THE EFFECT OF REACTIVE OXYGEN SPECIES ON THE SYNTHESIS OF PROSTANOIDS FROM ARACHIDONIC ACID

Reactive oxygen species (ROS), such as hydrogen peroxide, superoxide anion radical or hydroxyl radical, play an important role in inflammation processes as well as in transduction of signals from receptors to interleukin -1 beta (IL-1 beta), tumor necrosis factor a (TNF-alpha) or lipopolysaccharides (LPS). NADPH oxidase increases the ROS levels, leading to inactivation of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and protein tyrosine phosphatase (PTP): MAPK phosphatase 1 (MKP-1). Inactivation of phosphatases results in activation of mitogen-activated protein kinase (MAPK) cascades: c-Jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (Erk), which, in turn, activate cytosolic phospholipase A(2) (cPLA(2)). ROS cause cytoplasmic calcium influx by activation of phospholipase C (PLC) and phosphorylation of IP3-sensitive calcium channels. ROS activate nuclear factor kappa B (NF-kappa B) via I kappa B kinase (IKK) through phosphoinositide 3-kinase (PI3K), tumor suppressor phosphatase and tensin homolog (PTEN) and protein kinase B (Akt/PKB) or NF-kappa B-inducing kinase (NIK). IKK phosphorylates NF-kappa B alpha subunit (I kappa B alpha) at Ser32. Oxidative stress inactivates NIK and I kappa B kinase g subunit/NF-kappa B essential modulator (IKK gamma/NEMO), which might cause activation of NF-kappa B that is independent on IKK and inhibitor of I kappa B a degradation, including phosphorylation of Tyr42 at I kappa B a by c-Src and spleen tyrosine kinase (Syk), phosphorylation of the domain rich in proline, glutamic acid, serine and threonine (PEST) sequence by casein kinase II and inactivation of protein tyrosine phosphatase 1B (PTP1B). NF-kB and MAPK cascades-activated transcription factor activator protein 1 (AP-1) and CREB-binding protein (CBP/p300) lead to expression of cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2) and membrane-bound prostaglandin E synthase 1 (mPGES-1), and thus to increased release of arachidonic acid and production of prostaglandins, particularly prostaglandin E-2 (PGE(2)). ROS increase the activity of hematopoietic-type PGD synthase (H-PGDS), and, as a result, the production of prostaglandin D-2 (PGD(2)). However, the superoxide radical reacts with nitric oxide forming peroxynitrite that inactivates prostaglandin I synthase (PGIS), suppressing the production of prostaglandin I-2 (PGI(2)). ROS do not affect thromboxane synthesis in a direct manner; this is achieved by an increase in cPLA(2) activity and COX-2 expression. The aim of this review was to summarize knowledge of influence of ROS on the synthesis of prostanoids from arachidonic acid.