Species differential regulation of COX2 can be described by an NF kappa B-dependent logic AND gate

摘要

Cyclooxygenase 2 (COX2), a key regulatory enzyme of the prostaglandin/eicosanoid pathway, is an important target for anti-inflammatory therapy. It is highly induced by pro-inflammatory cytokines in a Nuclear factor kappa B (NF kappa B)-dependent manner. However, the mechanisms determining the amplitude and dynamics of this important pro-inflammatory event are poorly understood. Furthermore, there is significant difference between human and mouse COX2 expression in response to the inflammatory stimulus tumor necrosis factor alpha (TNF alpha). Here, we report the presence of a molecular logic AND gate composed of two NF kappa B response elements (NREs) which controls the expression of human COX2 in a switch-like manner. Combining quantitative kinetic modeling and thermostatistical analysis followed by experimental validation in iterative cycles, we show that the human COX2 expression machinery regulated by NF kappa B displays features of a logic AND gate. We propose that this provides a digital, noise-filtering mechanism for a tighter control of expression in response to TNF alpha, such that a threshold level of NF kappa B activation is required before the promoter becomes active and initiates transcription. This NF kappa B-regulated AND gate is absent in the mouse COX2 promoter, most likely contributing to its differential graded response in promoter activity and protein expression to TNF alpha. Our data suggest that the NF kappa B-regulated AND gate acts as a novel mechanism for controlling the expression of human COX2 to TNF alpha, and its absence in the mouse COX2 provides the foundation for further studies on understanding species-specific differential gene regulation.