule cells (21).…”

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CD40–CD40 Ligand Interaction Activates Proinflammatory Pathways in Pancreatic Islets

et al. 2006

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Pancreatic islet transplantation is becoming an alternative to insulin therapy in patients suffering from brittle type 1 diabetes. A major obstacle to the procedure is the early graft loss caused by nonspecific inflammation at the site of implantation. We recently discovered that CD40, a member of tumor necrosis factor (TNF) receptor family, is expressed in pancreatic ␤-cells. CD40 expression in nonhematopoietic cells is generally associated with inflammation. Therefore, we investigated the potential proinflammatory role of CD40 in human and nonhuman primate islets.

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Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF‐κB/Rel proteins via the p38 mitogen‐activated protein kinase pathway, and of the MEK‐1/ERK pathway

López‐Pedrera¹,

Buendía²,

Cuadrado³

et al. 2005

Arthritis & Rheumatism

192

157

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Objective. Antiphospholipid syndrome (APS) is characterized by thrombosis and the presence of antiphospholipid antibodies (aPL).In patients with primary APS, expression of tissue factor (TF) on the surface of monocytes is increased, which may contribute to thrombosis in these patients. However, the intracellular mechanisms involved in aPL-mediated upregulation of TF on monocytic cells are not understood. This study was undertaken to investigate the intracellular signals induced by aPL that mediate TF activation in monocytes from APS patients.Methods. We analyzed, both in vivo and in vitro, aPL interactions with proteins that have signaling functions, including mitogen-activated protein kinases (MAP kinases) and NF-B/Rel proteins.Results. In vivo studies demonstrated significantly higher levels of both TF messenger RNA and TF protein in monocytes from APS patients compared with controls. At the molecular level, increased proteolysis of I B␣ and activation of NF-B were observed. Constitutive activation of both p38 and ERK-1 MAP kinases was also found. Treatment of normal monocytes with aPL activated ERK-1 and p38 MAP kinases, as well as the I B/NF-B pathway, in a dose-dependent manner. NF-B activation and I B␣ degradation induced by aPL were inhibited by the NF-B inhibitor SN50 and the p38 MAP kinase inhibitor SB203580, thus suggesting crosstalk between these pathways. However, the MEK-1/ERK inhibitor PD98059 did not affect aPLinduced NF-B binding activity. TF expression induced by aPL was significantly inhibited by combined treatment with the 3 inhibitors.Conclusion. Our results suggest that aPL induces TF expression in monocytes from APS patients by activating, simultaneously and independently, the phosphorylation of MEK-1/ERK proteins, and the p38 MAP kinase-dependent nuclear translocation and activation of NF-B/Rel proteins.

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Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

Cited by 31 publications

References 57 publications

Amphoteric liposomes enable systemic antigen‐presenting cell–directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis

Amphoteric liposomes enable systemic antigen‐presenting cell–directed delivery of CD40 antisense and are therapeutically effective in experimental arthritis

CD40–CD40 Ligand Interaction Activates Proinflammatory Pathways in Pancreatic Islets

Antiphospholipid antibodies from patients with the antiphospholipid syndrome induce monocyte tissue factor expression through the simultaneous activation of NF‐κB/Rel proteins via the p38 mitogen‐activated protein kinase pathway, and of the MEK‐1/ERK pathway

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