Regulation of cytokine release from peritoneal macrophages of patients on continuous ambulatory peritoneal dialysis

textabstractThe foundation of this thesis was laid in 1982 when we made the first studies of the production of inflammatory mediators by macrophages collected from effluent dialysate of patients on Continuous Ambulatory Dialysis (CAPD). During the frrst experiments, these cells, harvested from infection-free patients, proved to be suitable for immunopharmacological studies (4). When macrophages were collected when CAPD was complicated by an infectious peritonitis, the cells exhibited some striking differences in comparison with macrophages that were collected when the patients were infection-free. Notably the finding that the release of prostaglandins and the intracellular cAMP levels were decteased in macrophages collected during an episode of peritonitis, was intriguing (2). While prostaglandins are well known for their proinflammatory properties they can have antiinflammatory properties as well thought to be mediated by stimulating intracellular cAMP levels (3). At that time emphasis was put on the proinflammatory properties of prostaglandins, while the relevance of t.l:te antiinflammatory properties to in vivo conditions was sometimes questioned. Tne finding that macrophages from an inflammatory environment showed a decrease in the release of prostaglandins, might indicate, that prostaglandins fulfil antiinflammatory-immunomodulatory rather than proinflammatory functions with regard to these macrophages during the acute phase of an inflammation. A decrease in the release of the antiinflammatory prostaglandins could allow macrophages to become "activated" during an infection (7). To test this postulate I proposed, in 1983, to i..-tvestigate the secretion of the proinfla.'lliDatory "factor" later identified as interleukin-1: IL-l, by using peritoneal macrophages isolated from CAPD patients during peritoPitis and during an infection-free period. The following questions had to be answered: 1) Is the decreased secretion of the antii'l.flammatory prostaglandins, as found during peritonitis, associated with increased secretion of the proinflammatory IL-l? 2) Do prostaglandins have inhibitory effects on IL-l secretion? These questions underlie the studies of this thesis. IL-l secretion by peritoneal macrophages from infected patients as compared to infection-free patients, is described in chapter 5. In chapter 6, the relationship between the secretion of IL-lB and that of prostaglandins (PGEz, PGI:J was studied. In chapter 7, the in vitro secretion of Tumor Necrosis Factor ex (TNFcx), an other cytokine with proinflammatory properties, by peritoneal macrophages from infected patients is compared with that of infection-free patients. To what extent the release of IL-lB and TNFcx from peritoneal macrophages is affected by exogenous PGEz or the cyclooxygenase inhibitor indomethacin, is discussed in chapter 8. These findi.'l.gs are summa.Tized in chapter 9. Furthermore the relevance of these findings with regard to the acquisition of functional competence by peritoneal macrophages during infection, is discusse