2,3,7,8-tetrachlorodibenzo-p-dioxin induces transcriptional activity of the human polymorphic hs1,2 enhancer of the 3'Igh regulatory region.
2,3,7,8-tetrachlorodibenzo-p-dioxin induces transcriptional activity of the human polymorphic hs1,2 enhancer of the 3'Igh regulatory region.
复制标题
DOI：
10.4049/jimmunol.1101111
复制
发表时间：
2012-04-01
期刊：
影响因子：
--
通讯作者：
Sulentic CE
中科院分区：
文献类型：
--
作者：
Fernando TM;Ochs SD;Liu J;Chambers-Turner RC;Sulentic CE
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxicant known to inhibit antibody secretion and Ig expression. Inhibition of Ig expression may be partially mediated through repression of the 3’Igh regulatory region (3’IghRR). TCDD inhibits mouse 3’IghRR activation and induces aryl hydrocarbon receptor (AhR) binding to dioxin response elements (DREs) within the 3’IghRR enhancers: hs1,2 and hs4. The human hs1,2 enhancer (hu-hs1,2) is polymorphic due to the presence of one to four invariant sequences (IS), which have been correlated with several autoimmune diseases. The IS also contains a DRE-core motif. Therefore, the objective was to determine if hu-hs1,2 activity is sensitive to TCDD. Utilizing a mouse B-cell line (CH12.LX), we compared the effects of TCDD on mouse (mo-hs1,2) versus hu-hs1,2 activity. TCDD inhibited mo-hs1,2 similar to the mouse 3’IghRR. In contrast, hu-hs1,2 was activated by TCDD and antagonist studies supported an AhR-dependent activation, which was replicated in a human B-cell line (IM-9). Absence of Pax5 binding sites is a major difference between the human and mouse hs1,2 sequence. Insertion of the high affinity Pax5 site in hu-hs1,2 markedly blunted reporter activity but did not alter TCDD’s effect (i.e. no shift from activation to inhibition). Additionally, deletional analysis demonstrated a significant IS contribution to hu-hs1,2 basal activity but TCDD-induced activity was not strictly IS number-dependent. Taken together our results suggest that hu-hs1,2 is a significant target of TCDD and support species differences in hs1,2 regulation. Therefore, sensitivity of hu-hs1,2 to chemical-induced modulation may influence the occurrence and/or severity of human diseases associated with hu-hs1,2.
登录
查看更多内容
影响因子：
6.5
作者：
Cianci, Rossella;Giambra, Vincenzo;Frezza, Domenico
通讯作者：
Frezza, Domenico
影响因子：
7.7
作者：
Linderson, Y;Eberhard, D;Pettersson, S
通讯作者：
Pettersson, S
DOI：
10.1080/026520300283351
发表时间：
2000-04-01
影响因子：
2.9
作者：
Birnbaum, LS;Tuomisto, J
通讯作者：
Tuomisto, J
影响因子：
3.6
作者：
Allan, LL;Sherr, DH
通讯作者：
Sherr, DH
影响因子：
6.4
作者：
Denizot, Y;Pinaud, E;Cogné, M
通讯作者：
Cogné, M