Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis

Baldwin, Helen; Ito‐Ihara, Toshiko; Isaacs, John D.; Hilkens, Catharien M. U.

doi:10.1136/ard.2009.110502

Cited by 60 publications

(49 citation statements)

References 40 publications

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“…3C, 3D). Our data also support a report on the reduced survival of LPS-stimulated DCs after TNF neutralization (41). Similar data obtained with human plasmacytoid pre-DCs as well as murine macrophages highlight the general relevance of TLR-induced autocrine TNF for the survival of APCs (42,43).…”

Section: Discussionsupporting

confidence: 79%

“…Therapeutic targeting of DCs has been suggested in autoimmune diseases such as rheumatoid arthritis (59). Just recently, Baldwin et al (41) reported impaired DC maturation and also increased apoptosis after TNF blockade in vitro and in vivo, also supporting the model in which TNF appears as the central cytokine regulating DC survival. Beyond illustrating the important role of different levels of autocrine TNF in the context of microbial stimulation, our data now reveal a molecular mechanism linking the capacity of the cell to produce its autocrine survival factor to the regulation of the intrinsic pathway of apoptosis by the balance of pro-and antiapoptotic members of the BCL-2 family.…”

Section: Discussionmentioning

confidence: 85%

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Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Lehner

Kellert

Proff

et al. 2012

The Journal of Immunology

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The life span of dendritic cells (DCs) is determined by the balance of pro- and antiapoptotic proteins. In this study, we report that serum-free cultured human monocyte-derived DCs after TLR stimulation with polyinosinic acid-polycytidylic acid or LPS underwent apoptosis, which was correlated with low TNF production. Apoptosis was prevented by the addition of exogenous TNF or by concomitant stimulation with R-848, which strongly amplified endogenous TNF production. Neutralization of TNF confirmed that DC survival was mediated by autocrine TNF induced either by stimulation with R-848 or by ligation of CD40. DCs stimulated by polyinosinic acid-polycytidylic acid or IFN-β, another known inducer of DC apoptosis, were characterized by high levels and activation of the proapoptotic protein BAK. The ratio of antiapoptotic BCL-2 to BAK correlated best with the survival of activated DCs. Addition of TNF increased this ratio but had little effect on BAX and XIAP. Knockdown experiments using small interfering RNAs confirmed that the survival of activated and also of immature DCs was regulated by BAK and showed that TNF was protective only in the presence of FLIPL. Together, our data demonstrate that the survival of DCs during differentiation and activation depends on autocrine TNF and that the inhibition of BAK plays an important role in this process.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 85%

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Lehner

Kellert

Proff

et al. 2012

The Journal of Immunology

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“…Autocrine TNF-a was previously shown to provide survival signals to DCs (20). Blocking of TNF-a with either soluble p55TNFR-Fc or anti-TNF-a mAb (infliximab) significantly reduced survival of LPS-matured DCs (31). We show in the present study that survival of Col-DCs was impaired by treatment with Enbrel, although to a much lower degree than by treatment with anti-OSCAR mAb.…”

Section: Discussionsupporting

confidence: 46%

Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

Schultz

Nitze

Zeuthen

et al. 2015

The Journal of Immunology

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Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-κB–dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR–collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs.

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“…Other studies reported on the direct effect of sulphasalazine on neutrophil apoptosis [176] or the role that monocytes play in the inhibition of glucocorticoid-mediated apoptosis in RA [177]. synoviocyte apoptosis have focused on those investigations in which RA patients have responded to these drugs in a clinically meaningful way [178][179][180][181][182].…”

Section: Apoptotic Responses To Anti-ra Therapiesmentioning

confidence: 99%

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

Malemud¹

2012

J Clin Cell Immunol

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Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis

Cited by 60 publications

References 40 publications

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL

Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

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