RESUMO
Diets rich in n-3 polyunsaturated fatty acid (n-3 PUFA) fish oil (FO) have beneficial effects in obesityassociated metabolic disease. However, contradictory roles in inflammatory disease intervention have been reported. Our previous work revealed that a highFO diet promoted myeloid cell differentiation by modifying the bone marrow microenvironment; however, its effects on liver inflammation and complement system activation remain unknown. By performing ELISA, reverse transcriptionquantitative polymerase chain reaction, flow cytometry and histology on mice fed with highFO and lowfat diets, the present study demonstrated that a 4week highFO diet promoted liver inflammation in mice without affecting body or liver weight. The livers of highFO diet mice exhibited increased infiltration of T cells and CD11b+ Gr1+ myeloid cells. Additionally, a higher level of IL1ß and MCP1 mRNA expression was detected, suggesting that the highFO diet promoted liver inflammation. Further experiments indicated that the highFO diet increased the total hemolytic complement activity (CH50), promoted the production of the membrane attack complex and increased the levels of various complement proteins in vivo, including complement components C3, C4b, C1qb and factor B. Furthermore, higher concentrations of triglyceride were detected in the peripheral blood of highFO diet mice, indicating the potential protective roles of n3 PUFAs in FO against lipotoxicity in hyperlipidemia. Collectively, the present study demonstrated that high FO intake induced inflammation and activated the complement system in the liver. However, further study is required to determine the exact mechanisms.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Proteínas do Sistema Complemento/metabolismo , Gorduras na Dieta/efeitos adversos , Ácidos Graxos Ômega-3/efeitos adversos , Fígado/metabolismo , Animais , Doença Hepática Induzida por Substâncias e Drogas/patologia , Gorduras na Dieta/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Fígado/patologia , Masculino , CamundongosRESUMO
Regulatory T cells (T(regs)) have potential applications in clinical disease therapy, such as autoimmune diseases and transplant rejection. However, their numbers are limited. Forkhead box protein 3 (FoxP3) is a key transcription factor that controls T(reg) development and function. Here, we generated a cell-permeable fusion protein, protein transduction domain (PTD)-conjugated mouse FoxP3 protein (PTD-mFoxP3), and evaluated whether PTD-mFoxp3 can alleviate rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. As expected, PTD-mFoxP3 was transduced into cells effectively, and inhibited T cell activation and attenuated the cell proliferation. It decreased interleukin (IL) 2 and interferon (IFN)-γ expression, and increased IL-10 expression in activated CD4(+)CD25(-) T cells. PTD-mFoxP3-transduced CD4(+)CD25(-) T cells attenuated proliferation of activated CD4(+)CD25(-) T cells. In addition, PTD-mFoxP3 blocked the Th17 differentiation programme in vitro and down-regulated IL-17 production from T cells by modulating induction and levels of retinoid-related orphan receptor gamma t (RORγt). Intra-articular delivery of PTD-mFoxP3 delayed disease incidence remarkably and alleviated autoimmune symptoms of CIA mice. Moreover, protective effects of PTD-mFoxP3 were associated with regulating the balance of T helper type 17 (Th17) and T(regs). These results suggest that PTD-mFoxP3 may be a candidate for RA therapy.
Assuntos
Artrite Experimental/tratamento farmacológico , Fatores de Transcrição Forkhead/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Linfócitos T Reguladores/citologia , Células Th17/citologia , Animais , Artrite Reumatoide/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Fatores de Transcrição Forkhead/genética , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-17/biossíntese , Interleucina-2/biossíntese , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas Recombinantes de Fusão/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Regulação para CimaRESUMO
Omega-3 polyunsaturated fatty acids enriched fish oil exerts beneficial anti-inflammatory effects in animal models with acute and chronic inflammatory diseases. Myeloid-derived suppressor cells (MDSCs), comprised of myeloid progenitors and precursors of myeloid cells, play vital roles in cancer. How fish oil affects the generation of MDSCs and the tumor development remains largely unexplored. Here, we show that dietary intake of high fish oil diet suppresses CD8(+) T cells activation and proliferation in vivo via elevated levels of MDSCs. Mechanistically, high fish oil diet induces the expression of immunosuppressive cytokine IL-10 and promotes myelopoiesis in the spleen as well as other peripheral tissues. The immature myeloid cells in the spleen exhibit morphological and functional characteristics of MDSCs with the capability to downregulate CD8(+) T cells activation. Depletion of MDSCs using anti-Gr-1 antibody decreases the growth of subcutaneously transferred B16 melanoma in mice on high fish oil diet. Interestingly, diet-induced production of MDSCs is not solely dependent of the spleen, as splenectomy has no effect on the tumor progress. Our data show that the liver functions as an alternative extramedullary hematopoiesis organ to support MDSCs differentiation and maintain tumor growth. Taken together, our study provides a novel insight into the physiological effects of fish oil and points to MDSCs as a possible mediator linking dietary fish oil intake and immunosuppression in cancer immunosurveillance.
Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/efeitos adversos , Melanoma Experimental/patologia , Células Mieloides/patologia , Animais , Apresentação de Antígeno/efeitos dos fármacos , Antígenos CD8/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Células Mieloides/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismo , Esplenectomia/métodosRESUMO
The development of hepatitis is associated with the infiltration and activation of immune cells in liver. N-3 polyunsaturated fatty acids (n-3 PUFAs) rich fish oil (FO) is used to prevent and treat inflammatory diseases. But, the effects of dietary FO on autoimmune hepatitis remain largely unknown. In this study, Concanavalin A (Con A) induced hepatitis was used to evaluate the actions of dietary FO. Unexpectedly, 2-week FO treatment had not shown any protection, on the contrary, exacerbated liver injury in this hepatitis model. The levels of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) statistically increased from 10,501 ± 2,154 and 30,394 ± 2,420 in low fat diet (LFD)/Con A group to 17,579 ± 693 and 49,439 ± 4,628 in FO/Con A group. Simultaneously, FO diet induced more necrotic liver tissues and apoptotic hepatocytes, and up-regulated the hepatic expression of TNF-α and IFN-γ after Con A challenge. Interestingly, FO promoted severe liver injury was accompanied by decreasing the percentage of CD4⺠T cell, NK1.1⺠cells and CD8⺠T cells in CD45⺠liver non-parenchymal hepatic cells (NPCs) through inducing apoptosis. Further experiments declared 2-week FO diet intake firstly increased the proportion of CD11bâºGr-1(hi) neutrophils in liver, but then dramatically expanded CD11bâºGr-1(int) inflammatory monocytes population after Con A administration. Collectively, our study indicated that high FO intake not only aggravated liver injury, but also altered the population of immune cells in liver. Thus, these results indicated that when dietary FO was used to benefit health in autoimmune diseases, its potential risks of side effect also need paying close attention.