Apoptosis as a target for gene therapy in rheumatoid arthritis

Rabinovich, Gabriel A.

doi:10.1590/s0074-02762000000700038

Cited by 13 publications

(4 citation statements)

References 55 publications

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“…Recent papers have shown that a pan-caspase inhibitor improves survival in a murine sepsis model (18). Caspases, as targets of gene therapy in rheumatoid arthritis, have been reported to have a therapeutic advantage (19). The effect of zVAD on the viability of macrophages could influence the outcome of these therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

Orphan Nuclear Receptor Nur77 Is Involved in Caspase-independent Macrophage Cell Death

Kim

Ono

Tobias

et al. 2003

The Journal of Experimental Medicine

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Activation-induced cell death in macrophages has been observed, but the mechanism remains largely unknown. Activation-induced cell death in macrophages can be independent from caspases, and the death of activated macrophages can even be triggered by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (zVAD). Here, we show that this type of macrophage death can occur in the septic mouse model and that toll-like receptor (TLR)-2 or TLR4 signaling is required in this process. We conclude that Nur77 is involved in the macrophage death because Nur77 expression correlates with cell death, and cell death is reduced significantly in Nur77-deficient macrophages. The extracellular signal–regulated kinase pathway, which is downstream of TLR2 or TLR4, and myocyte-specific enhancer binding factor 2 (MEF2) transcription factor activity, which is up-regulated by zVAD, are required for Nur77 induction and macrophage death. Reporter gene analysis suggests that Nap, Ets, Rce, and Sp1 sites in the Nur77 promoter are regulated by TLR4 signaling and that MEF2 sites in the Nur77 promoter are regulated by zVAD treatment. MEF2 transcription factors are constitutively expressed and degraded in macrophages, and zVAD increases MEF2 transcription factor activity by preventing the proteolytic cleavage and degradation of MEF2 proteins. This paper delineates the dual signaling pathways that are required for Nur77 induction in macrophages and demonstrates a role of Nur77 in caspase-independent cell death.

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Section: Introductionmentioning

confidence: 99%

Orphan Nuclear Receptor Nur77 Is Involved in Caspase-independent Macrophage Cell Death

Kim

Ono

Tobias

et al. 2003

The Journal of Experimental Medicine

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“…We assessed the preventive and therapeutic effects of Gal-1 in a murine model of CIA by means of gene and protein therapy strategies (Figure 3). Mice were immunized with type-II collagen to elicit cellular and humoral arthritogenic responses [115,116]. Daily injections of recombinant Gal-1 or transfer of genetically-modified fibroblasts secreting high levels of this lectin, reduced the frequency of circulating anti-collagen immunoglobulins, particularly IgG2a in mice with CIA.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

Recalibrating Immunity in Cancer and Autoimmune Inflammation by Galectin-1-Driven Regulatory Circuits

Bach¹,

Cutine²,

Laporte³

et al. 2020

scirevfew

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Endogenous lectins play key roles in cell homeostasis by decoding the information encrypted in glycans present on the cell surface or extracellular matrix. Galectins, a family of soluble lectins, have emerged as central regulators of innate and adaptive immune responses. In this article, we review seminal work demonstrating the immunoregulatory roles of Galectin-1 (Gal-1), a proto-type member of the galectin family, and highlight central mechanisms that control its functions in cancer and autoimmune inflammation. Understanding the cellular pathways that control Gal-1 expression and function in tumor and inflammatory microenvironments will set the bases for the design of rational therapies based on positive or negative modulation of this endogenous lectin in cancer and autoimmune diseases.

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“…It has already been demonstrated that the aberrant apoptosis of fibroblast‐like synoviocytes in patients with RA, which in turn facilitates pannus formation, consequently induces destruction of cartilage/bone and protection of infiltrated cells from apoptosis (Korb, Pavenstadt, & Pap, ). Some mechanisms are described to be involved in this process, such as increased levels of TNF‐α, which activates NF‐ κB and IL‐1β, which in turn induces overexpression of Bcl‐2 family protein and mutations of p53 (Rabinovich, ). Therefore, genetic synovectomy by targeting various suicide molecules, (listed in Table ), has been suggested for gene therapy to cover a broader therapeutic spectrum, including synovial cell apoptosis promotion, inflammatory exudates decrease, as well as new matrix deposition (Bokarewa, ).…”

Section: Therapeutic Strategies For Ra Gene Therapymentioning

confidence: 99%

Gene therapy in rheumatoid arthritis: Strategies to select therapeutic genes

Zavvar

Assadiasl

Soleimanifar

et al. 2019

Journal Cellular Physiology

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Significant advances have been achieved in recent years to ameliorate rheumatoid arthritis (RA) in animal models using gene therapy approaches rather than biological treatments. Although biological agents serve as antirheumatic drugs with suppressing proinflammatory cytokine activities, they are usually accompanied by systemic immune suppression resulting from continuous or high systemic dose injections of biological agents. Therefore, gene transfer approaches have opened an interesting perspective to deliver one or multiple genes in a target‐specific or inducible manner for the sustained intra‐articular expression of therapeutic products. Accordingly, many studies have focused on gene transferring methods in animal models by using one of the available approaches. In this study, the important strategies used to select effective genes for RA gene therapy have been outlined. Given the work done in this field, the future looks bright for gene therapy as a new method in the clinical treatment of autoimmune diseases such as RA, and by ongoing efforts in this field, we hope to achieve feasible, safe, and effective treatment methods.

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Apoptosis as a target for gene therapy in rheumatoid arthritis

Cited by 13 publications

References 55 publications

Orphan Nuclear Receptor Nur77 Is Involved in Caspase-independent Macrophage Cell Death

Orphan Nuclear Receptor Nur77 Is Involved in Caspase-independent Macrophage Cell Death

Recalibrating Immunity in Cancer and Autoimmune Inflammation by Galectin-1-Driven Regulatory Circuits

Gene therapy in rheumatoid arthritis: Strategies to select therapeutic genes

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