The mycotoxins citrinin, gliotoxin, and patulin affect interferon-gamma rather than interleukin-4 production in human blood cells.
Exposure to molds diminishes the numbers of T-helper type 1 (Th1) cells in the peripheral blood of children and is a risk factor for the development of allergic diseases (results of LARS: Leipzig Allergy Risk Children Study, Mueller et al. 2002). We hypothesized that mycotoxins are responsible for this effect and therefore investigated the influence of citrinin, gliotoxin, and patulin on human peripheral blood mononuclear cells (PBMC). CD3/CD28-stimulated PBMC of healthy donors were incubated for 24 h with the mycotoxins in serial dilutions and triplicates. Vitality and proliferation were tested using the MTT assay and T-cell function by the expression of cytokines (ELISA, intracellular cytokine staining, and real-time polymerase chain reaction (RT-PCR) for interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). The cytokine secretion was inhibited at concentrations 2-130 times lower compared to vitality (ELISA versus MTT assay). The strongest inhibition of cytokine expression was found for IFN-gamma: 8.3 microg/mL citrinin, 34.2 ng/mL gliotoxin, and 64.8 ng/mL patulin caused a 50% inhibition of the IFN-gamma release (50% inhibitory dose, ID(50)). For IL-4 release the corresponding ID(50) values were 21.6 microg/mL citrinin, 82.8 ng/mL gliotoxin, and 243.2 ng/mL patulin. Furthermore, 3 ng/mL patulin caused a significant increase of IL-4 but a significant suppression of IFN-gamma. On the mRNA level, after 24 h an unaltered or enhanced IL-4 was observed compared to a reduced IFN-gamma expression. Using a method of intracellular cytokine staining, we were able to show that the described effects are caused by a reduction of the number of IFN-gamma-producing T lymphocytes rather than by a reduced functional capacity of the single cell. We suggest that mycotoxins primarily cause stronger inhibition of IFN-gamma-producing Th1 cells, which may lead to T-cell polarization toward the Th2 phenotype and may raise the risk for the development of allergies.
UFZ Centre for Environmental Research Leipzig-Halle, Department of Human Exposure Research and Epidemiology, Permoser Strasse 15, Germany. guwich@expo.ufz.de
G
G
Wichmann
O
O
Herbarth
I
I
Lehmann
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002953:Citrinin / Q000494:pharmacology*; D005912:Gliotoxin / Q000494:pharmacology*; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D009153:Mutagens / Q000494:pharmacology*; D010365:Patulin / Q000494:pharmacology*; D010641:Phenotype; D012307:Risk Factors
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D009153:Mutagens; D015847:Interleukin-4; D002953:Citrinin; D005912:Gliotoxin; D007371:Interferon-gamma; D010365:Patulin