Interleukin 1ß and interleukin 6 production in human immune cells is stimulated by the antibacterial compound Triclosan.

Triclosan (TCS) is an antimicrobial compound widely used in personal hygiene products such as mouthwash and toothpaste; and has been found in human blood, breast milk, and urine. Interleukin (IL)-6 and IL-1 beta (IL-1ß) are pro-inflammatory cytokines regulating cell growth, tissue repair, and immune function; increased levels of each have been associated with many diseases, including cancer. Previous studies showed that TCS at concentrations between 0.05 and 5 µM consistently increased the secretion of IL-1ß and IL-6 from human immune cells within 24 h of exposure. The current study demonstrates that this increase in secretion was not due simply to release of existing stores but was due to an increase in cellular production/levels (both secreted and intracellular levels) of each of these cytokines. Production of IL-1ß and IL-6 was increased by exposure to one or more concentration of TCS at each length of exposure (10 min, 30 min, 6 h, and 24 h). TCS-induced stimulation of cytokine production was shown to be dependent on the mitogen-activated protein kinase (MAPK) p44/42 (ERK 1/2). It was also shown that these TCS-induced increases in IL-1ß and IL6 production were accompanied by increased mRNA for IL-1ß and IL-6. The ability of TCS to increase production indicates that rather than activating a self-limiting process of depleting cells of already existing stores of IL-1ß or IL-6, TCS can stimulate a process that has the capacity to provide sustained production of these cytokines and thus may lead to chronic inflammation and its pathological consequences.

Organotin and organochlorine toxicants activate key translational regulatory proteins in human immune cells.

Environmental contaminant exposures occur due to the widespread use of synthetic chemicals. Tributyltin (TBT), dibutyltin (DBT), and pentachlorophenol (PCP) are each used in a variety of applications, including antifouling paints and stabilizers in certain plastics. Each of these compounds has been found in human blood, as well as other tissues, and they have been shown to stimulate pro-inflammatory cytokine production in human immune cells, Inflammatory cytokines mediate response to injury or infection. However, if their levels are increased in the absence of an appropriate stimulus, chronic inflammation can occur. Chronic inflammation is associated with a number of pathologies including cancer. Stimulation of pro-inflammatory cytokine production by these toxicants is dependent on activation of ERK 1/2 and/or p38 MAPK pathways. MAPK pathways have the capacity to regulate translation by increasing phosphorylation of key translation regulatory proteins. There have been no previous studies examining the effects of TBT, DBT, or PCP on translation. The current study shows that ribosomal protein S6 (S6), eukaryotic initiation factor 4B (eIF4B), and eIF4E are phosphorylated (activated) and/or their total levels are elevated in response to each of these compounds at concentrations found in human blood. Activation/increased levels of translational proteins occurred at concentrations of the compounds that have been shown to elevate pro-inflammatory cytokine production, but where there is no increase in mRNA for those proteins was seen. Compound-stimulated increases in translation appear to be part of the mechanism by which they elevate protein production in immune cells.

Longitudinal Education and Career Outcomes of a Cancer Research Training Program for Underrepresented Students: The Meharry-Vanderbilt-Tennessee State University Cancer Partnership.

This study examined longitudinal education and career outcomes of the Meharry-Vanderbilt-Tennessee State University Cancer Partnership, the longest-running National Cancer Institute (NCI) Comprehensive Partnerships in Advancing Cancer Health Equity (CPACHE) program site in the United States. Degree completion rates were calculated and progression along the entire postsecondary "pipeline" was quantified for 204 participants recruited between 2011 and 2020. For participants who had entered the workforce, career outcomes were also analyzed. Relative to comparison data, participants completed degrees and progressed through the higher education "pipeline" to earn advanced degrees at remarkably high rates; the majority entered careers in which they support or conduct cancer research. The latter is important, because most participants identify with demographic categories currently underrepresented in the cancer research workforce. This article makes two contributions to knowledge on research training programs for underrepresented students: 1) it quantifies participants' progression along the entire postsecondary education pipeline as well as into the workforce, and 2) it identifies points where participants are most prone to exit the pipeline rather than progress. We identify two types of exits-permanent and temporary-and offer empirically supported operational definitions for both. Evaluators may find the quantitative model and/or definitions useful for analyzing similar programs.

Toll-like receptors in the mechanism of tributyltin-induced production of pro-inflammatory cytokines, IL-1ß and IL-6.

Tributyltin (TBT) is an environmental contaminant due to its use in a variety of applications as a biocide, including in marine anti-fouling paints. It has been detected in a number of human tissues including blood. Previous studies have shown that exposure to TBT increases the cellular production (secretion plus intracellular levels) of the pro-inflammatory cytokines IL-1ß and IL-6 by peripheral blood mononuclear cells (PMBCs) and this increase requires MAPK activation. Toll-like receptors (TLR) activate immune cells to produce pro-inflammatory cytokines in response to pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) leading to activation of MAPKs as well as other intracellular components that regulate cytokine production. The current study shows that selective inhibition of TLRs 4,1/2, and 8 diminishes the ability of TBT to stimulate IL-1ß and IL-6 production. However, selective inhibition of TLR3 enhanced the TBT-induced production of IL-1ß. This indicates that TBT may be either directly or indirectly interacting with certain TLR receptors as part of its mechanism of stimulating pro-inflammatory cytokine production. These results provide an important advance in understanding TBT stimulation of IL-1ß and IL-6, which has the potential to cause chronic inflammation and its attendant pathologies.

The Meharry-Vanderbilt-Tennessee State University Cancer Partnership (MVTCP): History and Highlights of 20 Years of Accomplishments.

Cancer health disparities among populations are the result of a combination of socioeconomic, environmental, behavioral, and biological factors, which affect cancer incidence, prevalence, mortality, survivorship, financial burden, and screening rates. The long-standing Meharry Medical College (MMC), Vanderbilt-Ingram Cancer Center (VICC), Tennessee State University (TSU) Cancer Partnership has built an exceptional cancer research and training environment to support the efforts of diverse investigators in addressing disparities. Over the past 20 years, collaborative partnership efforts across multiple disciplines have supported research into the determinants of cancer health disparities at a National Cancer Institute-designated comprehensive cancer center (VICC) along with enhancing research infrastructure and training at MMC and TSU, two institutions that serve predominantly underserved populations and underrepresented students. Moreover, the geographical placement of this partnership in Tennessee, a region with some of the highest cancer incidence and mortality in the United States, has provided an especially important opportunity to positively affect outcomes for cancer patients.

High-Fat Diet-Induced Obese Effects of Adipocyte-Specific CXCR2 Conditional Knockout in the Peritoneal Tumor Microenvironment of Ovarian Cancer.

Obesity contributes to ovarian cancer (OC) progression via tumorigenic chemokines. Adipocytes and OC cells highly express CXCR2, and its ligands CXCL1/8, respectively, indicating that the CXCL1/8-CXCR2 axis is a molecular link between obesity and OC. Here, we investigated how the adipocyte-specific CXCR2 conditional knockout (cKO) affected the peritoneal tumor microenvironment of OC in a high-fat diet (HFD)-induced obese mouse model. We first generated adipocyte-specific CXCR2 cKO in mice: adipose tissues were not different in crown-like structures and adipocyte size between the wild-type (WT) and cKO mice but expressed lower levels of CCL2/6 compared to the obese WT mice. HFD-induced obese mice had a shorter survival time than lean mice. Particularly, obese WT and cKO mice developed higher tumors and ascites burdens, respectively. The ascites from the obese cKO mice showed increased vacuole clumps but decreased the floating tumor burden, tumor-attached macrophages, triglyceride, free fatty acid, CCL2, and TNF levels compared to obese WT mice. A tumor analysis revealed that obese cKO mice attenuated inflammatory areas, PCNA, and F4/80 compared to obese WT mice, indicating a reduced tumor burden, and there were positive relationships between the ascites and tumor parameters. Taken together, the adipocyte-specific CXCR2 cKO was associated with obesity-induced ascites despite a reduced tumor burden, likely altering the peritoneal tumor microenvironment of OC.

Evaluation of triclosan exposures on secretion of pro-inflammatory cytokines from human immune cells.

Triclosan (TCS) is widely used in personal hygiene products, such as mouthwash and toothpaste, and is found in human tissues. Interleukin (IL)-1 beta (IL-1ß), IL-6, tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) are pro-inflammatory cytokines and inappropriately elevated levels of each have been associated with pathologies including rheumatoid arthritis and certain cancers. Here we examine effects of TCS on the secretion of the pro-inflammatory cytokines from human immune cell preparations. TCS at concentrations between 0.05-5 µM consistently increased the secretion of IL-1ß, IL-6, and TNFα within 24 h of exposure and the increases often maintained out to 6 days of exposure. TCS also induced increases in IFNγ secretion, however the increases were most consistent after 48 h of exposure rather than within 24 h. Additionally, a role for both p44/42 and p38 MAPK in TCS-stimulated increases in IL-1ß was seen in cells from some donors.

Dibutyltin alters immune cell production of the pro-inflammatory cytokines interleukin (IL) 1ß and IL-6: role of mitogen-activated protein kinases and changes in mRNA.

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) 1ß (IL-1ß) and IL-6 are pro-inflammatory cytokines produced by lymphocytes, monocytes, and other cells. Elevated levels of IL-1ß and IL-6 have been associated with pathologies including rheumatoid arthritis and cancers. DBT was shown to decrease IL-1ß 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-1ß 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-1ß 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.

The organochlorine pesticides pentachlorophenol and dichlorodiphenyltrichloroethane increase secretion and production of interleukin 6 by human immune cells.

The environmental contaminants pentachlorophenol (PCP) and 4, 4'-dichlorodiphenyltrichloroethane (DDT) are detected in some human blood samples at levels as high as 5 µM (PCP) and 260 nM (DDT). Several cancers are associated with exposures to these contaminants. IL-6 is a pro-inflammatory cytokine that when dysregulated stimulates inflammatory diseases and tumor progression. Immune cells exposed to PCP at 0.05-5 µM and DDT at 0.025-2.5 µM showed increased secretion of IL-6 when the cell preparations contained either T lymphocytes or monocytes. Increased IL-6 secretion was due to PCP and DDT induced cellular production of the cytokine and was dependent on MAP kinase signaling pathways (in the case of PCP). Compound-induced increases in IL-6 production were in part due to increases in either the transcription of and/or stability of its mRNA. Thus, both PCP and DDT have the potential to produce chronic inflammation by stimulating production of IL-6 by immune cells.

Exposures to the environmental contaminants pentachlorophenol and dichlorodiphenyltrichloroethane increase production of the proinflammatory cytokine, interleukin-1ß, in human immune cells.

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)-1ß is a proinflammatory cytokine and is involved in stimulating cell proliferation. High levels of IL-1ß 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-1ß. This study shows that the increased secretion of IL-1ß 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-1ß appeared to be maximal after 6 hours of exposure and then diminished by 24 hours. The increases seen in IL-1ß production stimulated by PCP appear to be at least partially due to compound-induced increases in IL-1ß mRNA. Although DDT caused increased production of IL-1ß, it did not appear to cause consistent increases in its mRNA. PCP- and DDT-induced increases in IL-1ß 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-1ß production in a p38 mitogen-activated protein kinase-dependent manner, which may have the potential to influence chronic inflammation.

Chemokine Network and Overall Survival in TP53 Wild-Type and Mutant Ovarian Cancer.

Ovarian cancer (OC) has the highest mortality rate among gynecological malignancies. Because chemokine network is involved in OC progression, we evaluated associations between chemokine expression and survival in tumor suppressor protein p53 (TP53) wild-type (TP53WT) and mutant (TP53m) OC datasets. TP53 was highly mutated in OC compared to other cancer types. Among OC subtypes, CXCL14 was predominantly expressed in clear cell OC, and CCL15 and CCL20 in mucinous OC. TP53WT endometrioid OC highly expressed CXCL14 compared to TP53m, showing better progression-free survival but no difference in overall survival (OS). TP53m serous OC highly expressed CCL8, CCL20, CXCL10 and CXCL11 compared to TP53WT. CXCL12 and CCL21 were associated with poor OS in TP53WT serous OC. CXCR2 was associated with poor OS in TP53m serous OC, while CXCL9, CCL5, CXCR4, CXCL11, and CXCL13 were associated with better OS. Taken together, specific chemokine signatures may differentially influence OS in TP53WT and TP53m OC.

Synthesis of interleukin 1 beta and interleukin 6 in human lymphocytes is stimulated by tributyltin.

Tributyltin (TBT) is a widespread environmental contaminant that is present in human blood and other tissues. It has been shown to disrupt the immune function of human natural killer (NK) cells and to alter the secretion of a number of pro-inflammatory cytokines from immune cells. Secretion of both interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) from human lymphocytes can be increased dependent upon the level of TBT exposure. This study shows that the TBT-induced increases in secretion of both cytokines are due to TBT-induced increases in the synthesis of these proteins and not simply because of the release of pre-existing cytokine. Furthermore, the data indicate that these TBT-induced increases in IL-1ß and IL-6 synthesis require MAP kinase signaling pathways. Additionally, elevated synthesis of IL-1ß and IL-6 seen at the highest exposures to TBT (200, 200, 50 nM) were accompanied by increases in the mRNA for these cytokines. TBT-induced increases in IL-1ß and IL-6 mRNAs were also shown to be dependent on MAP kinase signaling. The study suggests that TBT has the capacity to increase immune cell production of these 2 important pro-inflammatory cytokines and that this increase is in part explained by increased mRNA for the cytokines.

Tributyltin stimulates synthesis of interferon gamma and tumor necrosis factor alpha in human lymphocytes.

Tributyltin (TBT) is found in human blood and other tissues and thus is of considerable concern as to its effects on human health. Previous studies have demonstrated that TBT has detrimental effects on immune function. Recently, we found that exposures to TBT caused increased secretion of two important proinflammatory cytokines, tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). Elevation of either of these cytokines has the potential to cause chronic inflammation, which is an important factor in a number of diseases including cancer. The current study examined the mechanism of TBT-induced elevations of TNFα and IFNγ secretion and found that the p38 mitogen-activated protein kinase pathway was essential to the ability of TBT to stimulate secretion. Additionally, this study demonstrated that increased secretion of these cytokines was due to TBT-induced increases in their overall synthesis, rather than simply being due to an increase in the release of already formed proteins. The TBT-induced increases in synthesis were evident within 6 hours of exposure. The p38 mitogen-activated protein kinase pathway is also necessary for the TBT-induced increases in both TNFα and IFNγ synthesis. The role of increased transcription of TNFα and IFNγ mRNA in response to TBT exposures as a possible explanation for the increased synthesis of these cytokines was also examined. It was found that increased mRNA levels did not appear to explain fully the increases in either TNFα or IFNγ synthesis. Thus, TBT is able to increase secretion of two important proinflammatory cytokines by increasing their synthesis.

CXCR2 is a negative regulator of p21 in p53-dependent and independent manner via Akt-mediated Mdm2 in ovarian cancer.

Ovarian cancer (OC) has the highest rate of mortality among gynecological malignancy. Chemokine receptor CXCR2 in OC is associated with poor outcomes. However, the mechanisms by which CXCR2 regulates OC proliferation remain poorly understood. We generated CXCR2-positive cells from parental p53 wild-type (WT), mutant and null OC cells, and assessed the roles of CXCR2 on proliferation of OC cells in p53-dependent and independent manner. CXCR2 promoted cell growth rate: p53WT > mutant = null cells. Nutlin-3, a p53 stabilizer, inhibited cell proliferation in p53WT cells, but had little effect in p53-mutant or null cells, indicating p53-dependence of CXCR2-mediated proliferation. CXCR2 decreased p53 protein, a regulator of p21, and downregulated p21 promoter activity only in p53WT cells. The p53 responsive element (RE) of p21 promoter played a critical role in this CXCR2-mediated p21 downregulation. Moreover, CXCR2-positive cells activated more Akt than CXCR2-negative cells followed by enhanced murine double minute (Mdm2). Silencing Mdm2 or Akt1 upregulated p21 expression, whereas Akt1 overexpression downregulated p21 at the promoter and protein levels in p53WT cells. Cell cycle analysis revealed that CXCR2 decreased p21 gene in p53-null cells. Interestingly, romidepsin (histone deacetylase inhibitor)-induced p21 upregulation did not involve the p53 RE in the p21 promoter in p53-null cells. Romidepsin decreased the protein levels of Akt1 and Mdm2, leading to induction of p21 in p53-null cells. CXCR2 reduced romidepsin-induced p21 upregulation by activating Akt-induced Mdm2. Taken together, CXCR2 enhances cell proliferation by suppressing p21 through Akt-Mdm2 signaling in p53-dependent and independent manner.

Polysaccharide-mediated synthesis of melanins from serotonin and other 5-hydroxy indoles.

AIM: As a continuation of our research on the melanin formation from catecholamines, we studied the polysaccharide-mediated oxidation of serotonin and other 5-hydroxy indoles into melanin-like materials. As for the catecholamines, we observed that many polysaccharides promote the oxidation of such compounds, particularly in the presence of Cu2+. METHODOLOGY: The reactions were monitored using reverse phase-HPLC and size-exclusion chromatography techniques. Melanin-like materials were purified through dialysis and characterized using UV-Vis and Fourier transform IR spectroscopic techniques. RESULTS: One such material, synthesized from chondroitin sulfate type A and serotonin in the presence of Cu2+ was found to affect the release of IL-1ß and IL-6 cytokines from immune cells.

Flame retardants, hexabromocyclododecane (HCBD) and tetrabromobisphenol a (TBBPA), alter secretion of tumor necrosis factor alpha (TNFα) from human immune cells.

Hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) are flame retardants, used in a variety of applications, which contaminate the environment and are found in human blood. HBCD and TBBPA have been shown to alter the tumor killing function of natural killer (NK) lymphocytes and the secretion of the inflammatory cytokines interferon gamma (IFNγ) and interleukin 1 beta (IL-1ß). The current study examined the effects of HBCD and TBBPA on secretion of the critical pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) from human immune cells. Preparations of human immune cells that ranged in complexity were studied to determine if the effects of the compounds were consistent as the composition of the cell preparation became more heterogeneous. Cell preparations studied were: NK cells, monocyte-depleted (MD) peripheral blood mononuclear cells (PBMCs), and PBMCs. Exposure of NK cells to higher concentrations of HBCD (5 and 2.5 µM) caused decreased secretion of TNFα. However, when the cell preparation contained T lymphocytes (MD-PBMCs and PBMCs) these same concentrations of HBCD increased TNFα secretion as did nearly all other concentrations. This suggests that HBCD's ability to increase TNFα secretion from immune cells was dependent on the presence of T lymphocytes. In contrast, exposures to TBBPA decreased the secretion of TNFα from all immune cell preparations regardless of the composition of the cell preparation. Further, HBCD-induced increases in TNFα secretion utilized the p38 MARK pathway. Thus, both HBCD and TBBPA may have the capacity to disrupt the inflammatory response with HBCD having the potential to cause chronic inflammation.

Butyltin compounds alter secretion of interleukin 6 from human immune cells.

Butyltins (BTs), tributyltin (TBT) and dibutyltin (DBT) are organotin compounds that have been used in a variety of industrial applications; as a result, these compounds have been found in human blood. Interleukin (IL)-6 is a proinflammatory mediator that is produced by T lymphocytes and monocytes. It is responsible for immune response regulation as well as tissue repair and cellular growth. Both BTs decrease the ability of human natural killer cells to destroy tumor cells and alter the secretion of proinflammatory cytokines tumor necrosis factor alpha, interferon gamma and IL-1 beta (ß) from human lymphocytes ex vivo. Here, we show that BTs alter the secretion of IL-6 from increasingly reconstituted preparations of human immune cells. IL-6 secretion was examined after 24 hour, 48 hour or 6 day exposures to TBT and DBT in highly enriched human natural killer cells, monocyte-depleted peripheral blood mononuclear cells (PBMCs), PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes (PBMCs + granulocytes). The results indicated that both BTs altered IL-6 secretion from all cell preparations. Significant decreases of IL-6 secretion were seen at the highest concentration of TBT (200 nm) and DBT (5-2.5 µm) while the lower concentrations of DBT (0.05 and 0.1 µm) caused elevation of IL-6 secretion. The data indicate that BT-induced alterations of IL-6 secretion from immune cells may be a significant consequence of BT exposures that may potentially affect immune competence.

Obesity-Induced Peritoneal Dissemination of Ovarian Cancer and Dominant Recruitment of Macrophages in Ascites.

One-fifth of cancer deaths are associated with obesity. Because the molecular mechanisms by which obesity affects the progression of ovarian cancer (OC) are poorly understood, we investigated if obesity could promote the progression of OC cells using the postmenopausal ob/ob mouse model and peritoneal dissemination of mouse ID8 OC cells. Compared to lean mice, obese mice had earlier OC occurrence, greater metastasis throughout the peritoneal cavity, a trend toward shorter survival, and higher circulating glucose and proinflammatory chemokine CXCL1 levels. Ascites in obese mice had higher levels of macrophages (Mφ) and chemokines including CCL2, CXCL12, CXCL13, G-CSF and M-CSF. Omental tumor tissues in obese mice had more adipocytes than lean mice. Our data suggest that obesity may accelerate the peritoneal dissemination of OC through higher production of pro-inflammatory chemokines and Mφ recruitment.

Effects of pentachlorophenol and dichlorodiphenyltrichloroethane on secretion of interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) from human immune cells.

Pentachlorophenol (PCP) and dichlorodiphenyltrichloroethane (DDT) are pesticides that have been widely used and significantly contaminate the environment. Both are found in human blood and have been shown to alter the lytic and binding function of human natural killer (NK) cells. Interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) are pro-inflammatory cytokines, which regulate immune responsiveness to pathogens and tumors. Their levels require very tight control to prevent loss of immune competence or excessive inflammation. Here, we examined the capacity of PCP and DDT to alter the secretion of these critical pro-inflammatory cytokines from increasingly reconstituted (more complex) preparations of human immune cells which included NK cells, monocyte-depleted (MD) peripheral blood mononuclear cells (PBMCs) (a preparation that is predominantly lymphocytes) and PBMCs (a preparation containing lymphocytes and monocytes). Results indicated that exposure to PCP decreased IFNγ secretion at the highest exposures (2.5 and 5 µM) and increased IFNγ secretion at lower concentrations. These effects were seen irrespective of the complexity of the cell preparation. PCP at 2.5 and 5 µM generally decreased TNFα secretion from NK cells, but had inconsistent effects in MD-PBMCs and PBMCs. Exposure of each of the immune cell preparations to DDT caused increase in IFNγ secretion. DDT (2.5 µM) increased TNFα secretion from MD-PBMCs after either 24 h or 48 h of exposure. The mechanism of PCP-induced increase in IFNγ secretion appears to involve the p38 mitogen activated protein kinase (MAPK) pathway, based on loss of PCP stimulated increase when this pathway was inhibited.

Exposures to the environmental toxicants pentachlorophenol (PCP) and dichlorodiphenyltrichloroethane (DDT) modify secretion of interleukin 1-beta (IL-1ß) from human immune cells.

Pentachlorophenol (PCP) and Dichlorodiphenyltrichloroethane (DDT) are environmental contaminants found in human blood. Previous studies have shown that PCP and DDT inhibit the lytic function of highly purified human natural killer (NK) lymphocytes and decrease the expression of several surface proteins on NK cells. Interleukin-1 ßeta (IL-1ß) is a cytokine produced by lymphocytes and monocytes, and anything that elevates its levels inappropriately can lead to chronic inflammation, which among other consequences can increase tumor development and invasiveness. Here, PCP and DDT were examined for their ability to alter secretion of IL-1ß from immune cell preparations of various complexity: NK cells; monocyte-depleted (MD) peripheral blood mononuclear cells (PBMCS); and PBMCs. Cells were exposed to concentrations of PCP ranging from 5 to 0.05 µM and DDT concentrations of 2.5-0.025 µM for 24, 48 h, and 6 days. Results showed that both PCP and DDT increased IL-1ß secretion from all of the immune cell preparations. The specific concentrations of PCP and DDT that increased IL-1ß secretion varied by donor. Immune cells from all donors showed compound-induced increases in IL-1ß secretion at one or more concentration at one or more length of exposure. The mechanism of PCP stimulation of IL1-ß secretion was also addressed, and it appears that the MAPKs, ERK1/2 and p38, may be utilized by PCP to stimulate secretion of IL-1ß.