Oeth P, Yao J, Fan S T, Mackman N
Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA.
Blood. 1998 Apr 15;91(8):2857-65.
Expression of tissue factor (TF) by activated monocytes in several diseases leads to disseminated intravascular coagulation. Lipopolysaccharide (LPS)-induced monocyte TF expression is downregulated by the nuclear hormone all-trans retinoic acid (ATRA). In this study, we examined the mechanism by which ATRA inhibits monocyte TF expression. We show that ATRA selectively inhibited LPS induction of TF expression in human monocytes and monocytic THP-1 cells without affecting LPS induction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8). Inhibition of TF expression occurred at the level of transcription as determined by nuclear run-on. ATRA did not significantly alter the binding or functional activity of the transcription factors c-Fos/c-Jun and c-Rel/p65, which are required for LPS induction of the TF promoter in monocytic cells. In contrast to the ATRA inhibition of the endogenous TF gene, LPS induction of the cloned TF promoter was not inhibited by ATRA in transiently transfected THP-1 cells. Our results demonstrate that ATRA selectively inhibited LPS-induced TF gene transcription in human monocytic cells by a mechanism that does not involve repression of AP-1- or NF-kappaB-mediated transcription.
在多种疾病中，活化的单核细胞表达组织因子（TF）会导致弥散性血管内凝血。核激素全反式维甲酸（ATRA）可下调脂多糖（LPS）诱导的单核细胞TF表达。在本研究中，我们探究了ATRA抑制单核细胞TF表达的机制。我们发现，ATRA可选择性抑制人单核细胞和单核细胞系THP-1细胞中LPS诱导的TF表达，而不影响LPS诱导的肿瘤坏死因子-α（TNF-α）和白细胞介素-8（IL-8）。通过核转录分析确定，TF表达的抑制发生在转录水平。ATRA并未显著改变转录因子c-Fos/c-Jun和c-Rel/p65的结合或功能活性，而这些转录因子是单核细胞中LPS诱导TF启动子所必需的。与ATRA对内源性TF基因的抑制相反，在瞬时转染的THP-1细胞中，LPS诱导的克隆TF启动子不受ATRA抑制。我们的结果表明，ATRA通过一种不涉及抑制AP-1或NF-κB介导转录的机制，选择性抑制人单核细胞中LPS诱导的TF基因转录。
