BACKGROUND Acute mental stress evokes responses in the cardiovascular and the immune systems. In particular, the subset of natural killer (NK) cells is found to be responsive to mental stress. The role of beta-adrenergic mechanisms in these processes in the subject of this investigation. METHODS AND RESULTS Healthy male volunteers (n = 31) were subjected to two consecutive mental tasks. Subjects were randomly assigned to a beta-blocker (propranolol 40 mg) or a placebo group. The capsules were ingested 1 hour before the tasks. The tasks evoked sympathetic responses, as indicated by an increase in heart rate and a decrease in the preejection period. These effects were abolished under beta-blockade, indicating that effective beta-blockade was achieved. In the immune system, significant increases were found for the number of NK cells and NK cell activity in the placebo group; these increases were absent in the propranolol group. In addition, an increase in all lymphocyte subsets was observed in subjects who had ingested propranolol. This increase, however, was also observed in subjects who had received propranolol but had not performed the tasks, indicating that these non-subset-specific increases in lymphocytes were a side effect of the beta-blocker. CONCLUSIONS Mental stress induces activation of the sympathetic nervous system, with concomitant increases in the number of NK cells in the circulation. These changes were inhibited by propranolol, indicating that stress-induced increases in the number and activity of NK cells in the circulation are controlled by a beta-adrenergic mechanism.

Interleukin-6 (IL-6) is a monokine with a number of biological activities, which are intimately related to inflammatory responses. We have measured IL-6 levels in synovial fluid (SF) and serum (Se) of patients with rheumatic diseases. SF-IL-6 levels were a thousand-fold higher than corresponding Se levels and a positive correlation was found between SF and Se levels suggesting that Se-IL-6 is derived from IL-6 produced in the joint. Se levels of IL-6 were also positively correlated to C-reactive protein (CRP) levels, supporting the in vitro experiments showing that IL-6 stimulates hepatocytes to produce CRP. Finally we observed a positive correlation between SF-IL-6 levels and the local activity score.

Oral intake of protein leads to tolerance through the induction of regulatory T cells (Tr cells) in mesenteric lymph nodes (MLNs). Here we show that the inhibition of cyclooxygenase-2 (COX-2) in vivo suppressed oral tolerance and was associated with enhanced differentiation of interleukin (IL)-4-producing T cells and reduced Foxp3(+) Tr-cell differentiation in MLN. As a result, the functional suppressive capacity of these differentiated mucosal T cells was lost. IL-4 was causally related to loss of tolerance as treatment of mice with anti-IL-4 antibodies during COX-2 inhibition restored tolerance. Dendritic cells (DCs) in the MLN differentially expressed COX-2 and reductionist experiments revealed that selective inhibition of the enzyme in these cells inhibited Foxp3(+) Tr-cell differentiation in vitro. Importantly, the inhibition of COX-2 in MLN-DC caused increased GATA-3 expression and enhanced IL-4 release by T cells, which was directly related to impaired Tr-cell differentiation. These data provide crucial insights into the mechanisms driving de novo Tr-cell induction and tolerance in the intestine.

Summary Background Thiopurines are widely used for the treatment of inflammatory bowel disease, but are associated with the development of side effects. It has been suggested that the enzyme inosine triphosphate pyrophosphatase (ITPA) plays a role in the digestion of thiopurines and that defective activity resulting from polymorphisms in the inosine triphosphate pyrophosphatase encoding genes may be associated with thiopurine‐induced side effects. Current studies are controversial regarding this hypothesis. Aim To perform a meta‐analysis and gain more insight into a possible correlation between thiopurine‐induced side effects and ITPA polymorphisms. Methods We explored Medline for articles on ITPA polymorphisms and thiopurine toxicity. Studies that compared ITPA polymorphism frequencies among thiopurine‐tolerant and ‐intolerant adult inflammatory bowel disease patients were included in this meta‐analysis. Results Nine published studies investigated associations between ITPA polymorphisms and thiopurine toxicity. Six studies (with 751 patients included) met our inclusion criteria and were processed in the meta‐analysis. This analysis demonstrates that the ITPA 94C→A polymorphism, is not significantly associated with any of the studied side effect parameters. Conclusions This meta‐analysis does not prove a correlation between the development of thiopurine toxicity and the ITPA 94C→A polymorphism. This implies that there is no clinical relevance to determine ITPA polymorphisms in thiopurine‐treated patients.