INTER-DEPENDENCE BETWEEN CYTOKINES AND NO/NOS SYSTEM IN RESTING AND ACTIVATED ENDOTHELIAL CELLS

Cytokines are a heterogeneous and multifunctional group of molecules synthetized in various human cells. Structurally they are peptides (often glycosylated) used by cells for intercellular communication and control the inner environment of the cells in which they operate. Cytokines are produced by the cells involved in the immune response, inflammation, hemopoiesis, healing and systemic response to injury. Immunity, inflammatory reactions and haemostasis involve close interactions between immunocompetent cells and vascular endothelium. Vascular cells are both a target for cytokines and their source. The spectrum of endothelial cell responses challenged by cytokines is wide and varied, with different cytokines activating distinct, but overlapping, sets of functions. Under normal resting conditions endothelial cells constitutively express certain protective genes with the purpose to maintain the endothelial cells in their quiescent phenotype by inhibiting NF-kB activation and exerting antiapoptotic functions. In this status endothelial cells can exhibit their barrier and anticoagulant functions even in the presence of low levels of stimulants. When the endothelial cells are exposed to numerous stimuli such as TNF, IL-1, endotoxin or xenoreactive antibodies and complement, which are usually associated with infections, graft rejection or autoimmune diseases such as, vasculitis, NF-kB induces the expression of adhesion molecules such as E-selectin, chemokines such as IL-8 and procoagulant molecules such as TF. Besides the induction of expression of a functional programme related to thrombosis and inflammation, IL-1 and TNF also induce production of autocoids including nitric oxide (NO). Both the inducible form of NO synthase (iNOS) type II and the constitutive (type III) isoform of NOS are present in endothelial cells catalyzing the conversion of arginine into citruline and NO. The formation of NO is an ubiquitous biochemical pathway involved in the regulation of neurotransmission, vasodilatation, immunity and cytotoxicity. During inflammatory reaction NO produced by endothelial cells exerts its autocrine function through the inhibition of cytokine-induced expression of adhesion molecules and cytokine production by endothelial cells. Also, it has a protective role in inflammation through the inactivation of NADPH oxidase and the consequent impairment of superoxide production for cell mediated injury. On the other hand, there is considerable evidence that NO contributes to tissue destruction in inflammatory and immune diseases being a key component of the cytostatic/cytotoxic function of the immune system. The damage to target cells by NO released from activated macrophages or endothelial cells may involve both necrotic and apoptotic pathways of cell death.