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Males are known to have increased risk for septic complications after traumatic injury, which appears to be mediated by the inhibitory effects of testosterone on immune function. The role of testosterone in immunity after burn injury, however, remains unclear. Herein, we examined the effects of a testosterone receptor antagonist, flutamide, on delayed type hypersensitivity response (DTH), splenocyte proliferation, interleukin (IL)-2 secretion, and IL-2 receptor (IL-2R) expression in male BALB/c mice subjected to a 15% total body surface area burn or sham injury. Burn- or sham-injured mice were given flutamide s.c. at 30 min and 24 h after injury. At 48 h, burn injury caused a 48% (P<0.001) decrease in DTH response; however, mice that received flutamide treatment did not demonstrate significant suppression of DTH. Likewise, splenocyte proliferation and IL-2 production were depressed in burned animals in comparison with sham-injured controls, and flutamide treatment resulted in a partial restoration of these responses. In vitro studies indicated that splenocytes from sham- and burn-injured mice were equally sensitive to the suppressive effects of 5alpha-dihydrotestosterone in regard to proliferation and IL-2 production. Further evaluation revealed a decrease in IL-2R expression on splenocytes from burned mice and a partial restoration of this expression with flutamide treatment. Thus blocking testosterone receptor activation improves the cellular immunity in thermally injured mice, possibly through restoration of IL-2 production and IL-2R expression. It remains to be determined whether the effects of testosterone in this injury model are direct or indirect.

Previous studies in our laboratory have demonstrated that cell-mediated immune function was suppressed in female, but not male, mice at 10 days after burn injury and was mediated, in part, by increased production of interleukin-6 (IL-6). Because 17beta-estradiol (E(2)) influences immune function after trauma and the hormone is known to regulate IL-6 production, the effect of E(2) on immune function after thermal injury was examined. Increased circulating concentrations of E(2) corresponded with suppressed delayed-type hypersensitivity (DTH) and splenocyte-proliferative responses, and increased circulating concentrations of IL-6 in female mice after burn. Ovariectomy restored the suppressed DTH response and decreased IL-6 concentrations, and administration of exogenous E(2) to both ovariectomized females and intact male mice resulted in a suppressed DTH response. In addition, in vitro treatment with E(2) suppressed splenocyte proliferation in a macrophage-dependent manner and enhanced macrophage production of IL-6. These results strongly suggest that the sex difference in cell-mediated immunity 10 days after burn injury is mediated by altered concentrations of E(2), which in turn modulate key macrophage-derived immunoregulatory cytokines.