10 research outputs found
Aryl hydrocarbon receptor (AhR) agonists suppress interleukin-6 expression by bone marrow stromal cells: an immunotoxicology study
BACKGROUND: Bone marrow stromal cells produce cytokines required for the normal growth and development of all eight hematopoietic cell lineages. Aberrant cytokine production by stromal cells contributes to blood cell dyscrasias. Consequently, factors that alter stromal cell cytokine production may significantly compromise the development of normal blood cells. We have shown that environmental chemicals, such as aromatic hydrocarbon receptor (AhR) agonists, suppress B lymphopoiesis by modulating bone marrow stromal cell function. Here, we extend these studies to evaluate the potential for two prototypic AhR agonists, 7,12-dimethylbenz [a]anthracene (DMBA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), to alter stromal cell cytokine responses. METHODS: Bone marrow stromal cells were treated with AhR agonists and bacterial lipopolysaccharide (LPS) to mimic innate inflammatory cytokine responses and to study the effects of AhR ligands on those responses. Steady state cytokine RNA levels were screened by RNAse protection assays (RPA) and quantified by real-time PCR. Cytokine (IL-6) protein production was measured by ELISA. NF-ΞΊB EMSAs were used to study IL-6 transcriptional regulation. RESULTS: RPAs indicated that AhR(+ )bone marrow stromal cells consistently up-regulated genes encoding IL-6 and LIF in response to LPS, presumably through activation of Toll-like receptor 4. Pre-treatment with low doses of DMBA or TCDD selectively abrogated IL-6 gene induction but had no effect on LIF mRNA. Real-time-PCR indicated a significant inhibition of IL-6 mRNA by AhR ligands within 1 hour of LPS challenge which was reflected in a profound down-regulation of IL-6 protein induction, with DMBA and TCDD suppressing IL-6 levels as much as 65% and 88%, respectively. This potent inhibitory effect persisted for at least 72 hours. EMSAs measuring NF-ΞΊB binding to IL-6 promoter sequences, an event known to induce IL-6 transcription, indicated a significant decrease in the LPS-mediated induction of DNA-binding RelA/p50 and c-Rel/p50 heterodimers in the presence of DMBA. CONCLUSIONS: Common environmental AhR agonists can suppress the response to bacterial lipopolysaccharide, a model for innate inflammatory responses, through down-regulation of IL-6, a cytokine critical to the growth of several hematopoietic cell subsets, including early B cells. This suppression occurs at least at the level of IL-6 gene transcription and may be regulated by NF-ΞΊB
Combined influence of teichoic acids from Staphylococcus aureus and heterometallik Cu/Cd ethylenediamine complex on peritoneal macrophages and tumor cells
We investigated the effects of teichoic acid (TA) from Staphylococcus aureus Wood 46 on tumor growth and metastasis of the experimental Lewis lung carcinoma (LLC) in mice. Intranasal administration of TA alone aggravated both tumor growth and metastasis, whereas combined administration of TA with a synthetic bimetallic (copper: cadmium) ethylene diamine complex PO244 resulted in pronounced antitumor and antimetastatic effects. The group of animals subjected to the combined treatment with TA and PO244 manifested the highest degree of lymphocyte infiltration into the tumor tissue, compared to the control group and those exposed to TA or PO244 alone. Moreover, the combined treatment negatively affected the adhesive properties of peritoneal macrophages in the LLC bearing mice. Co-cultivation of the isolated macrophages with primary LLC cultures revealed significant (p < 0.05) cytotoxic and cytostatic effects, detected as an increased level of apoptosis and a reduced fraction of replicating cells.ΠΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π»ΠΈ ΠΌΠΎΠ΄ΠΈΡΠΈΡΠΈΡΡΡΡΠ΅Π΅ Π²Π»ΠΈΡΠ½ΠΈΠ΅ ΡΠ΅ΠΉΡ
ΠΎΠ΅Π²ΠΎΠΉ ΠΊΠΈΡΠ»ΠΎΡΡ (Π’Π) Π½Π° ΡΠΎΡΡ ΠΈ ΠΌΠ΅ΡΠ°ΡΡΠ°Π·ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΠΏΠ΅ΡΠ΅Π²ΠΈΠ²Π°Π΅ΠΌΠΎΠΉ ΠΊΠ°ΡΡΠΈΠ½ΠΎΠΌΡ Π»Π΅Π³ΠΊΠΈΡ
ΠΡΡΠΈΡ Ρ ΠΌΡΡΠ΅ΠΉ. ΠΡΡΠ²Π»Π΅Π½Π° Π³ΠΈΠΏΠ΅ΡΠ°ΠΊΡΠΈΠ²Π°ΡΠΈΡ ΡΠΎΡΡΠ° ΠΈ ΠΌΠ΅ΡΠ°ΡΡΠ°Π·ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΏΠ΅ΡΠ²ΠΈΡΠ½ΠΎΠΉ ΠΎΠΏΡΡ
ΠΎΠ»ΠΈ ΠΏΡΠΈ ΠΈΠ½ΡΡΠ°Π½Π°Π·Π°Π»ΡΠ½ΠΎΠΌ Π²Π²Π΅Π΄Π΅Π½ΠΈΠΈ ΠΆΠΈΠ²ΠΎΡΠ½ΡΠΌ Π’Π, Π² ΡΠΎ Π²ΡΠ΅ΠΌΡ ΠΊΠ°ΠΊ ΠΏΡΠΈ ΠΊΠΎΠΌΠ±ΠΈΠ½ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠΌ Π²Π»ΠΈΡΠ½ΠΈΠΈ Ρ Π Π244 Π½Π°Π±Π»ΡΠ΄Π°Π»ΠΈ ΡΡΠΈΠ»Π΅Π½ΠΈΠ΅ ΠΏΡΠΎΡΠΈΠ²ΠΎ-ΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²ΠΎΠ³ΠΎ ΡΡΡΠ΅ΠΊΡΠ°. Π‘Π°ΠΌΡΠΉ Π²ΡΡΠΎΠΊΠΈΠΉ ΡΡΠΎΠ²Π΅Π½Ρ ΠΈΠ½ΡΠΈΠ»ΡΡΡΠ°ΡΠΈΠΈ ΠΎΠΏΡΡ
ΠΎΠ»Π΅Π²ΠΎΠΉ ΡΠΊΠ°Π½ΠΈ Π»ΠΈΠΌΡΠΎΡΠΈΡΠ°ΠΌΠΈ Π·Π°ΡΠΈΠΊΡΠΈΡΠΎΠ²Π°Π»ΠΈ Π² Π³ΡΡΠΏΠΏΠ΅ ΠΆΠΈΠ²ΠΎΡΠ½ΡΡ
, ΠΊΠΎΡΠΎΡΡΠΌ ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΠ»ΠΈ ΠΊΠΎΠΌΠ±ΠΈΠ½ΠΈΡΠΎΠ²Π°Π½Π½ΡΡ ΡΠ΅ΡΠ°ΠΏΠΈΡ Π’Π Ρ Π Π 244. ΠΠΎΠΊΠ°Π·Π°Π½ΠΎ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ Π°Π΄Π³Π΅Π·ΠΈΠ²Π½ΡΡ
ΡΠ²ΠΎΠΉΡΡΠ² ΠΏΠ΅ΡΠΈΡΠΎΠ½Π΅Π°Π»ΡΠ½ΡΡ
ΠΌΠ°ΠΊΡΠΎΡΠ°Π³ΠΎΠ² ΠΏΠΎΠ΄ Π²Π»ΠΈΡΠ½ΠΈΠ΅ΠΌ Π±ΠΈΠΌΠ΅ΡΠ°Π»Π»ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΠ°. ΠΠΎΡΠ»Π΅ ΡΠΎΠΊΡΠ»ΡΡΠΈΠ²ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΠΌΠ°ΠΊΡΠΎΡΠ°Π³ΠΎΠ² ΠΎΡ ΠΆΠΈΠ²ΠΎΡΠ½ΡΡ
, ΠΊΠΎΡΠΎΡΡΠΌ ΠΏΡΠΎΠ²ΠΎΠ΄ΠΈΠ»ΠΈ ΠΊΠΎΠΌΠ±ΠΈΠ½ΠΈΡΠΎΠ²Π°Π½Π½ΡΡ ΡΠ΅ΡΠ°ΠΏΠΈΡ Ρ ΠΏΠ΅ΡΠ²ΠΈΡΠ½ΠΎΠΉ ΠΊΡΠ»ΡΡΡΡΠΎΠΉ LLC, Π²ΡΡΠ²Π»Π΅Π½ΠΎ Π·Π½Π°ΡΠΈΡΠ΅Π»ΡΠ½ΠΎΠ΅ (p < 0.05) ΡΠΈΡΠΎΡΠΎΠΊΡΠΈΡΠ΅ΡΠΊΠΎΠ΅/ΡΠΈΡΠΎΡΡΠ°ΡΠΈΡΠ΅ΡΠΊΠΎΠ΅ Π²Π»ΠΈΡΠ½ΠΈΠ΅, ΡΡΠΎ ΠΏΡΠΎΡΠ²Π»ΡΠ»ΠΎΡΡ Π² ΡΠ²Π΅Π»ΠΈΡΠ΅Π½ΠΈΠΈ ΡΡΠΎΠ²Π½Ρ Π°ΠΏΠΎΠΏΡΠΎΠ·Π° ΠΈ ΡΠΌΠ΅Π½ΡΡΠ΅Π½ΠΈΠΈ ΠΏΠΎΠΏΡΠ»ΡΡΠΈΠΈ ΠΊΠ»Π΅ΡΠΎΠΊ ΠΏΡΠΎΠ»ΠΈΡΠ΅ΡΠ°ΡΠΈΠ²Π½ΠΎΠ³ΠΎ ΠΏΡΠ»Π°