BMP-2 inhibits TF expression in human monocytes by shutting down MAPK signaling and AP-1 transcriptional activity.

Background: We have recently identified bone morphogenetic protein (BMP)-2 as a novel inhibitor of tissue factor (TF) expression in lipopolysaccharide (LPS)-activated human monocytes, and now sought for intracellular mechanisms.

Methods: Here, we studied activation status of mitogen activated protein kinases (MAPKs) extracellular signal-regulated protein kinase (Erk) 1/2, p38, and c-Jun N-terminal kinase (JNK) as well as transcription factors activator protein (AP)-1 and nuclear factor kappa B (NF-kB), which regulate inducible expression of TF.

Results: Human mononuclear cells (MNCs) responded to BMP-2 stimulation with activation of canonic Smad1/5/8 signaling. Pretreatment with BMP-2 prevented LPS-induced increase in surface presentation, intracellular accumulation, and fraction of TF-positive MNCs. Similarly, LPS-induced increase in levels of phosphorylated Erk1/2, p38, and JNK was markedly diminished by BMP-2 pretreatment. BMP-2 pretreatment prior to LPS significantly diminished LPS-induced transcriptional activation of AP-1-dependent reporter. In contrast, BMP-2 given prior to LPS did not dampen the transcriptional activation of NF-kB-sensitive luciferase reporter.

Conclusions: BMP-2 can inhibit LPS-induced TF protein expression and surface presentation in human MNCs by downregulation of Erk1/2, p38, and JNK signaling, as well as reduced transcriptional activity of AP-1, but not NF-kB.