The role of lymphotoxin-α in rheumatoid arthritis

Hirose, Tomohiro; Fukuma, Yuri; Takeshita, Ayumu; Nishida, Keiichiro

doi:10.1007/s00011-018-1139-6

Cited by 24 publications

(20 citation statements)

References 46 publications

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“…However, the involvement of LTα in inflammatory diseases is less well characterized than sTNF and a RA clinical trial using the anti-lymphotoxin-alpha antibody pateclizumab did not show statistically significant improvement in RA signs and symptoms (Kennedy et al, 2014). Differences between sTNF and LTα have been described elsewhere (Ruddle, 2014;Hirose et al, 2018). In this review, we will summarize the current knowledge of signal pathways emanating from the two TNFRs, their patho-/physiologic role and discuss recent promising results obtained in different disease models in the pre-clinical development of novel TNFR selective drugs.…”

Section: Introductionmentioning

confidence: 99%

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Fischer

Kontermann

Pfizenmaier

2020

Front. Cell Dev. Biol.

151

146

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Tumor necrosis factor (TNF) is a central regulator of immunity. Due to its dominant proinflammatory effects, drugs that neutralize TNF were developed and are clinically used to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. However, despite their clinical success the use of anti-TNF drugs is limited, in part due to unwanted, severe side effects and in some diseases its use even is contraindicative. With gaining knowledge about the signaling mechanisms of TNF and the differential role of the two TNF receptors (TNFR), alternative therapeutic concepts based on receptor selective intervention have led to the development of novel protein therapeutics targeting TNFR1 with antagonists and TNFR2 with agonists. These antibodies and bio-engineered ligands are currently in preclinical and early clinical stages of development. Preclinical data obtained in different disease models show that selective targeting of TNFRs has therapeutic potential and may be superior to global TNF blockade in several disease indications.

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Section: Introductionmentioning

confidence: 99%

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Fischer

Kontermann

Pfizenmaier

2020

Front. Cell Dev. Biol.

151

146

View full text Add to dashboard Cite

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“…However, further studies revealed many differences between TNFβ and TNFα, especially in cell origin, secretion dynamics, signal transduction pathway, and gene expression regulation. Both TNFα and LTα can bind to TNF-receptors (TNFR1 or TNFR2); however, when LTα exists in heterotrimer form (LTα 1 β 2 or LTα 2 β 1 ), it can also bind to another unique receptor, the LTβ receptor (LTβR) [24]. In addition, the herpesvirus entry mediator (HVEM) may also act as a receptor for LTα [13].…”

Section: Discussionmentioning

confidence: 99%

Elevated lymphotoxin-α (TNFβ) is associated with intervertebral disc degeneration

Zhu

Qiu

Mecca

et al. 2021

BMC Musculoskelet Disord

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Background Intervertebral disc degeneration (IVDD) is a primary cause of degenerative disc diseases; however, the mechanisms underlying the degeneration remain unclear. The immunoinflammatory response plays an important role in IVDD progression. The inflammatory cytokine lymphotoxin-α (LTα), formerly known as TNFβ, is associated with various pathological conditions, while its role in the pathogenesis of IVDD remains elusive. Methods Real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and enzyme-linked immunosorbent assays were used to assess the levels of LTα in human nucleus pulposus (NP) tissues between degeneration and control groups. The plasma concentrations of LTα and C-reactive protein (CRP) were compared between healthy and IVDD patients. Rat primary NP cells were cultured and identified via immunofluorescence. Methyl-thiazolyl-tetrazolium assays and flow cytometry were used to evaluate the effects of LTα on rat NP cell viability. After NP cells were treated with LTα, degeneration-related molecules (Caspase-3, Caspase-1, matrix metalloproteinase (MMP) -3, aggrecan and type II collagen) were measured via RT-qPCR and WB. Results The levels of both the mRNA and protein of LTα in human degenerated NP tissue significantly increased. Plasma LTα and CRP did not differ between healthy controls and IVDD patients. Rat primary NP cells were cultured, and the purity of primary NP cells was > 90%. Cell experiments showed inversely proportional relationships among the LTα dose, treatment time, and cell viability. The optimal conditions (dose and time) for LTα treatment to induce rat NP cell degeneration were 5 μg/ml and 48 ~ 72 h. The apoptosis rate and the levels of Caspase-3, Caspase-1, and MMP-3 significantly increased after LTα treatment, while the levels of type II collagen and aggrecan were decreased, and the protein expression levels were consistent with their mRNA expression levels. Conclusions This study demonstrated that elevated LTα is closely associated with IVDD and that LTα may induce NP cell apoptosis and reduce important extracellular matrix (ECM) proteins, which cause adverse effects on IVDD progress. Moreover, the optimal conditions for LTα treatment to induce NP cell degeneration were determined.

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“…LTA, also known as TNF-, mediates a large variety of inflammatory and immunostimulatory responses. 21 In vitro studies showed that LTA induced proliferation and inflammatory cascade signaling in RA synovial-fibroblasts (RASFs) and chondrocytes. 22,23 CD83, dendritic cell marker, belongs to the immunoglobulin superfamily and has previously been associated with autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Imperatorin and β-sitosterol have synergistic activities in alleviating collagen-induced arthritis

Guo

Zheng

et al. 2020

Journal of Leukocyte Biology

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Rheumatoid arthritis (RA) is a chronic disease with complex molecular network of pathophysiology, single drug is usually not full satisfactory because it is almost impossible to target the whole molecular network of the disease. Drug combinations that act synergistically with each another is an effective strategy in RA therapy. In this study, we aimed to establish a new strategy to search effective synergized compounds from Chinese herbal medicine (CHM) used in RA. Based on multi‐information integrative approaches, imperatorin (IMP) and β‐sitosterol (STO) were predicted as the most effective pair for RA therapy. Further animal experiments demonstrated that IMP+STO treatment ameliorated arthritis severity of collagen‐induced arthritis (CIA) rats in a synergistic manner, whereas IMP or STO administration separately had no such effect. RNA sequencing and IPA analysis revealed that the synergistic mechanism of IMP+STO treatment was related to its regulatory effect on 5 canonical signaling pathways, which were not found when IMP or STO used alone. Moreover, LTA, CD83, and SREBF1 were 3 important targets for synergistic mechanism of IMP+STO treatment. The levels of these 3 genes were significantly up‐regulated in IMP+STO group compared to model group, whereas IMP or STO administration separately had no effect on them. In conclusion, this study found that IMP and STO were 2 synergistic compounds from the CHM in RA therapy, whose synergistic mechanism was closely related to regulate the levels of LTA, CD83, and SREBF1.

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The role of lymphotoxin-α in rheumatoid arthritis

Abstract: In this review, we summarize the key characteristics of LTα and the most recent findings on the role of LTα in RA.

Cited by 24 publications

References 46 publications

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Elevated lymphotoxin-α (TNFβ) is associated with intervertebral disc degeneration

Imperatorin and β-sitosterol have synergistic activities in alleviating collagen-induced arthritis

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