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

Abstract

. Sex-specific p38 MAP kinase activation following trauma-hemorrhage: involvement of testosterone and estradiol. Am J Physiol Endocrinol Metab 285: E189-E196, 2003; 10.1152/ajpendo.00035. 2003.-Although immune functions are markedly depressed in males and not in proestrous females following traumahemorrhage (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 Ϯ 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 g/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.

Estradiol’s Salutary Effects on Keratinocytes Following Trauma-Hemorrhage Are Mediated by Estrogen Receptor (ER)-α and ER-β

“…MAPKs play an important role in the regulation of macrophage activation as well as other functions (4,(37)(38)(39)(40)(41)(42). Moreover, the production of various cytokines by macrophages involves MAPK signal transduction pathways (38,(43)(44)(45)(46). The present results demonstrate that p38, ERK1/2, and JNK were activated in keratinocytes after trauma-hemorrhage, a finding that suggests that the stress of trauma-hemorrhage per se caused the activation of some signaling pathways leading to MAPKs.…”

Castration prevents suppression of MHC class II (Ia) expression on macrophages after trauma-hemorrhage

“…Previous findings suggest that depletion of 5␣-dihydrotestosterone in castrated males is responsible for the improved immune responses after traumahemorrhage in those animals (2). In this respect, treatment of castrated males with 5␣-dihydrotestosterone resulted in suppressed splenic and peritoneal M⌽ cytokine responses after trauma-hemorrhage comparable to noncastrated male mice (7,8). Thus one would speculate that the testosterone derivate 5␣-dihydrotestosterone also plays a pivotal role for suppressing MHC II (Ia) expression.…”

Is the tumour necrosis factor-alpha response following resuscitation gender dependent in the swine model?

“…For instance, studies suggest a gender-specific difference in activation of p38 mitogen activated protein kinase via phosphorylation. 16,27 Evidence of oxidant injury appears rapidly after resuscitation from cardiac arrest, and activation of characteristic metabolic cascades responsible for reperfusion injury and the accompanying inflammatory response are to be expected. 1,2 Observational clinical studies in small series of patients have demonstrated elevated proinflammatory cytokine levels among individuals resuscitated from cardiac arrest.…”