Abstract
The Aryl Hydrocarbon Receptor (AHR) is a basic helix-loop-helix transcription factor, implicated as an important modulator of the immune system and early thymocyte development. Previously we have shown that AHR activation by the environmental contaminant and potent AHR agonist, 2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) leads to a significant decline in the percentage of S phase cells in the CD3-CD4-CD8- triple negative stage 3 (TN3) and TN4 T-cell committed thymocytes 9-12 hours after exposure. In the more immature TN1 or TN2 stage cells no effect on cell cycle was observed. In order to identify early molecular targets, which could provide insight into how the AHR acts as a modulator of thymocyte development and cell cycle regulation, we performed gene profiling experiments using RNA isolated from four intrathymic progenitor populations where the AHR was activated for 6 or 12 hours. This microarray analysis of AHR activation identified 108 distinct gene probes that were significantly modulated in the TN1-4 thymocyte progenitor stages. While most of the genes identified have specific AHR recognition sequences, only seven genes were altered exclusively in the two T-cell committed stages of early thymocyte development (TN3 and TN4) in which the decline of S phase cells is seen. Moreover, all seven of these genes were reduced in expression and five of these seven are associated with cell cycle regulatory processes. These 7 genes are novel targets for modulation by the TCDD activated AHR and may be involved in the observed cell cycle arrest and suppression of early thymocyte development
Footnotes
- Received November 17, 2009.
- Revision received January 21, 2010.
- Accepted February 12, 2010.
- The American Society for Pharmacology and Experimental Therapeutics