Hypoxia differentially affects IL-1 -stimulated MMP-1 and MMP-13 expression of fibroblast-like synoviocytes in an HIF-1 -dependent manner

Abstract. (5R)-5-hydroxytriptolide (LLDT-8) extracts fromTripterygium have anti-inflammatory, antineoplastic and immunity adjustment functions. The present study used a collagen-induced arthritis (CIA) model to evaluate whether LLDT-8 prevents collagen-induced arthritis, and investigated the signaling underlying this. Male Sprague-Dawley rats were induced to generate CIA, mimicking rheumatoid arthritis (RA). The presence of arthritis was determined using RA progression scores. The inflammatory cytokines interleukin (IL)-1β, IL-6 and nuclear factor-κB were detected using enzyme-linked immunosorbent assay kits. Induced nitric oxide synthase (iNOS) and matrix metalloprotease (MMP)-13 protein expression were measured using western blot analysis. Lastly, reverse transcription-quantitative polymerase chain reaction was used to evaluate osteoprotegerin (OPG) and receptor activator of nuclear factor κB (RANK) gene expression. LLDT-8 improved RA progression scores and reduced the incidence and severity of CIA. Furthermore, LLDT-8 administration inhibited collagen-induced inflammation and iNOS protein expression in arthritic rats. The current data indicated that MMP-13 production was suppressed and OPG/RANKL expression was increased by LLDT-8 treatment in the arthritic rat. The present results suggest that LLDT-8 attenuates CIA through OPG/RANK/RANK ligand signaling in a rat model of RA. IntroductionRheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that is characterized by erosive arthrosynovitis (1).The incidence of RA in females is more than that in males, at a ratio of 1:3 (2). The mortality rate of RA in worldwide populations varies from 0.01-0.05%, and prevalence rate is 0.18-1.07% (3). RA is also an impactful disease, resulting in labor loss and disability in China (2). According to US epidemiological investigation over the last 40 years, the difference in mortality rate between RA patients and the general population has increased (4). The risk of cognitive impairment for RA patients is higher than that of the general population (5). The etiology of RA is unclear. Previous studies suggest that RA is associated with genetic factors, infection, immunity and endocrine function (6,7).The main pathological characteristics of RA are hyperplasia of synovial cells and T cell accumulation during inflammation of synovial tissues, accompanied by pannus formation, followed by damage to the cartilage and bone (8). Finally, RA causes joint deformity and functional loss (9). These pathological changes may result from a combination of genetic mutations, activation of protooncogenes, lesions of synoviocytes, release of proinflammatory cytokines by inflammatory cells during infiltration of synovial tissues, chemotactic factors and enzymatic degradation of stromal proteins, amongst other factors (10). The etiology of RA is unclear, but it is universally believed to be a multifactorial disease, associated with genetic, environmental and infective factors (11). Autoimmunity may arise due to genetic factors, or as an ab...

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“…With increasing time, expression of MMP-1 increased (34). However, the expression of MMP-13 was markedly decreased in the current study.…”

contrasting

confidence: 55%

“…Previous studies have revealed that expression of MMP-1 and MMP-13 in cartilage and synovium were significantly higher than those of control group (34). With increasing time, expression of MMP-1 increased (34).…”

mentioning

confidence: 88%

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Zeng

Meng

et al. 2016

Experimental and Therapeutic Medicine

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“…Consistent with our data in TB, hypoxia and HIF-1α regulate MMP-driven tissue destruction in hypoxic fibroblasts within rheumatoid synovium. 36 In summary, we show for the first time that human TB lesions are severely hypoxic. Hypoxia increases MMP-1 gene expression and secretion during M.tb infection, and M.tb infection independently increases HIF-1α activity even under conditions of normoxia.…”

Section: Discussionmentioning

confidence: 60%

Hypoxia and tissue destruction in pulmonary TB

Belton

Brilha

Manavaki

et al. 2016

Thorax

134

115

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BackgroundIt is unknown whether lesions in human TB are hypoxic or whether this influences disease pathology. Human TB is characterised by extensive lung destruction driven by host matrix metalloproteinases (MMPs), particularly collagenases such as matrix metalloproteinase-1 (MMP-1).MethodsWe investigated tissue hypoxia in five patients with PET imaging using the tracer [18F]-fluoromisonidazole ([18F]FMISO) and by immunohistochemistry. We studied the regulation of MMP secretion in primary human cell culture model systems in normoxia, hypoxia, chemical hypoxia and by small interfering RNA (siRNA) inhibition.Results[18F]FMISO accumulated in regions of TB consolidation and around pulmonary cavities, demonstrating for the first time severe tissue hypoxia in man. Patlak analysis of dynamic PET data showed heterogeneous levels of hypoxia within and between patients. In Mycobacterium tuberculosis (M.tb)-infected human macrophages, hypoxia (1% pO2) upregulated MMP-1 gene expression 170-fold, driving secretion and caseinolytic activity. Dimethyloxalyl glycine (DMOG), a small molecule inhibitor which stabilises the transcription factor hypoxia-inducible factor (HIF)-1α, similarly upregulated MMP-1. Hypoxia did not affect mycobacterial replication. Hypoxia increased MMP-1 expression in primary respiratory epithelial cells via intercellular networks regulated by TB. HIF-1α and NF-κB regulated increased MMP-1 activity in hypoxia. Furthermore, M.tb infection drove HIF-1α accumulation even in normoxia. In human TB lung biopsies, epithelioid macrophages and multinucleate giant cells express HIF-1α. HIF-1α blockade, including by targeted siRNA, inhibited TB-driven MMP-1 gene expression and secretion.ConclusionsHuman TB lesions are severely hypoxic and M.tb drives HIF-1α accumulation, synergistically increasing collagenase activity which will lead to lung destruction and cavitation.

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“…Other proteases observed to be increased included collagenase 3, that is increased in expression in NFkB mediated inflammation in mammals [82-84] and during vitellogenesis induced muscle atrophy in salmonids [43]. Angiotensinogen, the precursor of both angiotensin I & II, was also increased in expression, and is known to interfere with the actions and production of IGF-I, which in mammals is mediated by the NFκB pathway in collaboration with protein kinase C [85,86].…”

Section: Discussionmentioning

confidence: 99%

Inflammatory responses in primary muscle cell cultures in Atlantic salmon (Salmo salar)

et al. 2013

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BackgroundThe relationship between fish health and muscle growth is critical for continued expansion of the aquaculture industry. The effect of immune stimulation on the expression of genes related to the energy balance of fish is poorly understood. In mammals immune stimulation results in major transcriptional changes in muscle, potentially to allow a reallocation of amino acids for use in the immune response and energy homeostasis. The aim of this study was to investigate the effects of immune stimulation on fish muscle gene expression.ResultsAtlantic salmon (Salmo salar) primary muscle cell cultures were stimulated with recombinant (r)IL-1β, a major proinflammatory cytokine, for 24 h in order to simulate an acute immune response. The transcriptomic response was determined by RNA hybridization to a 4 × 44 K Agilent Atlantic salmon microarray platform. The rIL-1β stimulation induced the expression of genes related to both the innate and adaptive immune systems. In addition there were highly significant changes in the expression of genes related to regulation of the cell cycle, growth/structural proteins, proteolysis and lipid metabolism. Of interest were a number of IGF binding proteins that were differentially expressed, which may demonstrate cross talk between the growth and immune systems.ConclusionWe show rIL-1β modulates the expression of not only immune related genes, but also that of genes involved in processes related to growth and metabolism. Co-stimulation of muscle cells with both rIGF-I and rIL-1β demonstrates cross talk between these pathways providing potential avenues for further research. This study highlights the potential negative effects of inflammation on muscle protein deposition and growth in fish and extends our understanding of energy allocation in ectothermic animals.

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Hypoxia differentially affects IL-1 -stimulated MMP-1 and MMP-13 expression of fibroblast-like synoviocytes in an HIF-1 -dependent manner

Cited by 45 publications

References 30 publications

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

(5R)-5-hydroxytriptolide (LLDT-8) prevents collagen-induced arthritis through OPG/RANK/RANKL signaling in a rat model of rheumatoid arthritis

Hypoxia and tissue destruction in pulmonary TB

Inflammatory responses in primary muscle cell cultures in Atlantic salmon (Salmo salar)

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