Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone

Schneider, Christian; Schwacha, Martin G.; Samy, T. S. Anantha; Bland, Kirby I.; Chaudry, Irshad H.

doi:10.1152/japplphysiol.00182.2003

Cited by 35 publications

(15 citation statements)

References 53 publications

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“…In agreement with the previous studies showing androgen suppression of innate immune response, our data show that phagocytic function in the spotless starling is strongly inhibited under moderate physiological concentrations of T (Slater & Schreck 1997; Al Afaleq & Homeida 1998; Schneider et al. 2003).…”

Section: Discussionsupporting

confidence: 93%

Male ornament size in a passerine predicts the inhibitory effect of testosterone on macrophage phagocytosis

Gil¹,

Culver

2011

Functional Ecology

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Summary1. The immunocompetence handicap hypothesis (ICHH) proposes that androgen-induced immunosuppression is the mechanism that restricts the expression of exaggerated male ornaments to superior males. Numerous tests of this hypothesis have been conducted on the humoral and cell-mediated components of immunity, with mixed results. Surprisingly, no study so far has addressed whether macrophage phagocytosis, a basic immune function, plays a role in the ICHH. 2. We tested whether the ornament size of male spotless starlings (Sturnus unicolor) is a predictor of in vitro macrophage phagocytosis. We found that a moderate physiological concentration of testosterone (T) induced strong phagocytic inhibition. We found no relationship between ornament size and phagocytic activity in basal conditions. 3. Basal phagocytosis was not significantly predicted by ornament size or original testosterone levels. Contrary to expectations, phagocytosis under a moderate T concentration was negatively related to ornament size. Furthermore, a nonsignificant trend for original T concentration to negatively affect T-medium phagocytosis was also found. 4. Our results provide support to the ICCH and suggest that males with exaggerated ornaments and high T concentrations may counteract the inhibitory action of testosterone by some compensatory mechanism. Possible candidates include the presence of immunoenhancing substances, such as melatonin or antioxidants, or differential receptor activity. These mechanisms should be evaluated when testing the reliability of the ICCH in wild populations.

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Section: Discussionsupporting

confidence: 93%

Male ornament size in a passerine predicts the inhibitory effect of testosterone on macrophage phagocytosis

Gil¹,

Culver

2011

Functional Ecology

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“…Whereas both testosterone and DHT provoked a significant increase in macrophage IL-6 gene expression without greatly affecting TNF-␣ or TGF-␤1 mRNA levels, fibroblast IL-6 and TGF-␤1 mRNA levels and protein secretion were significantly reduced by treatment with testosterone or DHT and TNF-␣ mRNA expression decreased in response to exposure to DHT. These findings are partially corroborated by previous studies which demonstrated that DHT and testosterone inhibit IL-6 production by oral and gingival fibroblasts and that DHT but not testosterone stimulates secretion of IL-6 by Kupffer cells (Coletta et al, 2002;Gornstein et al, 1999;Parkar et al, 1998;Schneider et al, 2003). The failure of testosterone to enhance macrophage TNF-␣ gene expression contrasts sharply with the situation in mice, in which testosterone has been shown to increase both basal and LPS-induced mRNA levels (Ashcroft and Mills, 2002).…”

Section: Discussionsupporting

confidence: 80%

Androgens modulate the inflammatory response during acute wound healing

Gilliver¹,

Ashworth²,

Mills³

et al. 2006

Journal of Cell Science

128

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Impaired wound healing states in the elderly lead to substantial morbidity and mortality, and a cost to the health services of over $9 billion per annum. In addition to intrinsic ageing processes that per se cause delayed healing, studies have suggested marked differences in wound repair between the sexes. We have previously reported that, castration of male mice results in a striking acceleration of local cutaneous wound healing and dampens the associated inflammatory response. In this study, we report that systemic 5α-reductase inhibition, which blocks the conversion of testosterone to its more active metabolite 5α-dihydrotestosterone, mimics the effects of castration in a rat model of cutaneous wound healing. The mechanisms underlying the observed effects involve a direct, cell-specific upregulation of pro-inflammatory cytokine expression by macrophages, but not fibroblasts, in response to androgens. Androgens require the transforming growth factor β signalling intermediate Smad3 to be present in order to influence repair and local pro-inflammatory cytokine levels. That reducing 5α-dihydrotestosterone levels through 5α-reductase antagonism markedly accelerates healing suggests a specific target for future therapeutic intervention in impaired wound healing states in elderly males.

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“…Other investigators have found divergent cytokine release when myocardia were exposed to estrogen and testosterone (1,2,10,40,49,51). Previously, we found that endogenous testosterone exposure increased myocardial cytokine production and decreased postischemic cardiac function, suggesting that endogenous testosterone exerts a deleterious effect on myocardium via increased myocardial inflamma- tion (45).…”

Section: Discussionmentioning

confidence: 62%

Brief exposure to exogenous testosterone increases death signaling and adversely affects myocardial function after ischemia

Crisostomo

Wang

Wairiuko

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Chronic endogenous testosterone exposure adversely affects proinflammatory and proapoptotic signaling after ischemia/reperfusion; however, it remains unknown whether a single acute testosterone exposure is equally detrimental. We hypothesized that acute exogenous testosterone infusion before ischemia would worsen myocardial functional recovery, increase the activation of MAPKs and caspase-3, and increase myocardial proinflammatory cytokine production. To study this, isolated-perfused rat hearts (Langendorff) from adult females and castrated males were subjected to 25-min ischemia and 40-min reperfusion with and without acute testosterone infusion (17beta-hydroxy-4-androstenone, 10 ng x ml(-1) x min(-1)) before ischemia. Myocardial contractile function was continuously recorded. After ischemia/reperfusion, hearts were assessed for levels of testosterone (ELISA), expression of proinflammatory cytokines (ELISA), and activation of MAPKs and caspase-3 (Western blot analysis). Data were analyzed with two-way ANOVA or Student's t-test; P < 0.05 was statistically significant. All indices of postischemic functional recovery were decreased with acute exogenous testosterone compared with the untreated groups. Acute testosterone infusion increased activation of MAPKs and caspase-3 following ischemia/reperfusion. However, there were no significant differences in the myocardial proinflammatory cytokine production after brief testosterone infusion. A single acute exposure to exogenous testosterone before ischemia worsens myocardial functional recovery and increases activation of MAPKs and caspase-3. These findings confirm the deleterious effects of testosterone on myocardium, elucidate the nongenomic mechanistic pathways of testosterone, and may have important clinical implications for patients who have acute exposure to exogenous testosterone.

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Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone

Cited by 35 publications

References 53 publications

Male ornament size in a passerine predicts the inhibitory effect of testosterone on macrophage phagocytosis

Male ornament size in a passerine predicts the inhibitory effect of testosterone on macrophage phagocytosis

Androgens modulate the inflammatory response during acute wound healing

Brief exposure to exogenous testosterone increases death signaling and adversely affects myocardial function after ischemia

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