DHEA-dependent and organ-specific regulation of TNF-α mRNA expression in a murine polymicrobial sepsis and trauma model

INTRODUCTION Dehydroepiandrosterone (DHEA) improves survival after trauma and sepsis, while mechanisms of action are not yet fully understood. Therefore, we investigated the influence of DHEA on local cytokine expression in a two-hit model. METHODS Male NMRI mice were subjected to femur fracture/hemorrhagic shock and subsequent sepsis. Sham-operated animals were used as controls. DHEA (25 mg/kg) or vehicle was administered daily. Mortality rate, activity and body temperature were determined daily after sepsis induction. TNF-alpha, IL-1beta and IL-10 mRNA expression pattern were investigated in lung and liver tissue after 48 and 96 hours. RESULTS DHEA treatment resulted in a significantly reduced mortality rate and improvements in the clinical status. On cytokine level, only TNF-alpha was significantly reduced in the cecal ligation and puncture (CLP)-vehicle group in both tissues after 48 hours. This suppression could be restored by DHEA administration. In contrast, after 96 hours, TNF-alpha was up-regulated in the CLP-vehicle group while remaining moderate by DHEA treatment in liver tissue. CONCLUSIONS The improved outcome after DHEA treatment and trauma is coherent with restoration of TNF-alpha in liver and lung after 48 hours and a counter-regulatory attenuation of TNF-alpha in liver after 96 hours. Thus, DHEA seems to act, time and organ dependent, as a potent modulator of TNF-alpha expression.