Mechanism of the immunomodulatory effects of mycotoxins

The molecular mechanism(s) of immunomodulation by aflatoxin and other mycotoxins remains to be clearly determined. However, available evidence suggests immunosuppression by several mycotoxins is due to inhibition of DNA, RNA and protein synthesis through many different mechanisms. T cells seem to be more sensitive to the effect of aflatoxin than B cells. Many studies (some are discussed in the previous section) show that aflatoxin exerts its immunomodulatory effects by modulating cytokine production (Rossano et al., 1999; Liu et al., 2002). Rossano et al. (1999) investigated the release and genetic expression of IL-1a, IL-6 and TNF-a by human monocytes incubated with low concentrations (0.01-1.0 pg/ml) of aflatoxin B1 and activated with bacterial lipopolysaccharide. At a concentration of 0.05 pg/ml aflatoxin B1 decreased each of the three cytokines and completely blocked transcription of their mRNAs. Since the mRNA of p-actin was not effected, the authors concluded that afla-toxin B1 exerts its effect on cytokine production through selective inhibition of specific mRNAs, without affecting protein synthesis in general. They propose that aflatoxin B1 may inactivate some kinases involved in the activation of genes that code for cytokines.

A study by Dugyala and Sharma (1996) showed that aflatoxin B1 markedly increased mRNA levels of major cytokines produced by macrophages but suppressed their corresponding protein levels. Corresponding doses of aflatoxin B1 slightly decreased mRNA and protein levels of cytokines produced by lymphocytes. Their data suggest that aflatoxin B1 preferentially affects macrophage functions and differentially affects transcription and translation in macrophages. Inhibition of DNA, RNA and protein synthesis by several dif ferent mechanisms seem to be responsible for the immunosuppressive effects of many other mycotoxins. Taranu et al. (2005) showed that fumonisin Bi increased IFN-y production by swine Peripheral Blood Mononuclear Cells (PBMCs) at both the mRNA and protein levels.

The data of Marin et al. (2002) and Jiang et al. (2005) support previous conclusions (Pier, 1986) that total T cell populations of peripheral blood lymphocytes are not affected by oral consumption of aflatoxin. However, the alterations in the different lymphocyte subsets and their cytokine secretions found by Jiang et al. (2005) and the significant decrease in secretory IgA found by Turner et al. (2003) indicate impairment in cellular and humoral immunity in people (adults or children) chronically exposed to aflatoxin in their diets. These individuals had accumulated high levels of aflatoxin B1-albumin adducts in their blood, and based on the immune results are expected to have decreased resistance to infection and cancer (supported by the association between aflatoxin with hepatocellular carcinoma), decreased immune responses to vaccines, and increased susceptibility to reactivation of chronic infections.

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