volving several other kinases as well as small GTP The cytokine tumor necrosis factor (TNF) a was binding proteins (For review see 1-3).found to stimulate the p38 mitogen activated protein Recently, two homologues of p38 MAP kinase have (MAP) kinase signalling cascade in human umbilical been identified in human monocytes by the use of a vein endothelial cells. TNFa increased the activity of class of pyridinyl imidazoles (4). These drugs inhibit the p38 substrate MAP kinase-activated-protein (MAP-the production of interleukin-1b and tumor necrosis KAP) kinase 2 and the subsequent phosphorylation of factor (TNF) by stimulated monocytes. The pyridinyl the small heat shock protein Hsp27 about two to three imidazole SB203580 specifically inhibits p38 MAP ki- expression of the intercellular cell adhesion molecule-1 (ICAM-1). The biological functions of these adhesion molecules are distinct. ICAM-1 binds leukocytes via their b2 integrins and can therefore serve to recruit both granulocytes and monocytes from the bloodstream Under conditions of cellular stress, such as heat to sites of tissue injury, whereas VCAM-1 binds monoshock, UV radiation and osmotic stimulation, as well cytes and lymphocytes expressing the integrins a4b1 as subsequent to cytokine treatment at least two and a4b7 specifically supporting the recruitment of members of the superfamily of mitogen-activated chronic inflammatory cells (10,11). In this paper we protein (MAP) kinases are rapidly activated. These have investigated whether there is a direct connection enzymes, which are distinct from the extra-cellularly between the p38 MAP kinase cascade and the expresregulated kinase (Erk)-1 and Erk2 stimulated by sion of the endothelial adhesion molecules. By the use growth factors, are p38 MAP kinase/reactivating kiof the inhibitor SB203580 we demonstrate that the exnase (RK) and c-jun amino terminal kinase (JNK)/ pression of VCAM-1, but not ICAM-1, is likely regustress-activated protein (SAP) kinase. Like Erk1/2 lated by the p38 MAP kinase at the post-transcripthese enzymes are activated through a cascade intional level.

Abstract. During inflammation, the superoxide anion (O°) and hydrogen peroxide (H202) are produced by stimulated polymorphonuclear leukocytes and macrophages. The toxic effects of these reactive oxygen intermediates increase when traces of iron are present, because iron catalyzes the formation of the hydroxyl radical (OH'). Partially saturated iron-binding proteins, such as transferrin and ferritin, are unable to catalyze OH formation in vitro. Mobilization of iron from these proteins is necessary for iron stimulation of OH" formation. This paper reports that stimulated polymorphonuclear leukocytes mobilize iron from human and horse ferritin, but not from human transferrin. Iron release from ferritin depends on O2 because it can be prevented by the addition of superoxide dismutase. Catalase and dimethylsulfoxide have no inhibitory effect on iron mobilization. The efficiency of the iron release increases at low levels of O2 production. Only O2 produced by granulocytes is sufficient for iron mobilization, because solid potassium superoxide is also able to release iron from ferritin. We propose that this reaction may potentiate the formation of the OH radical in inflammatory states.

No abstract

The effects of the lipid-peroxidation product 4-hydroxynonenal on the formation of fluorescent chromolipids from microsomes, mitochondria and phospholipids were studied. Incubation of freshly prepared rat liver microsomes or mitochondria with 4-hydroxynonenal results in a slow formation of a fluorophore with an excitation maximum at 360 nm and an emission maximum at 430 nm. The rate and extent of the development of the 430 nm fluorescence can be significantly enhanced by ADP-iron (Fe3+). With microsomes, yet not with mitochondria. NADPH has a catalytic effect similar to that of ADP-iron. Fluorescent chromolipids with maximum excitation and emission at 360/430 nm are also formed during the NADPH-linked ADP-iron-stimulated lipid peroxidation. Phosphatidylethanolamine and phosphatidylserine react with 4-hydroxynonenal revealing a fluorophore with the same spectral characteristics as that obtained in the microsomal and mitochondrial system. The findings suggest that the fluorescent chromolipids formed by lipid peroxidation are not derived from malonaldehyde, but are formed from 4-hydroxynonenal or similar reactive aldehydes via a NADPH and/or ADP-iron-catalysed reaction with phosphatidylethanolamine and phosphatidylserine contained in the membrane.

In the presence of other risk factors, serum ferritin may adversely affect ischemic heart disease risk in the elderly.