No abstract

Pentachlorophenol (PCP) and dichlorodiphenyltrichloroethane (DDT) are organochlorine environmental contaminants found in human blood at very significant levels (as high as 5 μM for PCP and 260 nM for DDT). Cancers of the blood (lymphoma and myeloma) and kidney as well as others have been associated with exposure to these contaminants. Interleukin (IL)-1β is a proinflammatory cytokine and is involved in stimulating cell proliferation. High levels of IL-1β are associated with inflammatory diseases and tumor progression. Previous studies showed that PCP and DDT at certain concentrations were able to stimulate secretion of IL-1β. This study shows that the increased secretion of IL-1β seen with both contaminants is due to compound-induced increases in the production of this cytokine. Increased production began within 6 hours of exposure to PCP and continued to increase up to 24 hours.DDT-induced stimulation of IL-1β appeared to be maximal after 6 hours of exposure and then diminished by 24 hours. The increases seen in IL-1β production stimulated by PCP appear to be at least partially due to compound-induced increases in IL-1β mRNA. Although DDT caused increased production of IL-1β, it did not appear to cause consistent increases in its mRNA. PCP-and DDT-induced increases in IL-1β production were dependent primarily on the p38 mitogen-activated protein kinase pathway. These results indicate that both PCP and DDT are able to increase IL-1β production in a p38 mitogen-activated protein kinase-dependent manner, which may have the potential to influence chronic inflammation.

Dibutyltin (DBT) is used to stabilize plastics and as a deworming agent in some poultry. It is found in human blood (levels as high as 0.3 μM). Interleukin (IL) 1β (IL‐1β) and IL‐6 are pro‐inflammatory cytokines produced by lymphocytes, monocytes, and other cells. Elevated levels of IL‐1β and IL‐6 have been associated with pathologies including rheumatoid arthritis and cancers. DBT was shown to decrease IL‐1β and IL‐6 secretion from immune cells at higher concentrations while causing increases at lower concentrations. However, it was not clear if these changes were due to DBT's alteration of the secretory process or due its ability to change cellular synthesis/production of these proteins. This study addresses this question, as well as mechanisms for any observed changes in synthesis/production. Monocyte‐depleted peripheral blood mononuclear cells (MD‐PBMCs) were exposed to DBT at concentrations of 5, 2.5, 1, 0.5, 0.25, 0.1, and 0.05 μM for 1, 6, and 24 h and the production (combination of secreted and intracellular levels from the same cells) of both IL‐1β and IL‐6 were measured. Effects of selected DBT exposures on cytokine production were also examined in PBMCs and DBT's effects were similar when monocytes were present. The 24‐h exposures to DBT decreased production of both IL‐1β and IL‐6 at the two highest concentrations but increased production at lower concentrations. Both decreases and increases in cytokine production appear to be explained by DBT‐induced changes in mRNA levels. DBT‐induced increases in cellular production of the cytokines appear to require p38 and ERK1/2 MAPK pathways.

Triclosan (TCS) is an antimicrobial agent that is incorporated into medical and personal care products such as topical antiseptics, deodorants, toothpastes, antibacterial soaps, dishwashing liquids, acne treatments, makeup, and lotions. TCS is readily absorbed through the skin. The usage of these products, which rely upon direct contact with skin, is a source of exposure to the compound. Studies have found approximately 1 μM of TCS in human blood plasma upon ingestion of TCS‐containing mouthwash. Interleukin‐1 beta (IL‐1β) is an important pro‐inflammatory cytokine produced by immune cells such as monocytes and lymphocytes, and plays a critical role in immune response regulation, tissue repair, and cellular growth. Overproduction of IL‐1β can contribute to chronic inflammation and inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. IL‐1β has also been shown to stimulate tumor development. A previous study in our lab showed that when peripheral blood mononuclear cells (PBMCs) were exposed to 0.05‐5 μM of TCS for a period of 24 hours, secretion of IL‐1β increased in an ERK 1/2 dependent manner. Mitogen activated protein kinases (MAPKs), such as ERK 1/2, are known to regulate both the secretion and production of IL‐1β. The purpose of the current study is to determine whether TCS is stimulating the immune cell's ability to produce IL‐1β (or solely releasing pre‐existing stores of this cytokine) as well as the role of ERK 1/2 pathway in any TCS‐induced elevation of IL‐1β production. PBMCs were exposed to TCS concentrations ranging from 0.05‐5 μM for time periods of 30 minutes, 6 hours, or 24 hours. The cellular production (combination of secreted and intracellular levels of IL‐1β) in response to this treatment was investigated by using Enzyme Linked Immunosorbent Assays to measure secretion and Western Blots to measure intracellular levels. The results indicate that production of IL‐1β was increased at each length of exposure, with the greatest TCS‐induced increases seen at 6 h. To investigate the mechanism of this increased production of IL‐1β, PBMCs were exposed to MEK inhibitor PD98059 to block ERK1/2 pathway activity. Prior exposure of PBMCs to the MEK inhibitor diminished TCS‐induced increases in IL‐1β production. Thus, TCS not only stimulates the secretion of IL‐1β from immune cells, but also increases production of this potent inflammatory cytokine, which can contribute to several pathologies. TCS‐induced increases in IL‐1β were shown to be dependent on the ERK 1/2 MAPK pathway.