Journal of Applied Physiology AJP: Heart and Circulatory Physiology
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J Appl Physiol 101: 448-453, 2006. First published April 13, 2006; doi:10.1152/japplphysiol.00166.2006
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Castration prevents suppression of MHC class II (Ia) expression on macrophages after trauma-hemorrhage

S. Mayr,1 C. R. Walz,1 P. Angele,2 T. Hernandez-Richter,1 I. H. Chaudry,3 F. Loehe,1 K. W. Jauch,1 and M. K. Angele1

1Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians University, Munich; 2Department of Trauma Surgery, University of Regensburg, Regensburg, Germany; and 3Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 8 February 2006 ; accepted in final form 16 March 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Several studies indicate that cell-mediated immune responses, i.e., macrophage (M{Phi}) cytokine release capacities, myosin heavy chain (MHC) class II (Ia) expression, etc., are suppressed after trauma-hemorrhage in male mice. Testosterone has been shown to be responsible for the depression of M{Phi} cytokine responses in males after trauma-hemorrhage. Antigen presentation via MHC class II plays a key role in initiating and maintaining cell-mediated and humoral immune responses. It remains unknown, however, whether testosterone has any effect on MHC class II after trauma-hemorrhage. To study this, male C3H/HeN mice were castrated or sham castrated 2 wk before trauma (midline laparotomy) and hemorrhage (Hem; blood pressure 35 ± 5 mmHg for 90 min and resuscitation) or sham operation. Four hours thereafter, MHC class II (Ia) expression was measured using flow cytometry. The results indicate that MHC class II (Ia) expression on peritoneal and splenic M{Phi} was significantly suppressed in male mice after trauma-hemorrhage. Prior castration, however, prevented the depression in MHC class II (Ia) expression on peritoneal and splenic M{Phi} after trauma-hemorrhage. Castration did not affect MHC class II (Ia) expression in M{Phi} from sham-castrated mice. Thus testosterone depresses MHC class II (Ia) expression on peritoneal and splenic M{Phi} after trauma-hemorrhage in males. Because MHC class II is necessary for an adequate immune response, our results suggest that depletion of male sex steroids or blockade of androgen receptors using agents such as flutamide might prevent immunosuppression via maintaining MHC class II (Ia) expression after trauma and severe blood loss.

antigen presentation; immunosuppression

HEMORRHAGIC SHOCK induces a severe depression of cell-mediated immune response that is associated with an increased susceptibility to sepsis (9, 10, 41). In this respect, the capacity of splenic and peritoneal macrophages (M{Phi}) to release proinflammatory cytokines in response to LPS in vitro has been found to be depressed after trauma-hemorrhage in male mice (6, 7). Furthermore, altered antigen presentation has been shown after trauma-hemorrhage in males (10). Presentation of foreign antigens by antigen-presenting cells, however, is essential for initiating and maintaining cell-mediated immune responses (21, 35). In particular, T-cell activation requires antigen presentation via myosin heavy chain (MHC) class II (13, 15). Similarly, in clinical studies, diminished capacities of peripheral blood mononuclear cells to present antigen as measured by MHC class II expression after major abdominal surgery resulted in higher infection (36) and mortality rates (27). Moreover, sex dimorphism in the immune and organ response, and the susceptibility to and morbidity from trauma and hemorrhagic shock, have been demonstrated. Sex hormones have been shown to contribute to this sex-dimorphic immune response after adverse circulatory conditions (1, 2). Specifically, studies indicate that androgens are responsible for the immunodepression after trauma-hemorrhage in males (1, 2, 28). Castration of male mice 2 wk before trauma-hemorrhage resulted in maintained LPS-induced cytokine responsiveness of splenic and peritoneal M{Phi} (6, 7). Similarly, testosterone depletion restored the depressed Th1 cytokine release, i.e., IL-2, interferon (IFN)-{gamma}, by T cells after trauma-hemorrhage (6).

Because antigen presentation is crucial for T-cell activation, maintained antigen presentation in castrated mice might contribute to improved T-cell responses in those animals. The aim of our study therefore was to determine if depletion of androgens by castration before hemorrhage has any salutary effects on the expression of major histocompatibility complex II on peritoneal and splenic M{Phi} after trauma-hemorrhage.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Animals.   Inbred C3H/HeN male mice (Charles River, Sulzfeld, Germany), between 5 and 7 wk of age were used in this study. All procedures were carried out in accordance with the guidelines set forth in the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health. The Institutional Animal Care and Use Committee of the Regierung von Oberbayern and the Ludwig-Maximilians University, Munich, Germany, approved this project.

Experimental groups.   Male mice were randomized into four groups (n = 6–8 per group): group I, noncastrated, sham operated (no trauma, no hemorrhage); group II, castrated, sham operated (no trauma, no hemorrhage); group III, noncastrated, trauma-hemorrhage; group IV, castrated, trauma-hemorrhage.

Castration procedure.   Mice were castrated 2 wk before the experiment as previously described (7). In brief, mice were anesthetized with isoflurane (Forene, Abbott, Wiesbaden, Germany), restrained in a supine position, and the skin of the scrotum was disinfected using 75% ethanol. The funiculus spermaticus was ligated, and the testes were removed. The scrotum incision was closed using 5–0 Ethilon sutures (Ethicon, Hamburg, Germany). Mice in groups I and III (noncastrated mice) underwent the same scrotum dissection; however, the testes were not removed.

Trauma-hemorrhage procedure.   Mice were lightly anesthetized with a mixture of Isoflurane (Forene), N2O, and O2, restrained in a supine position, and the skin was disinfected using 75% ethanol. A 2.5-cm midline laparotomy (i.e., trauma induced) was performed, and the muscular layer was then closed aseptically using 6–0 Ethilon sutures (Ethicon). The skin incision was closed using 5–0 Ethilon sutures (Ethicon). After midline laparotomy, both femoral arteries were aseptically cannulated with polyethylene-10 tubing (Clay-Adams, Parsippany, NJ) with the use of a minimal dissection technique. The animals were then allowed to awaken. Blood pressure was constantly monitored by attaching one of the catheters to a blood pressure analyzer (Digi-Med, Louisville, KY). On awakening, the animals were bled rapidly through the other catheter to a mean arterial blood pressure (BP) of 35 ± 5 mmHg (BP prehemorrhage was 95 ± 5 mmHg), which was maintained for 90 min. At the end of that period, four times the shed blood volume (the average shed blood volume was 0.95 ml, representing 60% of the circulating blood volume) was infused in the form of lactated Ringer solution (B. Braun Melsungen, Melsungen, Germany) to provide fluid resuscitation. Lidocaine (AstraZeneca, Wedel, Germany) was applied to the groin incision sites, the catheters were removed, the vessels were ligated, and the groin incisions were closed. No mortality was observed in this model of trauma-hemorrhage and resuscitation. The trauma-hemorrhage procedure was carried out at the same time of the day to avoid fluctuations of plasma hormone levels due to circadian rhythm.

Sham operation.   Sham-operated animals underwent the same groin dissection, which included ligation of both femoral arteries; however, neither trauma-hemorrhage norfluid resuscitation were carried out.

Cell harvesting procedure.   The animals were killed by methoxyflurane overdose 4 h after trauma-hemorrhage and resuscitation or sham operation to obtain the spleen and peritoneal M{Phi}.

Preparation of splenic M{Phi}.   The spleens were removed aseptically and placed in separate petri dishes containing cold (4°C) PBS (Merck, Darmstadt, Germany). The spleens were dissociated by grinding. The splenocyte suspension was used to establish a macrophage culture as previously described (23). The M{Phi} monolayers were incubated for 2 h (at 37°C, 5% CO2, and 90% humidity) in 2 ml Click's medium (Sigma-Aldrich, Taufkirchen, Germany) containing 10% FCS (GIBCO). At the end of 2 h of incubation, culture supernatants were removed and nonadherent cells were washed off. Adherent cells were harvested by scraping and, after this, were analyzed by flow cytometry.

Preparation of peritoneal M{Phi}.   Resident peritoneal macrophages were obtained from mice by lavaging the peritoneal cavities twice with 5 ml ice-cold PBS (Merck) and M{Phi} monolayers were established as previously described (12, 43). The M{Phi} monolayers were incubated for 2 h (at 37°C, 5% CO2, and 90% humidity) in 2 ml Click's medium (Sigma-Aldrich) containing 10% FCS (GIBCO). After 2 h of adherence, the supernatants were removed and nonadherent cells were washed off. Adherent M{Phi} were scraped and analyzed by flow cytometry.

Although purity of prepared splenic and peritoneal M{Phi} has not been determined in the present study, Ayala et al. (11) reported 90% positively stained cells for F4/80 (M{Phi} marker) after the same isolation procedure, suggesting a high purity of the macrophages (11).

Expression of MHC class II (Ia) (and CD11b as a M{Phi} marker).   Expression of CD11b, i.e., Mac-1, a M{Phi} marker, was assayed by direct immunfluorescence using rat anti-mouse FITC-conjugated monoclonal IgG (Pharmingen, Hamburg, Germany). MHC class II (Ia) expression was detected by R-phycoerythrin (R-PE)-conjugated mouse anti-mouse I-Ak (A{alpha}k) monoclonal IgG (Pharmingen). Before staining, unspecific binding was blocked by using purified rat anti-mouse CD16/CD32 (Fc{gamma} III/II receptor) monoclonal antibody (Fc block) (Pharmingen). Furthermore, IgG isotype-matched control antibodies were used to exclude unspecific binding (Pharmingen). The cells were incubated with saturating amounts of monoclonal antibody for 30 min at 4°C in darkness. After incubation, cells were washed twice with FACS buffer (PBS; Merck) containing 1% BSA (Sigma-Aldrich) and 0.1% Na-azide (Sigma-Aldrich), and then they were fixed by 1% paraformaldehyde (Sigma-Aldrich).

Analysis of at least 10,000 events was performed on a FACSort flow cytometer (Becton Dickinson, Heidelberg, Germany). M{Phi} were selectively analyzed for their fluorescence properties using a CellQuest data handling program (Becton Dickinson). The relative fluorescence intensity of a given sample was calculated by subtracting the signal obtained when cells were incubated with the corresponding isotype control from the signal generated by cells incubated with the test antibody (one time for all 4 groups).

Statistical analysis.   The results are presented as means ± SE. One-way ANOVA followed by the Student-Newman-Keuls test or Tukey's test as a post hoc test for multiple comparisons was used to determine the significance of the differences between experimental means. A P value of <0.05 was considered to be significant.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
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 ACKNOWLEDGMENTS
 REFERENCES
 
CD11b (Mac-1): expression on splenic and peritoneal M{Phi}.   In an attempt to verify the percentage of M{Phi} harvested with the immune cells, CD11b (Mac-1), a macrophage marker, was determined. The results indicate that the expression of CD11b on splenic (Fig. 1A) and peritoneal M{Phi} (Fig. 1B) was similar in castrated and sham-castrated mice. Moreover, the expression of CD11b was not affected by the trauma-hemorrhage procedure.


Figure 1
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  		Fig. 1. CD 11b expression on splenic (A) and peritoneal macrophages (M{Phi}; B) harvested 4 h after trauma-hemorrhage (groups III and IV) or sham operation (not traumatized and not shocked; groups I and II) from male C3H/HeN mice that were either castrated (groups II and IV) or sham castrated (groups I and III) 2 wk before the experiment. CD11b expression was analyzed by flow cytometry. Values are presented as means ± SE; n = 6 or 7/group. pos, Positive.

 
MHC class II (Ia): expression on splenic M{Phi}.   Trauma-hemorrhage resulted in a significant suppression of MHC class II (Ia) expression on splenic M{Phi} in sham-castrated animals (group III) compared with sham-castrated mice that were not subjected to trauma-hemorrhage (–19.9% group III vs. group I, P < 0.05; Fig. 2). Castration significantly increased the expression of MHC class II (Ia) expression on splenic M{Phi}after trauma-hemorrhage compared with sham-castrated trauma-hemorrhaged mice (30% group IV vs. group III, P < 0.05). Castration, however, did not affect MHC class II (Ia) expression on splenic M{Phi} harvested from sham-operated (groups I and II; not traumatized and not shocked) mice (Fig. 2). The representative histograms are shown in Fig. 3, A and B.


Figure 2
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  		Fig. 2. Myosin heavy chain (MHC) class II (Ia) expression on splenic M{Phi} harvested 4 h after trauma-hemorrhage (groups III and IV) or sham operation (not traumatized and not shocked; groups I and II) from male C3H/HeN mice that were either castrated (groups II and IV) or sham castrated (groups I and III) 2 wk before the experiment. MHC class II (Ia) expression was analyzed by flow cytometry. Values are presented as means ± SE; n = 6 or 7/group. Data were analyzed by ANOVA. *P < 0.05 vs. group I; #P < 0.05 vs. group III.

 

Figure 3
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  		Fig. 3. Representative histograms of MHC class II (Ia) expression on splenic M{Phi} harvested 4 h after trauma-hemorrhage (groups III and IV; shaded line) or sham operation (not traumatized and not shocked; groups I and II; solid line), sham castrated [groups I and III (A) and castrated (groups II and IV; B)]. Macrophages were analyzed by flow cytometry. FL2, fluorescence 2.

 
MHC class II (Ia): expression on peritoneal M{Phi}.   Similarly, the expression of MHC class II (Ia) expression on peritoneal M{Phi} significantly decreased in sham-castrated mice compared with sham-castrated mice that were not subjected to trauma-hemorrhage (–38.7% group III vs. group I, P < 0.05; Fig. 4). Castration 2 wk before trauma-hemorrhage restored the depressed MHC class II (Ia) expression on peritoneal M{Phi} after trauma-hemorrhage compared with sham-castrated trauma-hemorrhaged mice (89.5% group IV vs. group III, P < 0.05). Interestingly, castration did not affect MHC class II (Ia) expression on peritoneal M{Phi} from sham-operated (groups I and II; not traumatized and not shocked) mice (Fig. 4). The representative histograms are shown in Fig. 5, A and B.


Figure 4
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  		Fig. 4. MHC class II (Ia) expression on peritoneal M{Phi} harvested 4 h after trauma-hemorrhage (groups III and IV) or sham operation (not traumatized and not shocked; groups I and II) from male C3H/HeN mice that were either castrated (groups II and IV) or sham castrated (groups I and III) 2 wk before the experiment. MHC class II (Ia) expression was analyzed by flow cytometry. Values are presented as mean ± SE, n = 6 or 7/group. Data were analyzed by ANOVA. *P < 0.05 vs. group I; #P < 0.05 vs. group III.

 

Figure 5
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  		Fig. 5. Representative histograms of MHC class II (Ia) expression on peritoneal macrophages harvested 4 h after trauma-hemorrhage (groups III and IV; shaded line) or sham operation (not traumatized and not shocked; groups I and II; solid line). A: sham castrated (groups I and III). B: castrated (groups II and IV). Macrophages were analyzed by flow cytometry.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Several clinical and experimental studies have demonstrated depressed cell-mediated immune responses after trauma and blood loss (4, 18, 19, 42). In particular, a defective capacity of M{Phi} to present foreign antigens after trauma and blood loss (10, 18, 36) results in compromised initiation of an adoptive immune response. In this respect, compromised antigen presentation has been associated with depressed T-cell function (21, 35). Moreover, the depression of antigen presentation results in an increased infection rate and poor outcome after major surgery (18, 24, 36). On the basis of those findings, the crucial role of MHC class II in initiating an adequate immune response has been extrapolated, although this has not been investigated in the current study.

Recently, an important role of sex in mediating immune responses after trauma-hemorrhage has been established (3, 16, 40). Male mice exhibit suppressed immune responses, whereas female mice in the proestrus state do not show such a depression (40). Thus male sex hormones have been shown to be responsible for producing this immunosuppression in males (6, 7). Interestingly, androgen receptor blockade by flutamide after trauma-hemorrhage resulted in a decreased susceptibility to subsequent polymicrobial sepsis (9).

Although it could be speculated that depletion of testosterone will prevent depression of antigen presentation and thereby maintain bacterial defense mechanisms, this aspect has not yet been examined. To study this, male mice were castrated 2 wk before trauma-hemorrhage or sham operation. In several previous studies, castration of male mice 2 wk before the experiment has been shown to significantly lower plasma testosterone levels by ~95% (2, 6, 26, 39). This reduction in testosterone plasma levels after castration was comparable in all studies (2, 6, 26, 39). In view of this previous work, testosterone levels in the plasma were not determined in the present study to avoid redundancy.

The results of the present study indicate depressed MHC class II (Ia) expression by splenic and peritoneal M{Phi} harvested from intact male mice after trauma-hemorrhage. This is in agreement with previous findings demonstrating decreased MHC class II (Ia) expression in M{Phi} harvested from various compartments after trauma-hemorrhage in untreated male mice (10). Sham-castrated, sham-trauma-hemorrhaged mice (group I), which do not represent completely untreated animals, served as controls in the present manuscript. Nonetheless, MHC class II (Ia) expression on sham-castrated sham-trauma-hemorrhaged animals (group I) were similar to values reported previously in completely untreated C3H/HeN mice (11, 17). Thus the sham-castration procedure 2 wk before the experiment did not affect MHC class II (Ia) expression. The results further suggest that the decrease in MHC class II expression after trauma-hemorrhage in peritoneal M{Phi} might be due to redistribution among two different cell populations, i.e., dendritic cells and M{Phi}. In contrast, in splenic M{Phi} a leftward shift in fluorescence intensity is evident. This discrepancy appears to be due the different compartments from which the cells were harvested, i.e., peritoneum vs. spleen.

The present study extended that observation and also indicated that castration of animals before trauma-hemorrhage prevented the depression of MHC class II (Ia) expression by splenic and peritoneal M{Phi}. Previous findings suggest that depletion of 5{alpha}-dihydrotestosterone in castrated males is responsible for the improved immune responses after trauma-hemorrhage in those animals (2). In this respect, treatment of castrated males with 5{alpha}-dihydrotestosterone resulted in suppressed splenic and peritoneal M{Phi} cytokine responses after trauma-hemorrhage comparable to noncastrated male mice (7, 8). Thus one would speculate that the testosterone derivate 5{alpha}-dihydrotestosterone also plays a pivotal role for suppressing MHC II (Ia) expression. This hypothesis, however, needs to be verified in additional studies using castrated male mice treated with physiological amounts of 5{alpha}-dihydrotestosterone. Alternatively, the use of a specific testosterone receptor blocker, i.e., flutamide, in normal male mice would further clarify the role of testosterone in suppressing MHC class II expression after trauma and blood loss. Additional support for our results comes from the studies of Weinstein et al. (37), which showed that in vitro primed M{Phi} harvested from female mice are more efficient than male cells in initiating a secondary response in lymphocytes. Their study also showed that castration of male mice enhanced, whereas administration of 5{alpha}-dihydrotestosterone in female mice reduced, the efficiency of antigen presentation by primed M{Phi} (37).

The percentage of CD11b-positive cells, a marker of macrophage activation, was unaffected by trauma-hemorrhage or castration between the study groups. The results further indicate, however, a disparity in the percentage of CD11b-positive cells between splenic and peritoneal M{Phi}, demonstrating a compartment-dependent variation between the spleen and the peritoneum. These findings are in accordance with previous studies (34). Moreover, the activation status of harvested M{Phi} was similar in all study groups as indicated by a comparable CD11b expression (34). T cells might depress M{Phi} functions in the spleen, resulting in lower CD11b levels after trauma-hemorrhage. In addition, the number or viability of M{Phi} obtained from the peritoneum or the spleen has been shown to be similar in hemorrhaged and sham-operated mice in previous studies (10). These findings suggest that the decreased percentage of MHC II (Ia) expression in hemorrhaged mice is not due to variations in cell distribution or loss of viability. Because dendritic cells capable of expressing MHC class II also stick to culture plates, dendritic cells might be included in the analyzed cell suspension. This is a limitation of the present study, and therefore further studies are required to investigate the effect of trauma-hemorrhage and castration on separated antigen-presenting cells.

Interestingly, castration of male mice did not alter MHC II (Ia) expression in sham-castrated mice. However, depletion of testosterone by castration restored the depressed cytokine release capacity of splenic and peritoneal M{Phi} after trauma-hemorrhage, whereas cell-mediated immune responses in sham-castrated mice were not affected (7, 39). These findings suggest that physiological levels of testosterone are only harmful in an immunologically compromised host but not in normal animals. Differences in the kinetics of testosterone might explain the immunosuppressive effects of physiological testosterone plasma levels in those animals. In this regard, the sex steroid synthesis has been shown to be altered after hemorrhage (31, 32, 44). Those studies demonstrate increased intracellular levels of 5{alpha}-dihydrotestosterone and decreased catabolism of this steroid hormone after trauma-hemorrhage due to alteration in the activity of enzymes involved in the steroid synthesis (31, 44). In particular, 5{alpha}-reductase activity was increased, whereas 17beta-hydroxysteroid dehydrogenase activity decreased, after trauma-hemorrhage in lymphocytes harvested from male mice. In accordance with our findings, other studies have also shown that androgens do not depress M{Phi} cytokine release from normal animals (3, 7, 29).

In the present study, M{Phi} antigen presentation per se was not determined. Nonetheless, the expression of MHC class II (Ia) has been shown to correlate with the capacity of M{Phi} to present antigens (10, 11). In this respect, Ayala et al. (10, 11) demonstrated that the diminished antigen presentation capacity of peritoneal and spleen M{Phi} after trauma-hemorrhage was due to the loss of MHC class II (Ia) expression (10, 11). In addition, T-helper cell activation requires presentation of foreign antigens via MHC class II (13, 15, 33). The decreased expression of MHC class II by antigen-presenting cells leads to severe immunodeficiency (25). In clinical studies, diminished MHC II expression was associated with increased infection and mortality rates (18, 24, 36). Thus one would speculate that diminished MHC class II is associated with defective antigen presentation. Further studies, however, are required to validate this notion.

MHC II (Ia) measurements were restricted to 4 h after trauma-hemorrhage. It should be noted that an early restoration of immune responses in our trauma-hemorrhage model was associated with prolonged protection against subsequent sepsis (4, 9, 22, 38). In this regard, studies indicate that restoration of immune responses 4 h after trauma-hemorrhage due to testosterone depletion is associated with increased survival after the induction of subsequent sepsis on the third postoperative day (9). Thus it appears likely that MHC II (Ia) expression is improved for a prolonged time after trauma-hemorrhage in castrated mice. Additional studies, however, are required to verify this notion.

The exact underlying mechanism for the lack of depression in MHC II (Ia) expression in castrated animals remains unknown. Multiple factors that include decreased metabolic activity, anti-inflammatory cytokines, prostaglandins, and nitric oxide appear to be responsible for producing the depression in M{Phi} antigen presenting capacity (5). A moderate inflammation in testosterone-depleted animals, i.e., release of IL-6 and TNF-{alpha}, as opposed to an excessive inflammatory response in noncastrated males after trauma-hemorrhage has been previously demonstrated (3, 7). This effect of castration might contribute to the maintained MHC II (Ia) expression in castrated mice (3, 7). In this respect, beneficial effects of low levels of circulating TNF-{alpha} on M{Phi} MHC II (Ia) expression have been shown (14). Alternatively, defective T-cell responses, i.e., depressed IL-2 and IFN-{gamma} release, in noncastrated male mice (6) might be the cause for diminished M{Phi} functions. Administration of INF-{gamma} in vitro and in vivo markedly improves the expression of MHC class II antigen after hemorrhage in mice and severely injured patients (10, 20). Although several parameters in castrated mice after trauma-hemorrhage have been determined, the precise mediator that directly affects MHC class II expression has not been identified. Moreover, it remains unknown whether castration exerts its effects on MHC class II expression through genomic or nongenomic mechanisms. In this respect, recent studies indicate that decreased MHC II RNA expression is responsible for suppressed MHC II expression after septic shock (30). Those studies therefore suggest that suppression of MHC class II after shock is due to alterations at the transcriptional level. In summary, the precise mechanism by which MHC class II expression is decreased after trauma-hemorrhage and how depletion of testosterone prevents its decrease was, however, beyond the scope of the present study.

Our results indicate that MHC II (Ia) expression on splenic and peritoneal M{Phi} was impaired after trauma-hemorrhage in intact male mice. Castration of male mice 2 wk before trauma-hemorrhage prevented the depression in MHC II (Ia) expression. Although the effect of an androgen receptor blocker on MHC II (Ia) expression has not been evaluated, previous findings suggest that short-term treatment with flutamide after trauma-hemorrhage might also beneficially influence MHC II (Ia) expression (9, 38). Thus attempts to improve MHC II (Ia) expression after trauma-hemorrhage by treatment with androgen receptor blockers might represent useful adjunct for maintaining innate and adoptive immunity and for decreasing the incidence of infections in surgical patients.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This investigation was supported by Deutsche Forschungsgesellschaft Grant DFG AN 357/1–1.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
Presented at the 25th Annual Conference on Shock, Phoenix, Arizona, June 8–11, 2003.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. K. Angele, Dept. of Surgery, Klinikum Grosshadern, Ludwig-Maximilians Univ., Marchioninistr. 15, 81377 Munich, Germany (e-mail: martin.angele{at}med.uni-muenchen.de)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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