Signalling networks regulating cyclooxygenase-2.

Cyclooxygenease-2 (COX-2) is the key enzyme regulating the production of prostaglandins, central mediators of inflammation. The expression of cyclooxygenease-2 is induced by several extra cellular signals including pro-inflammatory and growth-promoting stimuli. All signals converge to the activation of mitogen-activated protein kinases (MAPK) that regulate cyclooxygenease-2 mRNA levels both at the transcriptional and post-transcriptional level. The machinery appears to be highly specialized involving activation of distinct signalling molecules depending on the type of extracellular stimulus. Expression of cyclooxygenease-2 mRNA is regulated by several transcription factors including the cyclic-AMP response element binding protein (CREB), nuclear factor kappa B (NFkB) and the CCAAT-enhancer binding protein (C/EBP). Cyclooxygenease-2 is also affected post-transcriptionaly, at the level of mRNA stability. Finally, cyclooxygenease-2 can be affected directly at its enzymatic activity by nitric oxide and nitric oxide synthase (iNOS). Each step of cyclooxygenease-2 regulation can be used as potential therapeutic target.