Differential expression of the TP alpha and TP beta isoforms of the human T Prostanoid receptor during chronic inflammation of the prostate: Role for FOXP1 in the transcriptional regulation of TP beta during monocyte-macrophage differentiation

摘要

Inflammation is linked to prostate cancer (PCa) and to other diseases of the prostate. The prostanoid thromboxane (TX)A(2) is a pro-inflammatory mediator implicated in several prostatic diseases, including PCa. TXA(2) signals through the TP alpha and TP beta isoforms of the T Prostanoid receptor (TP) which exhibit several functional differences and transcriptionally regulated by distinct promoters Prm1 and Prm3, respectively, within the TBXA2R gene. This study examined the expression of TP alpha and TP beta in inflammatory infiltrates within human prostate tissue. Strikingly, TP beta expression was detected in 94% of infiltrates, including in B- and T-lymphocytes and macrophages. In contrast, TP alpha was more variably expressed and, where present, expression was mainly confuted to macrophages. To gain molecular insight into these findings, expression of TP alpha and TP beta was evaluated as a function of monocyte-to-macrophage differentiation in THP-1 cells. Expression of both TP alpha and TP beta was upregulated following phorbol-12-myristate-13-acetate (PMA)-induced differentiation of monocytic THP-1 to their macrophage lineage. Furthermore, FOXP1, an essential transcriptional regulator down-regulated during monocyte-to-macrophage differentiation, was identified as a key trans-acting factor regulating TP beta expression through Prm3 in THP-1 cells. Knockdown of FOXP1 increased TP beta, but not TP alpha, expression in THP-1 cells, while genetic reporter and chromatin immunoprecipitation (ChIP) analyses established that FOXP1 exerts its repressive effect on TP beta through binding to four cis-elements within Prm3. Collectively, FOXP1 functions as a transcriptional repressor of TP beta in monocytes. This repression is lifted in differentiated macrophages, allowing for upregulation of TP beta expression and possibly accounting for the prominent expression of TP beta in prostate tissue-resident macrophages.