ABSTRACT
BACKGROUND: Multiple sclerosis (MS) is characterized by a combination of inflammatory and demyelination processes in the spinal cord and brain. Conventional drugs generally target the autoimmune response, without any curative effect. For that reason, there is a great interest in identifying novel agents with anti-inflammatory and myelinating effects, to counter the inflammation and cell death distinctive of the disease. METHODS AND RESULTS: An in vitro assay showed that curcumin (Cur) at 10 µM enhanced the proliferation of C8-D1A cells and modulated the production of Th1/Th2/Th17 cytokines in the cells stimulated by LPS. Furthermore, two in vivo pathophysiological experimental models were used to assess the effect of curcumin (100 mg/kg). The cuprizone model mimics the de/re-myelination aspect in MS, and the experimental autoimmune encephalomyelitis model (EAE) reflects immune-mediated events. We found that Cur alleviated the neurological symptomatology in EAE and modulated the expression of lymphocytes CD3 and CD4 in the spinal cord. Interestingly, Cur restored motor and behavioral deficiencies, as well as myelination, in demyelinated mice, as indicated by the higher index of luxol fast blue (LFB) and the myelin basic protein (MBP) intensity in the corpus callosum. CONCLUSIONS: Curcumin is a potential therapeutic agent that can diminish the MS neuroimmune imbalance and demyelination through its anti-inflammatory and antioxidant effects.
Subject(s)
Curcumin , Encephalomyelitis, Autoimmune, Experimental , Multiple Sclerosis , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Curcumin/pharmacology , Curcumin/therapeutic use , Disease Models, Animal , Mice , Mice, Inbred C57BL , Models, Theoretical , Multiple Sclerosis/metabolismABSTRACT
BACKGROUND AND AIMS: Interleukin (IL)-15 delivers signals that drive chronic inflammation in several diseases, including celiac disease. Smad3-transforming growth factor-beta (TGF-beta) signaling is instrumental to counteract proinflammatory signals and maintain immune homeostasis. Our goal has been to investigate why the proinflammatory effects of IL-15 cannot be efficiently controlled by TGF-beta in celiac disease. METHODS: The impact of IL-15 on TGF-beta signaling in T cells and in the intestinal mucosa of celiac disease patients was analyzed by combining cell and organ cultures, immunohistochemistry, flow cytometry, real-time polymerase chain reaction, electromobility gel shift, and Western blot. RESULTS: IL-15 impaired Smad3-dependent TGF-beta signaling in human T lymphocytes downstream from Smad3 nuclear translocation. IL-15-mediated inhibition was associated with a long-lasting activation of c-jun-N-terminal kinase and reversed by c-jun antisense oligonucleotides, consistent with the demonstrated inhibitory effect of phospho-c-jun on the formation of Smad3-DNA complexes. In active celiac disease, intestinal lymphocytes showed impaired TGF-beta-Smad3-dependent transcriptional responses and up-regulation of phospho-c-jun. Anti-IL-15 antibody and c-jun antisense both downmodulated phospho-c-jun expression and restored TGF-beta-Smad-dependent transcription in biopsies of active celiac disease. c-jun antisense decreased interferon gamma transcription. CONCLUSIONS: Impairment of TGF-beta-mediated signaling by IL-15 might promote and sustain intestinal inflammation in celiac disease. More generally, our data provide a new rationale for the potent proinflammatory effects of IL-15, and further support the concept that IL-15 is a meaningful therapeutic target in inflammatory diseases associated with irreducible elevation of IL-15.
