alternariol and Inflammation

The mycotoxin alternariol (AOH) can be found in food products infected by

Topics: Alternaria; Humans; Inflammation; Lactones; Male; Mycotoxins; Prostate; Prostatic Neoplasms

Topics: Animals; Cell Proliferation; Cells, Cultured; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclooxygenase 2; Dinoprostone; Female; Inflammation; Keratinocytes; Lactones; Mice; Receptors, Prostaglandin E, EP2 Subtype; Signal Transduction; Skin

Alternariol (AOH) is a secondary metabolite formed by black mold of the genus Alternaria alternata. Due to limited hazard and occurrence data, AOH is still considered as an "emerging mycotoxin" and, as such, not monitored and regulated yet. Recent studies indicate immunosuppressive effects in vitro by altering the expression of CD molecules and proinflammatory cytokines, which are indispensable in mounting an innate immune response. However, the mode of action by which AOH exerts its immunosuppressive effects has not been unraveled yet. The present study aimed to characterise the impact of AOH on the nuclear factor kappa B (NF-κB) pathway, the expression of NF-κB target cytokines and involved regulatory microRNAs (miRNAs). In THP-1 derived macrophages, AOH (1-20 µM) was found to suppress lipopolysaccharide (LPS)-induced NF-κB pathway activation, decrease secretion of the proinflammatory cytokines IL-8, IL-6, TNF-α and to induce secretion of the anti-inflammatory IL-10. Thereby, a distinct pattern of cytokine mRNA levels was monitored, varying between short- and long-term exposure. Concomitantly, AOH (2-20 µM) affected the transcription levels of miR-146a and miR-155 in LPS-stimulated THP-1 derived macrophages dose-dependently by down- and upregulation, respectively. In contrast, transcription of miR-16 and miR-125b, two other immune-related miRNAs, was not modulated. In the absence of a LPS stimulus, AOH (20 µM) did not affect basal NF-κB activity, but increased IL-10 transcription. Collectively, our results indicate, that AOH itself does not induce a proinflammatory immune response in human macrophages; however, in an inflamed environment it possesses the ability to repress inflammation by targeting the NF-κB signalling pathway and regulatory miRNAs.

Topics: Cytokines; Humans; Immunosuppressive Agents; Inflammation; Lactones; Lipopolysaccharides; Macrophages; NF-kappa B; Signal Transduction; THP-1 Cells; Transcription, Genetic

Topics: Alternaria; Animals; Cell Cycle Checkpoints; Cell Line; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Epithelial Cells; Host-Pathogen Interactions; Humans; Immunity, Innate; Immunomodulation; Inflammation; Lactones; Lipopolysaccharides; Macrophages; Mice; Mycotoxins

Alternariol (AOH), a mycotoxin produced by Alternaria fungi, is frequently found as a contaminant in fruit and grain products. Here we examined if AOH could modify macrophage phenotype and inflammatory responses. In RAW 264.7 mouse macrophages AOH changed the cell morphology of from round to star-shaped cells, with increased levels of CD83, CD86, CD11b, MHCII and endocytic activity. TNFα and IL-6 were enhanced at mRNA-level, but only TNFα showed increased secretion. No changes were found in IL-10 or IL-12p40 expression. Primary human macrophages changed the cell morphology from round into elongated shapes with dendrite-like protrusions in response to AOH. The levels of CD83 and CD86 were increased, HLA-DR and CD68 were down-regulated and CD80, CD200R and CD163 remained unchanged. Increased secretion of TNFα and IL-6 were found after AOH exposure, while IL-8, IL-10 and IL-12p70 were not changed. Furthermore, AOH reduced macrophage endocytic activity and autophagosomes. AOH was also found to induce DNA damage, which is suggested to be linked to the morphological and phenotypical changes. Thus, AOH was found to change the morphology and phenotype of the two cell models, but either of them could be characterized as typical M1/M2 macrophages or as dendritic cells (DC).

Topics: Animals; Cell Cycle Checkpoints; Cells, Cultured; Cytokines; DNA Damage; Female; Humans; Inflammation; Lactones; Macrophages; Mice; Mycotoxins; Phenotype; Reactive Oxygen Species