Differential regulation of chemokine production in human peritoneal mesothelial cells: IFN-gamma controls neutrophil migration across the mesotheliumin vitro and in vivo

Leukocyte recruitment into the infected peritoneal cavity consists of an ea rly, predominant polymorphonuclear leukocyte (PMN) influx and subsequent, p rolonged mononuclear cell migration phase. Although chemokine secretion by resident peritoneal cells plays a primary role in mediating this migration, the mechanisms involved in controlling the switch in phenotype of cell inf iltrate remain unclear. The present study investigates a potential role for the Th1-type cytokine IEFN-gamma in the process of leukocyte recruitment i nto the peritoneal cavity. Stimulation of cultured human peritoneal mesothe lial cells with IFN-gamma (1-100 U/ml) alone or in combination with IL-1 be ta (100 pg/ml) or TNF-alpha (1000 pg/ml) resulted in significant up-regulat ion of monocyte chemoattractant protein-1 and RANTES protein secretion. In contrast, IFN-gamma inhibited basal and IL-1 beta-, and TNF-a-induced produ ction of IL-8. The modulating effects of IFN-gamma on chemokine production occurred at the level of gene expression, and the degree of regulation obse rved was dependent on the doses of IL-1 beta and TNF-alpha used. Analysis o f the functional effects of IFN-gamma on IL-1 beta -induced transmesothelia l PMN migration with an in vitro human transmigration system and an in vivo murine model of peritoneal inflammation demonstrated that IFN-gamma was ab le to down-regulate PMN migration induced by optimal doses of IL-1 beta. Th ese effects were mediated in vivo via down-regulation of CXC chemokine synt hesis. These findings suggest that IFN-gamma may play a role in controlling the phenotype of infiltrating leukocyte during the course of an inflammato ry response, in part via regulation of resident cell chemokine synthesis.