Expression and modulation of progesterone induced blocking factor (PIBF) and innate immune factors in human leukemia cell lines by progesterone and mifepristone

Abstract

Progesterone (P), required for successful pregnancy, influences autoimmune, infectious, and malignant diseases via adaptive and innate immune effects. P induces NK inhibitor progesterone induced blocking factor (PIBF) in CD8+ T cells. PIBF isoforms could permit solid tumor immune escape. Expression and modulation of PIBF and innate immune proteins by P in leukemia cells and leukocyte subpopulations have not been reported. Ten T, seven myeloid, six B, five epithelial, fibroblast BG9, G-CSF mobilized CD34+ stem cells, and peripheral blood mononuclear cells were screened for PIBF mRNA by RT-PCR, and protein by immunohistochemistry in SRIK-NKL, MOT, U937, HL60, R-CLL, MD-E, 729pH6neo, SRIH-B(ATL), SRIK-B(T-PLL), and MeWo. Cell lines expressing PIBF and exemplifying myeloid/monoblast, natural killer/T, and B lineages were cultured with and without 0.5 - 5 microM P or 0.5 - 0.05 microM mifepristone (RU486) for 24 h. Subsequently they were examined for changes in the expression of mRNA by RT-PCR and protein by immunohistochemistry for PIBF and some innate immune factors. All cells expressed PIBF mRNA; protein only in four (SRIK-NKL, U937, SRIK-B(T-PLL) and HL60) out of 10 cell lines tested. P increased and RU486 decreased PIBF in U937, SRIK-B(T-PLL) and SRIK-NKL. P upregulated TLR-4 in U937, and HNP1 - 3, LL-37, IRAK-2, and IRAK-4 in multiple lines and RU486 down regulated these. PIBF may be used by some leukemias to evade immune surveillance and is a potential therapeutic target. P may impact infection and autoimmunity via effects on LPS receptor, TLR signaling, and antimicrobial peptides.

Progesterone induces a switch in oligosaccharyltransferase isoform expression: Consequences on IgG N-glycosylation

“…What is more, multiple forms of PIBF are expressed in breast tumors independently from the progesterone receptor status [25]. Furthermore, Srivastava et al [35] reported that progesterone up regulated PIBF protein expression in only four out of ten hematological tumor cell lines that constitutively expressed PIBF. These data suggest that P4-regulation in tumor cell lines does not depend on whether the cell constitutively expresses PIBF.…”

Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF)

“…The progesterone receptor modulator abortifacient mifepristone has been found to decrease intracytoplasmic PIBF production of the 34-36-kDa intracytoplasmic splice variant [25]. Yet, mifepristone does not decrease serum PIBF levels [27].…”

“…Progesterone has been found to not only increase the serum PIBF but to also increase the level of a PIBF intracellular splice variant (that is similar in size to circulating PIBF) in rapidly growing cells, e.g., the cells of the fetal placental unit (or cancer cells) [1,25,26]. The progesterone receptor modulator abortifacient mifepristone has been found to decrease intracytoplasmic PIBF production of the 34-36-kDa intracytoplasmic splice variant [25].…”

Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity

“…Recently it was shown that PIBF is up-regulated in undifferentiated proliferating cells (e.g, trophoblast cells) as well as in a set of malignancies [10][11][12][13][14]. Several breast cancers overexpress PIBF compared to normal breast tissues [12]; moreover, MCF-7 breast carcinoma cells produce PIBF independently of progesterone [12].…”