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Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol

¹Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294; ²Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, Rhode Island 02903; ³Department of Surgery, Ludwig-Maximilians University, Klinikum Grosshadern, 81377 Munich; ⁴Department of Surgery, University of Regensburg, 93053 Regensburg; and ⁵Department of Trauma Surgery, University of Ulm, 89075 Ulm, Germany

Submitted 24 January 2002 ; accepted in final form 27 March 2003

Although immune functions are markedly depressed in males and not in proestrous females following trauma-hemorrhage (T-H), the mechanisms responsible for the divergent responses remain unknown. Because sex steroids modulate the activation of p38, our aim was to determine whether differences in the activation of p38 by phosphorylation (p38-P) might contribute to the sex-dimorphic immune response following T-H. The effects of testosterone and estradiol on the activation of p38 were also examined. Intact male mice (C3H/HeN), castrated males treated with vehicle, 5-dihydrotestosterone (DHT), or 17-estradiol, and proestrous females were subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (35 ± 5 mmHg for 90 min and resuscitation) or sham operation. At 2 h thereafter, splenic (SM) and peritoneal macrophages (PM) were harvested and cultured (with 10 µg/ml LPS), and Western blot analysis was carried out for quantification of p38 and p38-P. Sex, testosterone and estradiol plasma levels, and T-H did not alter the constitutive expression of p38 in SM and PM. In contrast, the activated form of p38 (p38-P) was markedly increased in SM and PM from female shams compared with male shams. Moreover, the phosphorylation of p38-P increased in males after T-H, whereas it decreased in females under those conditions. Castration before T-H prevented the increase in p38-P in males. Castrated animals treated with DHT displayed increased p38-P following T-H, whereas 17-estradiol had no effect on p38-P in castrated mice. Thus 1) sex influences the activation of p38 MAP kinase, 2) DHT is responsible for the increased activation of p38 in male mice, and 3) this sex-specific activation of p38 might be responsible for the sexually dimorphic immune response following T-H.

cell signaling; sex steroids; hemorrhage; immune depression; macrophages

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