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Immune dysfunction is a major cause of mortality in septic patients. Current evidence indicates an important role for dendritic cells (DCs) in the pathophysiology of immune dysfunction, and these cells are potential targets of immunomodulation therapies. In the present study, our aim was to enhance the resistance of endotoxemic mice to bacterial translocation and secondary infection and to improve the outcome of these infections using a combination therapy consisting of thymosin alpha1 and dexamethasone in a timely manner according to the changes of DCs' number. The effect of treatment with dexamethasone (DXM) and thymosin alpha1 (Tα1) on DCs was investigated by examining their number, MHCII and CD86 expression and their capacity to induce T cell activation. Endotoxemic mice were randomly divided into five treatment groups. The survival rates, the levels of TNF-α and IL-10, the occurrence of bacterial translocation, and the ability to clear secondary infections were determined. Additionally, the behavior of DCs over time was also evaluated. Tα1 induced significant increases in DC numbers in vivo, whereas DXM reduced cell numbers both in vitro and in vivo. However, neither drug induced significant changes in the capacity of DCs to induce T cell activation or their expression of MHCII or CD86. Among the five treatment groups, the mice treated with a combination of DXM and Tα1 had the highest survival rate; this increased survival was associated with a decrease in bacterial translocation to extra-intestinal organs and an enhanced ability to eradicate secondary infections by reversing the change in DC numbers during endotoxemia. Immunomodulatory therapy that combines Tα1 and DXM in a timely manner and was based on changes in DCs enhanced the resistance of endotoxemic mice to bacterial translocation and secondary infections, improving the outcome of the infection.

It is known that the loss of DC plays an important role for immune suppression during endotoxemia or sepsis. To verify our hypothesis that pre-enrichment of the lamina propria (LP) DC pool may improve protective immunity to bacterial translocation and outcome in endotoxemic mice, we pre-treated mice with Flt3L or normal saline, and then challenged them with or without LPS. Twelve hours later the population size and maturity of DC in the LP and circulation were analyzed by flow cytometry. Bacterial translocation to distant organs, inflammatory responses in the intestine and the survival rate of mice were evaluated. We observed that pretreatment of Flt3L significantly expanded DC in the LP and blood, but did not alter their maturation. However, exacerbation of DC growth induced by Flt3L-pretreatment aggravated intestinal inflammation and increased the mortality of endotoxemic mice rather than enhancing their resistance to bacterial translocation.

Objective: The omega-3 polyunsaturated fatty acids (PUFAs) play a key role as immune response modulators and suppressors of immunologic functions, such as lymphocyte proliferation, cytokine production, and cell surface molecular expression in T lymphocytes, monocytes, and natural killer cells. However, little is known about the effect of omega-3 PUFAs on dendritic cells (DCs). We studied the effect of omega-3 PUFAs on DCs and the related intracellular signal transduction pathway., Methods: Dendritic cells were generated from human peripheral blood monocytes in the presence of granulocyte-macrophage colony-stimulating factors and interleukin (IL)-4 and treated with eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and stearic acid for 24 h. Lipopolysaccharide (LPS) was used for maturation of the DCs. The expressions of CD40, CD80, CD86, and human leukocyte antigen-DR (HLA-DR) were analyzed by flow cytometry; production of IL-12 and tumor necrosis factor-alpha were detected by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. The proliferative ability of allogeneic T cells stimulated by DCs was evaluated by tritiated thymidine ((3)H-TdR). Western blot analysis of p38 mitogen-activated protein kinase was conducted., Results: The omega-3 PUFAs reduced expression levels of costimulatory molecules CD80 and CD86 and major histocompatibility complex HLA-DR. IL-12 and tumor necrosis factor-alpha levels decreased significantly in the EPA and DHA groups. EPA and DHA also significantly reduced the proliferative ability of allogeneic T cells stimulated by DCs. The omega-3 PUFAs significantly inhibited LPS-induced p38 phosphorylation., Conclusion: The omega-3 PUFAs may inhibit LPS-induced DC maturation and upregulate cytokine production. Impaired p38 mitogen-activated protein kinase activity is a potential critical intracellular signaling transduction mechanism.

Abstract: Objective: The ω-3 polyunsaturated fatty acids (PUFAs) play a key role as immune response modulators and suppressors of immunologic functions, such as lymphocyte proliferation, cytokine production, and cell surface molecular expression in T lymphocytes, monocytes, and natural killer cells. However, little is known about the effect of ω-3 PUFAs on dendritic cells (DCs). We studied the effect of ω-3 PUFAs on DCs and the related intracellular signal transduction pathway. Methods: Dendritic cells were generated from human peripheral blood monocytes in the presence of granulocyte-macrophage colony-stimulating factors and interleukin (IL)-4 and treated with eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and stearic acid for 24 h. Lipopolysaccharide (LPS) was used for maturation of the DCs. The expressions of CD40, CD80, CD86, and human leukocyte antigen-DR (HLA-DR) were analyzed by flow cytometry; production of IL-12 and tumor necrosis factor-α were detected by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. The proliferative ability of allogeneic T cells stimulated by DCs was evaluated by tritiated thymidine (3H-TdR). Western blot analysis of p38 mitogen-activated protein kinase was conducted. Results: The ω-3 PUFAs reduced expression levels of costimulatory molecules CD80 and CD86 and major histocompatibility complex HLA-DR. IL-12 and tumor necrosis factor-α levels decreased significantly in the EPA and DHA groups. EPA and DHA also significantly reduced the proliferative ability of allogeneic T cells stimulated by DCs. The ω-3 PUFAs significantly inhibited LPS-induced p38 phosphorylation. Conclusion: The ω-3 PUFAs may inhibit LPS-induced DC maturation and upregulate cytokine production. Impaired p38 mitogen-activated protein kinase activity is a potential critical intracellular signaling transduction mechanism. [Copyright &y& Elsevier]