By way of CD154-induced CD154 expression, human endothelial cells thus seem capable of influencing the progression of proinflammatory reactions, including atherogenesis through activation of extravasating monocytes.

The interaction of proinflammatory type 1 T helper (Th1) cells expressing the CD40 ligand (CD154) with endothelial cells expressing the corresponding receptor (CD40) may play an important role in chronic inflammation including arteriosclerosis. Here we demonstrate that activation of CD40 in human cultured endothelial cells (e.g. by interaction with freshly isolated human T cells) not only up‐regulates expression of various adhesion molecules, chemokines and cytokines, but within 12–24 h also causes the release of bioactive interleukin‐12 (IL‐12 p70) through induction of IL‐12 p40 synthesis. IL‐12 p35, on the other hand, appears to be constitutively expressed in these cells. Despite enhancing expression of the other gene products, cytokines such as interferon‐γ (IFN‐γ) or tumor necrosis factor‐α, alone or in combination, failed to induce IL‐12 p40 expression, whereas IFN‐γ markedly augmented CD154‐induced IL‐12 p40 and p70 release. Of note was that the magnitude of CD154‐induced IL‐12 synthesis in the cultured endothelial cells was comparable to that evoked in freshly isolated human monocytes. This CD40‐mediated induction of endothelial IL‐12 synthesis may thus lead to an enhanced activation of the adherent CD154‐expressing Th1 cells, thereby fuelling the proinflammatory response.

1 Immune response-modulating drugs such as thalidomide may be of therapeutic value in the treatment of chronic in¯ammatory bowel diseases including Crohn's disease (CD). In the present study, we have investigated whether thalidomide exerts this e ect by impairing endothelial cellleukocyte interaction through down-regulation of the expression of pro-in¯ammatory gene products in these cells. 2 Transient CD-like colitis was induced in male Wistar rats by single enema with trinitrobenzene sulphonic acid (TNBS) in ethanol followed by macroscopic scoring, histology, intravital microscopy, RT ± PCR and immunohistochemistry (IHC) analyses. Thalidomide or its analogue supidimide were administered in olive oil by intragastric instillation 6 h prior to the induction of colitis and then daily for one week. 3 Both thalidomide and supidimide (200 mg kg 71 d 71 ) signi®cantly attenuated TNBS-induced colitis as compared to vehicle-treated control animals (44 and 37% inhibition, respectively), and this e ect persisted for 7 days post cessation of thalidomide treatment (46% inhibition). 4 Moreover, thalidomide signi®cantly reduced leukocyte sticking to postcapillary venular endothelial cells in the submucosa (by 45%), improved functional capillary density and perfusion, and attenuated endothelial interleukin-8 expression, as judged by IHC analysis. According to RT ± PCR analysis, both thalidomide and supidimide also signi®cantly reduced vascular cell adhesion molecule-1 mRNA expression in the a ected part of the descending colon. 5 These ®ndings suggest that thalidomide and one of its derivatives impairs CD-like TNBS-induced colitis in the rat by down-regulating endothelial adhesion molecule and chemokine expression and, as a consequence, the interaction of these cells with circulating leukocytes.

The actute phase reaction mediated by the proinXammatory cytokine IL6 initiates a number of metabolic changes in the liver, which may contribute to the pathogenesis of the septic shock during prolonged exposition. Here, the impact of IL6 on the hepatic glucose providing capacity was studied by monitoring glycogen degradation and the expression of the gluconeogenic phosphoenolpyruvate carboxykinase (PCK1) in rat livers during the daily feeding rhythm. Eight hours after i.p. injection of IL6, mRNA levels of 2-macroglobulin, a prominent acute phase reactant in rat liver, were elevated as shown by Northern blot analysis and in situ hybridization (ISH). PCK1 mRNA levels were decreased by IL6 to 50% of levels in untreated animals due to the reduction of PCK1 mRNA in the periportal zone of the liver as shown by ISH. PCK1 enzyme activity was not aVected by IL6. Glycogen degradation was accelerated by IL6, which led to nearly complete depletion of glycogen pools in periportal areas 8 h after IL6 injection. This was very likely due to inhibition of glycogen pool replenishment. Thus, the depletion of glycogen stores in the liver might contribute to the impairment of hepatic glucose production during prolonged acute phase challenge.