ABSTRACT
BACKGROUND: Trauma causes a release of catecholamines, transforming growth factor-beta (TGF-beta), and T-helper II cytokines (TH2). Individually, these substances also induce arginase in macrophages. The purpose of this study was to determine the synergistic interactions between isoproterenol, TGF-beta, and TH2 cytokines on arginase expression in macrophages. METHODS: Confluent RAW 264.7 macrophages were incubated with various combinations of interleukins 4, 10, and 13 (IL-4, IL-10, IL-13), and TGF-beta with isoproterenol over 48 hours. Arginase activity, as well as arginase I expression by Western blot and reverse transcriptase-polymerase chain reaction, were measured. RESULTS: Although isoproterenol, IL-4, IL-10, and IL-13 individually induced arginase, significant synergy between the combination of isoproterenol with either TGF-beta or the TH2 cytokines was observed. All cytokines except IL-10 also induced arginase I protein and mRNA. Arginase II protein was detected in cells exposed to IL-10. CONCLUSIONS: We conclude that isoproterenol synergizes with IL-4, IL-13, and TGF-beta to increase arginase I mRNA and protein, as well as arginase activity in RAW 264.7 macrophages. Further, IL-10 synergizes with isoproterenol to increase arginase activity and arginase II protein. These synergistic mechanisms may compete with nitric oxide synthase for l-arginine substrate, thus shunting away available arginine from nitric oxide production and contributing to cellular immunosuppression observed after trauma.