Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone

Abstract

Women are conferred with greater immunologic and survival benefits compared to men. Female sex steroids contribute to this sexual dimorphism. Furthermore, during human pregnancy when female sex hormones are elevated, neutrophil apoptosis is delayed. This study examines the specific effects of estradiol and progesterone on neutrophil apoptosis and function in healthy adult men and women. We also examined the contribution of these hormones to the persistence and resolution of an inflammatory response. Spontaneous apoptosis was significantly decreased in women compared with men. Physiologic doses of estradiol and progesterone caused a further delay in spontaneous apoptosis in both men and women but did not diminish Fas antibodyinduced apoptosis. The delay in apoptosis was mediated at the level of the mitochondria with decreased release of cytochrome c, which may alter caspase cleavage and activity. There were no associated alterations in neutrophil CD11b, but production of reactive oxygen intermediates (ROIs) in women was increased. Thus, female sex hormones mediate delayed neutrophil apoptosis in both sexes and enhance female intracellular production of ROIs. Modulating hormonal responses may be an effective therapeutic tool in combating inflammatory diseases. IntroductionFrom conception to senescence, women have a significant survival advantage. 1 Men are more susceptible to sepsis and subsequent morbidity and mortality than women of reproductive age. [2][3][4] The incidence of sepsis in postmenopausal women increases to levels almost equal to those seen in age-matched men. 5,6 The exact mechanism mediating this sexual dimorphism is unclear. However, female sex hormones have been implicated because they modulate the immune system under normal and stress conditions. 7 Following trauma or hemorrhage, female mice maintain their immune function, whereas male mice have significantly depressed responses. 8 Estradiol has been shown to be protective in organ ischemia-reperfusion injury and shock by preventing androgeninduced immunosuppression in male animals. 9-12 Thus, female sex hormones may be a useful adjunct in preventing trauma-induced immunosuppression and the associated increased susceptibility to sepsis. 13 Estrogen treatment, testosterone depletion, and testosterone receptor antagonists improve outcome in male animals following trauma and sepsis. 14 The exact role of changes in the estradiol-testosterone ratio in immune function requires further clarification. Estrogens are also cited as having a protective role in neurodegenerative and cardiac diseases through a variety of mechanisms including blockade of oxidation, antagonism of nitric oxide synthase activity, 15 and interference with the apoptotic process in a variety of cell systems.Altered neutrophil apoptosis has been implicated in the pathogenesis of several inflammatory conditions. 16,17 Excessively delayed neutrophil apoptosis is associated with the systemic inflammatory response syndrome (SIRS). This syndrome is also characterized by activated neutro...

Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

“…Women also have a higher systemic neutrophil count compared with men (Bain and England, 1975a), and neutrophil counts correlate with estradiol levels during menstruation (Bain and England, 1975b) and pregnancy (Efrati et al, 1964) suggesting that sex hormones influence neutrophilia and overall resistance to sepsis most likely by delaying apoptosis in neutrophils (Molloy et al, 2003). In order to eliminate pathogens during infections, neutrophils are armed with a variety of weapons including engulfment and intracellular degradation of microbes (Hampton et al, 1998;Segal, 2005), release of oxygen species and granule proteins (Lehrer and Ganz, 1999) and release of extracellular chromatin fibers bound to granular, nuclear and cytoplasmic proteins called neutrophil extracellular traps (NETs) (Brinkmann et al, 2004).…”

Influence of sex steroids on the viability and CD11b, CD18 and CD47 expression of blood neutrophils from dairy cows in the last month of gestation

“…Cox [7] and Liles et al [17] report that progesterone has no influence on the apoptosis of blood PMN, whereas Molloy et al [22] describe that physiological doses of 17β-estradiol and progesterone cause a delay in PMN apoptosis. In the latter study the combination of 17β-estradiol and progesterone was additionally evaluated for its influence on viability, apoptosis and necrosis.…”

“…Evaluation of the administration of 17β-estradiol and/or progesterone to human PMN confirmed this suggestion. Physiological doses of 17β-estradiol and progesterone caused a delay in spontaneous apoptosis [22].…”

“…The exact influence of sex steroids is, however, still incompletely understood. Indeed, their effect on viability, apoptosis and necrosis and on the CD11b, CD18 and CD47 expression of PMN is only poorly documented and reports are limited to human PMN [7,11,17,22].…”

“…A positive influence of endogenous sex steroid levels on the viability of human PMN has been suggested since a delay in spontaneous apoptosis is observed in women of reproductive age compared with agematched men [22]. Moreover, apoptosis of PMN from women at the end of pregnancy is extensively delayed [37].…”