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Instituto de Inmunología, Facultad de Ciencias Médicas, Santa Fé 3100, Universidad Nacional de Rosario, 2000 Rosario, Argentina
1 Ilex-Conicet, Instituto de Investigaciones Hematológicas, Pacheco de Melo 308, Academia Nacional de Medicina, 1425 Buenos Aires, Argentina
2 Department of Immunophysiology, Institute of Physiology, Medical Faculty, Deutschhausstrasse 2, Philipps University, 35037 Marburg, Germany
(Requests for offprints should be addressed to A del Rey; Email: delrey{at}mailer.uni-marburg.de)
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Abstract |
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blood levels were increased in infected mice of both strains treated with RU486. Furthermore, the blockade of glucocorticoid receptors accelerated death in C57Bl/6J mice and increased lethality to 100% in Balb/c mice. The results obtained represent the first evidence that an endocrine host response that is coupled to the immune process can strongly affect the course of a parasite infection. |
Introduction |
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Due to their different sensitivities, infected Balb/c and C57Bl/6 mice are useful models to study differences in the immune response to intracellular pathogens (Wrightsman et al. 1982, Andrade et al. 1985, Appelberg et al. 1994, Heinzel et al. 1998). We have previously shown that inoculation of T. cruzi into C57Bl/6 mice leads to a progressive and lethal disease with profound thymic atrophy and loss of CD4+CD8+thymocytes, while more than 50% of the Balb/c mice recover (Roggero et al. 2002). Increased morbidity of C57Bl/6 mice does not seem to result from an aggravated infection since parasitemia, myocardial parasite nests and amastigote counts in peritoneal macrophages were comparable in both strains. The main differences between infected C57Bl/6J and Balb/c mice were observed in cytokine levels. Although blood levels of tumor necrosis factor- (TNF-), interferon-
(IFN-), interleukin (IL)-1ß (IL-1ß), and IL-10 increased in both strains of mice, C57Bl/6 mice display higher TNF-, lower IL-10, and IL-1ß levels than Balb/c mice. Interestingly, peritoneal macrophages from C57Bl/6J mice also produce more TNF- than those from Balb/c mice when exposed to the parasite in vitro. These results suggest that the fatal outcome in C57Bl/6 mice may be linked to an unbalanced relation between cytokines, a proposal that agrees with the report that the cachexia associated with T. cruzi infection in mice is attenuated by antibodies to TNF- (Truyens et al. 1995).
In the past two decades, there have been several studies on the immunopathogenesis of T. cruzi infection, but there are few reports available on the role that neuroendocrine mechanisms may play in the development of the disease (Savino et al. 1989, Leite de Moraes et al. 1991). We have chosen to study, in particular, the significance of endogenous glucocorticoids levels for the course of T. cruzi infection, because the cytokine pattern and the thymic alterations described supported the hypothesis that the hypothalamus–pituitary–adrenal (HPA) axis might be activated in the model of Chagas’disease used in our studies. TNF-, IL-1ß, IL-6, and IFN-, which can stimulate the HPA axis (for review, see Besedovsky & del Rey, 1996, Turnbull & Rivier, 1999), are among the cytokines released during T. cruzi infection (Gao & Pereira, 2002, Roggero et al. 2002). Although cytokines produced during infectious diseases can be initially protective, they can also cause tissue injury and metabolic derangements when produced in excess. These deleterious effects can be expressed when endogenous levels of glucocorticoids are not enough to control the production of pro-inflammatory cytokines (Sapolsky et al. 2000). In particular, an insufficient control of TNF- production is expected to mediate harmful effects since, as mentioned above, it has been shown that this cytokine is the main mediator of the lethal course of experimental T. cruzi infection (Truyens et al. 1995). Thus, to gain some insight into the possible activation of the HPA axis accompanying this protozoan infection, plasma corticosterone levels were measured at different times during the acute infection in Balb/c and C57Bl mice. The effect of endogenous glucocorticoids on the susceptibility and clinical course of the disease was evaluated by blockade of glucocorticoid receptors. Furthermore, since this hormone affects thymic cell turnover and negative selection (Jondal et al. 1993), the number of CD4+CD8+thymocytes was determined in infected C57Bl/6J, Balb/c mice, and in mice of both strains treated with the glucocorticoid receptor antagonist RU486. TNF- levels in plasma were also evaluated in these animals. The results obtained show that the HPA axis is stimulated during T. cruzi infection, although earlier in the less susceptible Balb/c strain, and that the blockade of this endocrine response prevents thymus involution, but aggravates the disease.
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Materials and Methods |
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The Tulahuén strain of T. cruzi used in this study was maintained by serial passages in Balb/c suckling mice. Male Balb/c and C57Bl/6 mice were bred in the animal facilities of the Medical Faculty of Rosario. Experimental procedures were approved by the local ethical committee. One hundred trypomastigotes suspended in 100 µl physiological saline were injected s.c. (50 µl in each flank), when mice were 8–10 weeks old. Bloodstream forms of T. cruzi were counted under standardized conditions by direct microscopic observation of 5 µl heparinized blood obtained from the tip of the tail. Data are expressed as number of parasites/50 fields.
Corticosterone determinations
Mice were housed individually for 1 week before the experiments were started and kept single-caged throughout the experiments in temperature-, humidity-, and light (12 h light: 12 h darkness cycles)-controlled rooms. Plasma samples for hormone determinations were obtained from the tip of the tail under light ether narcosis between 0800 and 1000 h at 3, 5, 7, 14, and 18 days postinjection (p.i.). Blood samples were also obtained from age- and sex-matched controls subjected to the same experimental conditions. Plasma corticosterone levels were determined by RIA as previously described (Besedovsky et al. 1991).
Blockade of glucocorticoid receptors
Mifepristone (RU486; Sigma) dissolved in sesame oil (Sigma) was inoculated i.p. at a daily dose of 1 mg in 0.1 ml vehicle, starting 2 or 10 days after infection and until the end of the experiments. Control mice received 0.1 ml sesame oil under the same schedule.
Adrenalectomy
Mice were anesthetized with 100 mg/kg ketamine and 2 mg/kg xylazine and bilateral adrenalectomy was performed via a dorsal approach. Two small incisions were made on each side of the back just below the rib cage and the adrenal glands were removed with curved forceps. Sham mice were operated in a similar manner, but without removing the adrenals. The animals were used 1 week after the operation for further experimentation.
Heart histology
Hearts were removed on day 18 p.i., sliced transversally in three sections, and fixed in buffered formalin. Paraffin-embedded 5 µm sections were stained with hematoxylin and eosin. Tissue parasitism was evaluated by counting the number of parasite nests that were visualized in three sections. The three sections were examined by an experienced pathologist blinded to the study groups.
Thymus weight
Thymi were removed at 18 days p.i. and weighed. The relative thymus weight was calculated as thymus weight/body weight x 100.
Flow cytometry analysis
Thymocytes (106) resuspended in buffer (RPMI-1640 without phenol red supplemented with 3% fetal bovine serum, 0.1% sodium azide, and 10 mM N-2-hydroxyethyl-piperazine-N'-2-ethane sulfonic acid sodium salt (HEPES)) were stained with cychrome-coupled anti-CD4 and phycoerythrin-coupled anti-CD8a monoclonal antibodies (PharMingen, San Diego, CA, USA). A minimum of 105 events was acquired using a FACScan flow cytometer (Becton Dickinson, New Jersey, USA). Living cells were gated on the basis of forward- and side-cell scatter. Results were analyzed using Cell Quest software (Becton Dickinson).
Determination of TNF- levels in plasma
Mice were bled by cardiac puncture at 18 days p.i. Blood was collected in sterile, endotoxin-free tubes and kept refrigerated until centrifugation. The serum was stored frozen at –20 °C until used. TNF- and IL-6 concentrations were evaluated by ELISA, using commercially available kits (R&D; detection limits 5.1 pg/ml for TNF- and 15.6 pg/ml for IL-6). All the samples were assayed in duplicate.
Statistical analysis
Results are expressed as means ± S.E.M. Datawere analyzed using one-way ANOVA followed by Fisher’s test for multiple comparisons or by nonparametric tests (Mann–Whitney U-test for two samples and Kruskall–Wallis test for k samples).
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Results |
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We first analyzed blood glucocorticoid levels during the course of acute infection in C57Bl/6 and Balb/c mice. Basal corticosterone levels in blood of control C57Bl/6 mice (0.37 ± 0.03 µg/dl, n = 25) were significantly lower (P < 0.0002) than those of the Balb/c counterparts (0.76 ± 0.11 µg/dl, n = 18). No major changes were detected in glucocorticoid blood levels in C57Bl/6J mice during the first week following inoculation with 100 T. cruzi trypomastigotes, whereas Balb/c mice showed a progressive increase in the levels of this hormone on days 3, 5, and 7 following injection of the parasite (Fig. 1
). Two weeks after infection, increased levels of corticosterone were detected in both mouse strains. The analysis of the increase in glucocorticoid blood levels relative to the mean levels of control mice also showed that, during the early phase of infection, the HPA-axis of Balb/c mice was, in contrast to C57Bl/6 mice, already stimulated. For example, on day 5 after T. cruzi injection, there was no significant increase in corticosterone blood levels in C57Bl/6J mice relative to the untreated controls, whereas the levels were about twofold increased in infected Balb/c mice. However, 18 days after injection, the relative increase in glucocorticoid levels was twofold higher in C57Bl/6 compared to Balb/c mice.
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The finding described above prompted us to analyze whether the blockade of glucocorticoid receptors affects corticosterone levels and the changes in the thymus observed during T. cruzi infection. For this purpose, Balb/c and C57Bl/6 mice infected with 100 T. cruzi trypomastigotes received the steroid receptor antagonist RU486 once daily from day 10 p.i. till the end of the experiment. The control mice received the vehicle alone at the same intervals. As can be seen in Table 1, the blockade of glucocorticoids receptors in infected mice resulted in a more pronounced elevation of corticosterone levels on day 18 p.i. when compared to infected mice injected with the vehicle. Plasma corticosterone concentrations in the control mice receiving RU486 did not differ from vehicle-only injected controls.
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). Injection of RU486 alone induced a comparable decrease in the weight of this organ in both strains (21–24%). However, when the antagonist was administered to infected animals, the weight of the thymus was significantly recovered in both C57Bl/6 and Balb/c mice. Comparable results were obtained when the weight of the organ was calculated relative to the body weight.
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). However, the blockade of glucocorticoid receptors by RU486 administration resulted in a significant recovery of the relative proportion of DP thymic cells in infected mice of both strains.
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The blockade of glucocorticoid receptors by daily administration of RU486, starting 10 days after infection with T. cruzi, did not significantly affect parasitemia and the number of inflammatory foci in the heart and only a tendency towards a decrease in the number of amastigote nests was observed in both strains of mice (Table 4).
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As mentioned, infection of C57Bl/6 mice with T. cruzi is lethal. Under our conditions, C57Bl/6 mice that received only 100 parasites had a mean survival time of 21.8 ± 0.5 days. Daily treatment with the blocker RU486, starting on day 10 after inoculation, decreased the mean survival time to 16.8 ± 0.3 days. The cumulative percentage of survival time is shown in Fig. 2. The Balb/c strain is more resistant to infection, since more than half of the animals that received the same number of parasites as the C57Bl/6 mice survive (Roggero et al. 2002). In the present study, only 40% of the infected Balb/c mice died within 23.7 ± 0.4 days of infection. Treatment with the blocker RU486 not only significantly shortened the survival time, but also resulted in death of all the infected Balb/c mice (Fig. 2).
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). In C57Bl/6 mice, there was no difference between the RU2 and RU10 groups. In contrast, Balb/c mice treated with the blocker from day 2 died earlier than those in which the blockade was delayed until day 10 p.i. Furthermore, when the infected Balb/c mice were treated with RU486 from day 2, the difference between the survival time of infected Balb/c and C57Bl/6 mice observed, when the treatment started on day 10, disappeared. These results strongly indicate that the early increase in corticosterone blood levels induced by T. cruzi inoculation into Balb/c hosts contributes to protect these animals.
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Blockade of glucocorticoid receptors results in increased TNF- levels in blood of infected mice
It is known that TNF- levels are increased during the immune response to T. cruzi (Revelli et al. 1999, Truyens et al. 1999, Holscher et al. 2000, Roggero et al. 2002) and it is likely that this cytokine is also involved in the immunopathological processes during the disease (Truyens et al. 1995, Holscher et al. 2000). On the other hand, TNF- and IL-6 can also activate the HPA-axis (Bernardini et al. 1990, Besedovsky et al. 1991). Since glucocorticoids are known to block the production of several cytokines (for review, see Besedovsky & del Rey, 1996), it was important to evaluate the concentration of these cytokines in the blood of infected mice that received RU486. Results depicted in Fig. 3 show that the blockade of glucocorticoid receptors resulted in a significant increase in TNF- and IL-6 concentrations in the blood of C57Bl/6 and Balb/c mice, although the increase was less pronounced in Balb/c mice. However, it has to be emphasized that all mice were sacrificed 18 days after injection of the parasites, at a stage of a disease that was closer to death in RU486-treated C57Bl/6 mice than in Balb/c mice subjected to the same treatment (see Fig. 2
).
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Discussion |
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We and others (Leite de Moraes et al. 1991, Roggero et al. 2002, Mantuano-Barradas et al. 2003) have shown that during the acute phase of T. cruzi infection, there is a marked thymus atrophy, mainly characterized by the loss of CD4+CD8+ cells. The results reported here show that endogenous glucocorticoids play an important role in mediating this effect, since blockade of the receptors for these hormones significantly reverted the reduction of DP cells observed in the infected mice. It has been shown that RU486 exerts a weak agonist effect upon binding to glucocorticoid receptors, since a limited fraction of the receptor–antagonist complex can be translocated to the nucleus and mediate the biological effects of glucocorticoids (Gruol & Altschmied, 1993, Nordeen et al. 1993). This partial agonist effect would explain our observation of a reduced thymus weight in uninfected mice treated with RU486. The blockade of GC receptors in infected mice, which have elevated levels of corticosterone, results in a further increase in the levels of this hormone. One possibility is that prolonged treatment with RU486 interferes with the glucocorticoid feedback when the HPA axis is being stimulated by T. cruzi infection. This effect might not be observed under basal conditions. However, further studies are necessary to clarify this issue.
It has been reported that both TNF- and glucocorticoids are involved in LPS-induced thymocyte apoptosis (Kato et al. 1995). Our results would agree with this study since glucocorticoid blockade did not completely revert the reduction in thymus weight induced by the infection and, at the same time, increased TNF- levels. Thus, the absence of glucocorticoid effects seems to be compensated by increased TNF- levels, which have been shown to induce apoptosis in the thymus (Hernandez-Caselles & Stutman, 1993). Our results are at variance with studies in adrenalectomized mice, in which glucocorticoids appeared not to be involved in thymus atrophy during acute T. cruzi infection (Leite de Moraes et al. 1991). Variations in the experimental conditions and study design, such as differences in parasite load and the use of a different T. cruzi strain, may account for this difference. Moreover, it should be emphasized that the existence of extra-adrenal corticosteroidogenic systems, which might be activated following adrenalectomy, has been shown (Davies & MacKenzie, 2003). Indeed, in the study by Leite de Moraes et al.(1991), it was reported that corticosterone levels in T. cruzi-infected adrenalectomized animals were higher than those of non-infected counterparts.
There is evidence that the increase in endogenous glucocorticoid levels plays a protective role for the host, for example, during experimentally induced autoimmune encephalomyelitis (MacPhee et al. 1989) and arthritis (Tonelli et al. 2001). In addition, the demonstration that adrenalectomy in mice infected with lymphocyte choriomeningitis virus increases lethality as well as TNF-, IL-6, and IL-1ß production (Ruzek et al. 1999) reinforces the view that glucocorticoids prevent an excessive inflammatory response. In addition, treatment of mice with RU486 enhances the susceptibility to experimental endotoxemia and the inflammatory and toxic effects of TNF- (Laue et al. 1988, Lazar et al. 1992, Fan et al. 1994). The results reported here show for the first time that interference with the increase of endogenous corticosterone levels, in a model of intracellular parasite, not only accelerates death of C57Bl/6 mice, but also results in 100% mortality in the less susceptible strain Balb/c.
The existence of a feedback circuit based on cytokine–HPA axis interactions is now well established (Besedovsky & del Rey, 1996, Turnbull & Rivier, 1999). The data reported here showing that the blockade of glucocorticoid action resulted in a further increase in TNF- production following T. cruzi inoculation show that this circuit also operates during parasite infection. Glucocorticoids inhibit the synthesis of TNF- and other cytokines by interfering with the activation of transcription factors such as nuclear factor-
ß (NF-B) (Neeck et al. 2002). On the other hand, pro-inflammatory cytokines not only induce HPA activation but may also affect glucocorticoid effects by preventing the binding of these hormones to their receptors (Almawi et al. 1991, Kam et al. 1993) or by inducing the synthesis of transcription factors (as NF-B and activator protein-1 (AP-1)) that interfere with glucocorticoid activities (Funder, 1992). Since, as mentioned, the activation of the HPA axis was observed in C57Bl/6 mice during the third week of infection, it might have been ineffective to completely counteract harmful effects of TNF- and other pro-inflammatory cytokines. In contrast, the modest, but early and prolonged, glucocorticoid increase observed in infected Balb/c mice might have contributed to a better control of TNF- production and, as consequence, to the reduced mortality rate of these animals during T. cruzi infection (Roggero et al. 2002). The role of TNF- and probably of other pro-inflammatory cytokines in mediating the lethal course of the disease is supported by our observation that the blockade of endogenous glucocorticoids, when the infection was already established, did not significantly affect several pathophysiological parameters such as parasitemia and the degree of myocardial lesions, as reflected by the number of amastigote nests and inflammatory loci. In contrast, TNF- production was markedly increased following administration of RU486 to T. cruzi-infected mice of both strains, indicating that this cytokine significantly contributes to lethality.
In summary, the results reported here indicate that a cytokine–HPA axis feedback circuit operates during acute infection with T. cruzi parasites. Although the activation of this circuit induced thymus involution and decreased the number of DP thymocytes, it was protective for the host, since interference with the effect of elevated glucocorticoid levels resulted in increased TNF- production, accelerated death of C57Bl/6 mice, and caused 100% lethality in otherwise less susceptible Balb/c mice. Thus, the present results show that not only the immune response but also an endocrine host response determines the course of a parasitic infection.
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Acknowledgements |
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Received in final form 29 April 2006
Accepted 2 May 2006
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