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

Abstract

Research highlights:•TPα and TPβ isoforms differentially upregulated in prostate inflammatory infiltrates •TPβ found in 94% of infiltrates, including in B-& T-lymphocytes and in macrophages •TP found in 72% of infiltrates, but expression is mainly confined to macrophages •TPα and TPβ upregulated after monocyte-to macrophage differentiation of THP-1 cells •Tumour suppressor FOXP1 transcriptionally regulates TPβ expression in macrophages AbstractInflammation is linked to prostate cancer (PCa) and to other diseases of the prostate. The prostanoid thromboxane (TX)A2 is a pro-inflammatory mediator implicated in several prostatic diseases, including PCa. TXA2 signals through the TPα and TPβ 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 TPα and TPβ in inflammatory infiltrates within human prostate tissue. Strikingly, TPβ expression was detected in 94% of infiltrates, including in B-and T-lymphocytes and macrophages. In contrast, TPα was more variably expressed and, where present, expression was mainly confined to macrophages. To gain molecular insight into these findings, expression of TPα and TPβ was evaluated as a function of monocyte-tomacrophage differentiation in THP-1 cells. Expression of both TPα and TPβ 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 TPβ expression through Prm3 in THP-1 cells. Knockdown of FOXP1 increased TPβ, but not TPα, expression in THP-1 cells, while genetic reporter and chromatin immunoprecipitation (ChIP) analyses established that FOXP1 exerts its repressive effect on TPβ through binding to four cis-elements within Prm3. Collectively, FOXP1 functions as a transcriptional repressor of TPβ in monocytes. This repression is lifted in differentiated macrophages, allowing for upregulation of TPβ expression and possibly accounting for the prominent expression of TPβ in prostate tissue-resident macrophages.

G9a promotes inflammation in Streptococcus pneumoniae induced pneumonia mice by stimulating M1 macrophage polarization and H3K9me2 methylation in FOXP1 promoter region

“…Flow cytometry revealed CD86 was increased and CD206 was decreased, and RT-qPCR elicited that iNOS was increased and Arg-1 was decreased after simultaneously silencing G9a and FOXP1. Foxp3+ regulatory T cells promote recovery from severe pneumonia in mice (39), and downregulation of FOXP1 might trigger the secretion of IL-1β and IL-6 (40) and is required for monocyte differentiation and macrophage function (41,42). Taken together, FOXP1 silencing in vitro can avert the inhibitory effect of G9a knockdown on M1 macrophages.…”