Expression of 5-lipoxygenase and 15-lipoxygenase in rheumatoid arthritis synovium and effects of intraarticular glucocorticoids

Gheorghe, Karina Roxana; Korotkova, Marina; Catrina, Anca I.; Backman, Linda; Klint, Erik af; Claesson, Hans‐Erik; Rådmark, Olof; Jakobsson, Per‐Johan

doi:10.1186/ar2717

Cited by 88 publications

(66 citation statements)

References 56 publications

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“…5-lipoxygenase is reported to be present in RA synovium and mostly expressed in macrophages, neutrophils and mast cells in the sublining layer [16]. Here we found that synovial fibroblasts isolated from rheumatoid arthritis patients express high protein levels of 5-LOX which is consistent with high levels of leukotriene B4, a 5-LOX downstream metabolite, found in synovial fluid in rheumatoid arthritis patients [6].…”

Section: Discussionsupporting

confidence: 84%

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

Lin

et al. 2014

PLoS ONE

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The lipoxygenase isoform of 5-lipoxygenase (5-LOX) is reported to be overexpressed in human rheumatoid arthritis synovial tissue and involved in the progress of inflammatory arthritis. However, the detailed mechanism of how 5-lipoxygenase regulates the inflammatory response in arthritis synovial tissue is still unclear. The aim of this study was to investigate the involvement of lipoxygenase pathways in TNF-α-induced production of cytokines and chemokines. Human synovial fibroblasts from rheumatoid patients were used in this study. 5-LOX inhibitors and shRNA were used to examine the involvement of 5-LOX in TNF-α-induced cytokines and chemokines expression. The signaling pathways were examined by Western Blotting or immunofluorescence staining. The effect of 5-LOX inhibitor on TNF-α-induced chemokine expression and paw edema was also explored in vivo in C57BL/6 mice. Treatment with 5-LOX inhibitors significantly decreased TNF-α-induced pro-inflammatory mediators including interleukin-6 (IL-6) and monocyte chemo-attractant protein-1 (MCP-1) in human synovial fibroblasts. Knockdown of 5-LOX using shRNA exerted similar inhibitory effects. The abrogation of NF-κB activation was involved in the antagonizing effects of these inhibitors. Furthermore, 5-LOX inhibitor decreased TNF-α-induced up-regulation of serum MCP-1 level and paw edema in mouse model. Our results provide the evidence that the administration of 5-LOX inhibitors is able to ameliorate TNF-α-induced cytokine/chemokine release and paw edema, indicating that 5-LOX inhibitors may be developed for therapeutic treatment of inflammatory arthritis.

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Section: Discussionsupporting

confidence: 84%

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

Lin

et al. 2014

PLoS ONE

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“…Besides these, other cytokines (IL-1β, IL-6, IL-23), growth factors (TGF-β), inflammatory mediators (signal transducer and activator of transcription (STAT)-3, toll-like receptor (TLR)-2) and genetic factors (coiled-coil alpha-helical rod protein 1 (CCHCR1), steroidogenic acute regulatory protein (StAR), vitamin D receptor (VDR)) significantly accelerate the inflammatory processes in psoriasis (Honma et al 2012;Tiala et al 2007). 15-Lipoxygenase (15-LOX) enzyme in humans is known to be involved in the production of leukotrienes that act as proinflammatory products, giving rise to allergic reactions (Brash et al 1997;Vanderhoek and Bailey 1984), thereby responsible for pathogenesis of many inflammatory disorders, including rheumatoid arthritis, Alzheimer's dementia and psoriasis (Giannopoulos et al 2013;Gheorghe et al 2009). 15-LOX-2 has been implicated in IFN-γ-induced inflammatory processes in psoriatic skin (Setsu et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of imiquimod-induced psoriasis-like dermatitis in mice by herbal extracts from some Indian medicinal plants

2015

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Psoriasis is a chronic autoimmune human skin disorder that is characterized by excessive proliferation of keratinocytes, scaly plaques, severe inflammation and erythema. The pathophysiology of psoriasis involves interplay between epidermal keratinocytes, T lymphocytes, leukocytes and vascular endothelium. Increased leukocyte recruitment and elevated levels of cytokines, growth factors and genetic factors like interleukin (IL)-1β, IL-6, IL-17, IL-22, IL-23, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, toll-like receptor (TLR)-2, signal transducer and activator of transcription (STAT-3), 15-lipoxygenase (LOX)-2, coiled-coil alpha-helical rod protein 1 (CCHCR1), steroidogenic acute regulatory protein (StAR) and vitamin D receptor (VDR) are the most critical factors governing the exacerbation of psoriasis. In the present study, an attempt was made to elucidate the preventive role of herbal extracts of four dermo-protective Ayurvedic plants, Tinospora cordifolia (TC), Curcuma longa (CL), Celastrus paniculatus (CP) and Aloe vera (AV), against psoriasis-like dermatitis. Parkes (P) strain mice were initially induced with psoriasis-like dermatitis using topical application of imiquimod (IMQ, 5 %), followed by subsequent treatment with the herbal extracts to examine their curative effect on the psoriasis-like dermatitis-induced mice. The extracts were orally/topically administered to mice according to their ED/LD50 doses. Phenotypical observations, histological examinations, and semi-quantitative reverse transcription PCR (RT-PCR) analyses of the skin and blood samples of the control, IMQ-treated and herbal extract-treated psoriasis-like dermatitis-induced mice lead to the conclusion that the combination extract from all the plants was instrumental in downregulating the overexpressed cytokines, which was followed by the CL extract. Moreover, lesser yet positive response was evident from CP and TC extracts. The results suggest that these plants can prove to have tremendous preventive potential against the disease and can open the way to new therapeutic strategies for psoriasis treatment.

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“…Tepoxalin, a COX/LOX dual inhibitor, would have unique inflammatory properties as an NSAIDs and directly or indirectly suppress viability of inflammatory synoviocytes by inhibition of LOX. Many reports have shown that 5-LOX plays an important role in various diseases associated with cell proliferation and that inhibition of 5-LOX resulted in cytotoxicity [10,16,31]. Overexpression of 5-LOX in tissue samples of primary tumor, as well as in established cancer cell lines, has been reported [5].…”

Section: Discussionmentioning

confidence: 99%

Pro-Apoptotic Effects of Tepoxalin, a Cyclooxygenase/Lipoxygenase Dual Inhibitor, on Canine Synovial Fibroblasts

Sunaga

Hosoya

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. Canine osteoarthritis occurs frequently and causes secondary synovitis. Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is one of the major therapeutic options for pain management of joint diseases. Tepoxalin has an unique property as an NSAIDs that suppresses both cyclooxygenase and lipoxygenase. The purpose of this study was to evaluate antiproliferative effects of tepoxalin on cultured canine synovial cells. Cytotoxic effects of tepoxalin, carprofen, meloxicam and AA-861 on cultured canine synoviocytes were evaluated by MTT colorimetric assay. Apoptosis was detected by morphological observations with Giemsa or annexin V/Hoechst 33342 staining and by the inhibition of caspase-3 activity with N-Ac-Asp-Glu-Val-Asp-CHO (Ac-DEVD-CHO). Cytotoxic effects of tepoxalin were evident in comparison with the effects of carprofen or meloxicam. The same tendency of cytotoxicity was observed when 5-lipoxygenase was inhibited by AA-861. The morphological findings and contradictory effects of Ac-DEVD-CHO with regard to the cytotoxicity proved the proapoptotic effects of tepoxalin. In conclusion, tepoxalin might control osteoarthritic synovitis by inducing apoptosis in proliferating synoviocytes, while most NSAIDs that selectively inhibit cyclooxygenase-2 most likely would not suppress synovial proliferation.

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Expression of 5-lipoxygenase and 15-lipoxygenase in rheumatoid arthritis synovium and effects of intraarticular glucocorticoids

Cited by 88 publications

References 56 publications

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

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

Inhibition of imiquimod-induced psoriasis-like dermatitis in mice by herbal extracts from some Indian medicinal plants

Pro-Apoptotic Effects of Tepoxalin, a Cyclooxygenase/Lipoxygenase Dual Inhibitor, on Canine Synovial Fibroblasts

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