Verinaud Liana, Lopes Stefanie Costa Pinto, Prado Isabel Cristina Naranjo, Zanucoli Fábio, Alves da Costa Thiago, Di Gangi Rosária, Issayama Luidy Kazuo, Carvalho Ana Carolina, Bonfanti Amanda Pires, Niederauer Guilherme Francio, Duran Nelson, Costa Fábio Trindade Maranhão, Oliveira Alexandre Leite Rodrigues, Höfling Maria Alice da Cruz, Machado Dagmar Ruth Stach, Thomé Rodolfo
Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil.
Department of Genetics Evolution and Bioagents, Institute of Biology, University of Campinas, Campinas, SP, Brazil.
PLoS One. 2015 May 4;10(5):e0125409. doi: 10.1371/journal.pone.0125409. eCollection 2015.
Inflammation is a necessary process to control infection. However, exacerbated inflammation, acute or chronic, promotes deleterious effects in the organism. Violacein (viola), a quorum sensing metabolite from the Gram-negative bacterium Chromobacterium violaceum, has been shown to protect mice from malaria and to have beneficial effects on tumors. However, it is not known whether this drug possesses anti-inflammatory activity. In this study, we investigated whether viola administration is able to reduce acute and chronic autoimmune inflammation. For that purpose, C57BL/6 mice were intraperitoneally injected with 1 μg of LPS and were treated with viola (3.5mg/kg) via i.p. at the same time-point. Three hours later, the levels of inflammatory cytokines in the sera and phenotypical characterization of leukocytes were determined. Mice treated with viola presented a significant reduction in the production of inflammatory cytokines compared with untreated mice. Interestingly, although viola is a compound derived from bacteria, it did not induce inflammation upon administration to naïve mice. To test whether viola would protect mice from an autoimmune inflammation, Experimental Autoimmune Encephalomyelitis (EAE)-inflicted mice were given viola i.p. at disease onset, at the 10th day from immunization. Viola-treated mice developed mild EAE disease in contrast with placebo-treated mice. The frequencies of dendritic cells and macrophages were unaltered in EAE mice treated with viola. However, the sole administration of viola augmented the levels of splenic regulatory T cells (CD4+Foxp3+). We also found that adoptive transfer of viola-elicited regulatory T cells significantly reduced EAE. Our study shows, for the first time, that violacein is able to modulate acute and chronic inflammation. Amelioration relied in suppression of cytokine production (in acute inflammation) and stimulation of regulatory T cells (in chronic inflammation). New studies must be conducted in order to assess the possible use of viola in therapeutic approaches in human autoimmune diseases.
炎症是控制感染的必要过程。然而，急性或慢性的过度炎症会对机体产生有害影响。紫罗碱（viola）是革兰氏阴性菌紫色杆菌产生的一种群体感应代谢产物，已被证明能保护小鼠免受疟疾侵害，并对肿瘤有有益作用。然而，尚不清楚这种药物是否具有抗炎活性。在本研究中，我们调查了给予紫罗碱是否能够减轻急性和慢性自身免疫性炎症。为此，给C57BL/6小鼠腹腔注射1μg脂多糖（LPS），并在同一时间点经腹腔注射紫罗碱（3.5mg/kg）进行治疗。三小时后，测定血清中炎性细胞因子的水平以及白细胞的表型特征。与未治疗的小鼠相比，用紫罗碱治疗的小鼠炎性细胞因子的产生显著减少。有趣的是，尽管紫罗碱是一种源自细菌的化合物，但给未接触过的小鼠给药时它并未诱发炎症。为了测试紫罗碱是否能保护小鼠免受自身免疫性炎症，在实验性自身免疫性脑脊髓炎（EAE）发病时，即免疫后第10天，给患有EAE的小鼠腹腔注射紫罗碱。与用安慰剂治疗的小鼠相比，用紫罗碱治疗的小鼠患轻度EAE疾病。在用紫罗碱治疗的EAE小鼠中，树突状细胞和巨噬细胞的频率未改变。然而，单独给予紫罗碱可提高脾脏调节性T细胞（CD4+Foxp3+）的水平。我们还发现，移植紫罗碱诱导的调节性T细胞可显著减轻EAE。我们的研究首次表明，紫罗碱能够调节急性和慢性炎症。改善依赖于抑制细胞因子产生（在急性炎症中）和刺激调节性T细胞（在慢性炎症中）。必须进行新的研究，以评估紫罗碱在人类自身免疫性疾病治疗方法中的可能用途。
