RESUMEN
Magnesium has been suggested to have anti-inflammatory properties in short-term, mostly in vitro studies. To examine the effect of dietary magnesium modifications in arthritis severity and joint damage DA rats were placed on one of three diet regimens before the induction of autoimmune pristane-induced arthritis (PIA): a 4 wk low-magnesium diet, normal diet, and a magnesium-supplemented diet. The diets were switched to a normal diet 14 days after the induction of PIA (typical time of disease onset). Arthritis severity was scored for 38 days, and joints were examined by histology and quantitative PCR for proinflammatory genes. Rats on the low-magnesium diet were significantly and reproducibly protected and had 70% lower median arthritis severity score, with preservation of normal joint histology without erosive changes. Rats on the normal or magnesium-supplemented diets were not protected and developed equally severe and erosive disease. While the dietary modifications were at disease onset (day 14 postinduction), the protective effect of the short-term low-magnesium diet persisted, suggesting a lasting effect on a critical pathogenic pathway. Rats on the low-magnesium diet had significant reduction in synovial tissue expression of IL-6, RORA, and RORC, which are genes required for the development of Th17 T cells. This study revealed a novel role for dietary magnesium in the regulation of autoimmune arthritis and opens new possibilities for the treatment of autoimmune diseases such as rheumatoid arthritis and psoriatic arthritis with short courses of dietary or drug-induced modulations of magnesium levels.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Magnesio/uso terapéutico , Animales , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Ratas , Membrana Sinovial/metabolismo , Células Th17/metabolismoRESUMEN
Chemokines facilitate the recruitment of inflammatory cells into tissues, contributing to target organ injury in a wide range of inflammatory and autoimmune diseases. Targeting either single chemokines or chemokine receptors alters the progression of disease in animal models of rheumatoid arthritis and lupus with varying degrees of efficacy but clinical trials in humans have been less successful. Given the redundancy of chemokine-chemokine receptor interactions, targeting of more than one chemokine may be required to inhibit active inflammatory disease. To test the effects of multiple-chemokine blockade in inflammation, we generated an adenovirus expressing bovine herpesvirus 1 glycoprotein G (BHV1gG), a viral chemokine antagonist that binds to a wide spectrum of murine and human chemokines, fused to the Fc portion of murine IgG2a. Administration of the adenovirus significantly inhibited thioglycollate-induced migration of polymorphonuclear leukocytes into the peritoneal cavity of BALB/c mice and reduced both clinical severity and articular damage in K/BxN serum transfer-induced arthritis. However, treatment with BHV1gG-Ig fusion protein did not prevent monocyte infiltration into the peritoneum in the thioglycollate model and did not prevent renal monocyte infiltration or nephritis in lupus-prone NZB/W mice. These observations suggest that the simultaneous inhibition of multiple chemokines by BHV1gG has the potential to interfere with acute inflammatory responses mediated by polymorphonuclear leukocytes, but is less effective in chronic inflammatory disease mediated by macrophages.
Asunto(s)
Movimiento Celular/inmunología , Inflamación/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Proteínas Virales/inmunología , Animales , Artritis Experimental/inmunología , Artritis Experimental/prevención & control , Calcio/inmunología , Calcio/metabolismo , Bovinos , Movimiento Celular/efectos de los fármacos , Quimiocinas/metabolismo , Herpesvirus Bovino 1/genética , Sueros Inmunes/inmunología , Fragmentos Fc de Inmunoglobulinas/genética , Fragmentos Fc de Inmunoglobulinas/inmunología , Inflamación/metabolismo , Ratones Endogámicos BALB C , Ratones Endogámicos , Ratones SCID , Monocitos/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Unión Proteica , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/farmacología , Tioglicolatos/inmunología , Tioglicolatos/farmacología , Proteínas Virales/metabolismo , Proteínas Virales/farmacologíaRESUMEN
OBJECTIVE: To use microarray analyses of gene expression to characterize the synovial molecular pathways regulated by the arthritis regulatory locus Cia25 and to determine how it operates to control disease severity and joint damage. METHODS: Synovial tissues from DA rats and DA.ACI(Cia25) rats obtained 21 days after induction of pristane-induced arthritis were used for RNA extraction and hybridization to Illumina RatRef-12 Expression BeadChips (22,228 genes). Genes with a P value≤0.01 and a fold difference in expression≥1.5 between DA rats and DA.ACI(Cia25) rats were considered significant. RESULTS: Interleukin-1ß (IL-1ß) (7.4-fold), IL-6 (67-fold), Ccl2, Cxcl10, Mmp3, Mmp14, and innate immunity genes were expressed at increased levels in DA rats and at significantly lower levels in DA.ACI(Cia25) congenic rats. DA.ACI(Cia25) rats had increased expression of 10 nuclear receptor (NR) genes, including those known to interfere with NF-κB activity and cytokine expression, such as Lxra, Pparg, and Rxrg. DA.ACI(Cia25) rats also had increased expression of NR targets, suggesting increased NR activity. While Vdr was not differentially expressed, a Vdr expression signature was detected in congenic rats, along with up-regulation of mediators of vitamin D synthesis. CONCLUSION: This is the first description of the association between increased synovial levels of NRs and arthritis protection. The expression of NRs was inversely correlated with the expression of key mediators of arthritis, suggesting reciprocally opposing effects either via NF-κB or at the genomic level in the synovial tissue. We consider that the NR signature may have an important role in maintaining synovial homeostasis and an inflammation-free tissue. These processes are regulated by the Cia25 gene and suggest a new function for this gene.
Asunto(s)
Artritis Experimental/genética , Receptores Citoplasmáticos y Nucleares/genética , Membrana Sinovial/metabolismo , Animales , Artritis Experimental/metabolismo , Inmunidad Innata/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Articulaciones/metabolismo , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Terpenos , Regulación hacia ArribaRESUMEN
OBJECTIVE: The synovial fibroblast, or fibroblast-like synoviocyte (FLS), has a central role in pannus invasion and destruction of cartilage and bone in rheumatoid arthritis (RA). However, regulation of the FLS remains incompletely understood. The aim of this study was to determine whether the invasive properties of FLS are genetically regulated by arthritis severity loci. METHODS: DA rats (arthritis susceptible) and rat strains congenic for arthritis-protective intervals were studied. Primary FLS cell lines were generated from each strain and used in a well-established FLS invasion model through a collagen-rich barrier. Cells or culture supernatants were analyzed for gene expression, activity of different matrix metalloproteinases (MMPs), cytoskeleton integrity, and cell proliferation. RESULTS: The median number of FLS from DA.F344(Cia5d) rats that invaded through the collagen-rich barrier was reduced 86.5% compared with the median number of invading FLS from DA rats. Histologic examination showed that DA.F344(Cia5d) rats preserved a normal joint without pannus, hyperplasia, or erosions. FLS from DA.F344(Cia5d) rats produced significantly lower levels of active MMP-2 compared with FLS from DA rats, but the levels of proMMP-2 and MMP-2 messenger RNA in DA.F344(Cia5d) rats were similar to those in DA rats. Treatment of FLS from DA rats with an MMP-2 inhibitor reduced cell invasion to a level similar to that in DA.F344(Cia5d) rats, demonstrating that MMP-2 activity accounted for the difference between FLS from these 2 strains. Analysis of MMP-2-activating pathways revealed increased levels of soluble membrane type 1 (MT1)-MMP in DA rats compared with DA.F344(Cia5d) rats. CONCLUSION: These data represent the first evidence for a genetic component in the regulation of FLS invasion. A gene located within the Cia5d interval accounts for this effect and operates via the regulation of soluble MT1-MMP production and MMP-2 activation. These observations suggest novel potential pathways for prognostication and therapy.