Efeitos imuno-moduladores do Ácido Linoléico Conjugado (CLA) na colite e no adenocarcinoma de cólon murino

Abstract

The lymphoid tissue associated with the intestinal mucosa is separated from the gut lumen by a single layer of epithelial cells and coexists adjusted in a relationship with the different components of dietary food. Vitamins, Carbohydrates, Proteins and Lipids are recognized by different immune cells. Therefore, these dietary components play an important antigenic function beyond their nutritional role. Different lipid forms present in food can affect the immune system directly through modulation of gene expression. In this work, we studied the immunological effects of Conjugated Linoleic Acid (CLA), the geometric and positional isomerof Linoleic acid that activates the transcriptional factor peroxime proliferator PPAR- and modulates several functions of the body. Due to its already described anti-carcinogenic and anti-inflammatory effects, CLA was chosen as modulating agent of Inflammatory Bowel Diseases (DII) that are strongly correlated with the development of colon cancer. We demonstrated that dietary supplementation with CLA was able to prevent DII, reducing the mucosal damage and inflammatory infiltrates in an experimental model of colitis induced by dextran sodium sulfate (DSS). Macrophages with M2 profile (antiinflammatory) were players in this effect. In the other hand, LysMCre PPARflox/flox mice PPAR- deficient in myeloid cells supplemented with CLA diet was not protected from colitis. Thus, the CLA effect over the colitis is PPAR- dependent. By using the DSS model, we also observed that the steatosis process in CLA-supplementated naïve mice is reverted on colitis due the metabolic alteration caused by the inflammatory disease, that enables the CLA use as therapeutic tool on DII. Although effective in preventing DSS-induced colitis, CLA supplementation significantly worsened the tumor processes found in colorectal cancer (CRC) induced by a combination of DSS and azoxymethane. This effect was associated with the generation of CD4+LAP+ regulatory T cells (membrane-bound TGF-) and TGF- producer macrophages in the gut lamina propria of CLA-suplemmented mice. We showed, in vitro, by using the PPAR- agonist, that the TGF- induction on lymphocytes and macrophages is PPAR- dependent. Neutralization of the pro-tumor effect of CLA by in vivo administration of anti-TGF- antibodies and the use of LysMCre PPARflox/flox mice show the role of the cytokine TGF- ans the transcriptional factor PPAR- over CLA protumoral effect. We conclude, therefore, the anti-inflammatory properties of CLA are positively associated with prevention of DSS-induced colitis but also with development of colon tumors.