Differential Regulation of Chemokine Production in Human Peritoneal Mesothelial Cells: IFN-γ Controls Neutrophil Migration Across the Mesothelium In Vitro and In Vivo

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Abstract
Leukocyte recruitment into the infected peritoneal cavity consists of an early, predominant polymorphonuclear leukocyte (PMN) influx and subsequent, prolonged 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 infiltrate remain unclear. The present study investigates a potential role for the Th1-type cytokine IFN-γ in the process of leukocyte recruitment into the peritoneal cavity. Stimulation of cultured human peritoneal mesothelial cells with IFN-γ (1–100 U/ml) alone or in combination with IL-1β (100 pg/ml) or TNF-α (1000 pg/ml) resulted in significant up-regulation of monocyte chemoattractant protein-1 and RANTES protein secretion. In contrast, IFN-γ inhibited basal and IL-1β-, and TNF-α-induced production of IL-8. The modulating effects of IFN-γ on chemokine production occurred at the level of gene expression, and the degree of regulation observed was dependent on the doses of IL-1β and TNF-α used. Analysis of the functional effects of IFN-γ on IL-1β-induced transmesothelial PMN migration with an in vitro human transmigration system and an in vivo murine model of peritoneal inflammation demonstrated that IFN-γ was able to down-regulate PMN migration induced by optimal doses of IL-1β. These effects were mediated in vivo via down-regulation of CXC chemokine synthesis. These findings suggest that IFN-γ may play a role in controlling the phenotype of infiltrating leukocyte during the course of an inflammatory response, in part via regulation of resident cell chemokine synthesis.