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The Journal of Immunology, 2008, 180, 6168 -6175
Copyright © 2008 by The American Association of Immunologists, Inc.
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Alternatively Activated Myeloid Cells Limit Pathogenicity Associated with African Trypanosomiasis through the IL-10 Inducible Gene Selenoprotein P1

Tom Bosschaerts*,{dagger}, Martin Guilliams*,{dagger}, Wim Noel*,{dagger}, Michel Hérin{ddagger}, Raymond F. Burk§, Kristina E. Hill§, Lea Brys*,{dagger}, Geert Raes*,{dagger}, Gholamreza Hassanzadeh Ghassabeh*,{dagger}, Patrick De Baetselier*,{dagger} and Alain Beschin2,*,{dagger}

* Department of Molecular and Cellular Interactions and {dagger} Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels; {ddagger} Cell and Tissue Laboratory, Unité de Recherche en Physiologie Moléculaire, Facultés Universitaires Notre-Dame de la Paix, Namur, Belgium; and § Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Uncontrolled inflammation is a major cause of tissue injury/pathogenicity often resulting in death of a host infected with African trypanosomes. Thus, comparing the immune response in hosts that develop different degrees of disease severity represents a promising approach to discover processes contributing to trypanosomiasis control. It is known that limitation of pathogenicity requires a transition in the course of infection, from an IFN-{gamma}-dependent response resulting in the development of classically activated myeloid cells (M1), to a counterbalancing IL-10-dependent response associated with alternatively activated myeloid cells (M2). Herein, mechanisms and downstream effectors by which M2 contribute to lower the pathogenicity and the associated susceptibility to African trypanosomiasis have been explored. Gene expression analysis in IL-10 knockout and wild-type mice, that are susceptible and relatively resistant to Trypanosoma congolense infection, respectively, revealed a number of IL-10-inducible genes expressed by M2, including Sepp1 coding for selenoprotein P. Functional analyses confirm that selenoprotein P contributes to limit disease severity through anti-oxidant activity. Indeed, Sepp1 knockout mice, but not Sepp1{Delta}240-361 mice retaining the anti-oxidant motif but lacking the selenium transporter domain of selenoprotein P, exhibited increased tissue injury that associated with increased production of reactive oxygen species and increased apoptosis in the liver immune cells, reduced parasite clearance capacity of myeloid cells, and decreased survival. These data validate M2-associated molecules as functioning in reducing the impact of parasite infection on the host.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
The plasticity of macrophages and other CD11b+ myeloid cells (MCs)3 in response to microenvironmental signals results in a continuum of different activation forms. At one end of the spectrum, type 1 cytokine-associated MCs (M1)-induced by IFN-{gamma}, TNF-{alpha}, and microbial products like LPS represent the classical form of activation state and play a critical role in type 1 inflammation and in the fight against intracellular pathogens and tumors. At the other end of the spectrum, distinct subsets of type 2 cytokine-associated MCs (M2) exerting overlapping functions have been recognized (1). Indeed, IL-4/IL-13-activated MCs (designated M2a), that promote type 2 immune response and inflammation, share common characteristics with IL-10-induced/deactivated MCs (M2c) and type II activated MCs (M2b) polarized via exposure to immune complexes and ligands of TLRs or IL-1R. M2c contribute to tissue remodeling whereas M2b induce type 2 immune responses and suppress type 1 inflammation but promote type 2 inflammation.

In a recent investigation, we have identified a common gene signature for peritoneal and splenic M2, by gene expression analysis in MCs elicited in various pathologies including African trypanosomiasis, helminthiasis, and lymphoma progression (2). The wide-ranging M2 signature includes genes that were earlier documented as M2 markers (Arg1, Retnla, MglI, MglII, Mrc1, and Chi3l3/4) and genes that were not before associated with M2 (Pla2g7, Psap, Sepp1, Pmp22, Trem2, Folr2, and Cdh1). Together with the gene expression profile of tumor-associated macrophages (3) and nematode infection elicited macrophages (4) exhibiting an M2 phenotype, the common M2 gene signature constitutes a resourceful tool to explore the functions of M2. In this regard, we have investigated the functional implication of a number of M2 signature genes in helminthiasis (5) and tumor progression (6). In the present work, we have examined the significance of M2-associated genes in African trypanosomiasis.

It has been documented that the heterogeneity of MCs affects the outcome of African trypanosomiasis (7). In both Trypanosoma congolense- and Trypanosoma brucei-infected mice, the development of IFN-{gamma}-dependent M1 in the acute stage of infection restricts parasite growth by secreting molecules like TNF-{alpha}, IL-6, and IL-12 as well as reactive oxygen and nitrogen species (8, 9, 10, 11, 12, 13, 14). This type 1 immune response is followed at later stage by the emergence of M2 and the expansion of Foxp3+CD4+ regulatory T cells (Tregs) in type 2 cytokine environment in T. congolense- but not in T. brucei-infected C57BL/6 mice. Moreover, the inability of T. brucei-infected mice to suppress the type 1 immune response correlates with the increased pathogenicity of the disease that results in tissue injury and early death of the host (15, 16, 17, 18). Of note, in both T. congolense- and T. brucei-infected mice, IL-10 is able to avoid the inflammation mediated by IFN-{gamma}, including overwhelming activation of M1, that results in destruction of the liver and uncontrolled parasite growth (13, 17, 18). Since 80% of these extracellular parasites have been suggested to be cleared from the circulation by liver MCs (19), these data indicate that IL-10, by reducing the pathogenicity of the disease, protects the integrity of the liver and hereby its trypanosome clearance capacity.

Considering the essential role of IL-10 in limiting the pathogenicity and, thus, the susceptibility to the infection, the set of genes induced in M2 of C57BL/6 mice that are relatively resistant to T. congolense infection (2) provides a basis for exploration of the processes that prevent disease severity in African trypanosomiasis. Herein, a number of genes that are inducible by IL-10 in the liver of T. congolense-infected C57BL/6 mice were identified. In addition, we demonstrated that one of these M2-associated genes, Sepp1 which codes for selenoprotein P, is clearly involved in the limitation of the pathogenicity associated with T. congolense infection and, thus, decreases the impact of the inflammatory immune response on the host.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Mice, parasites, and infections

Female wild-type and IL-10 knockout (KO) C57BL/6 mice were purchased from Harlan and B&K Universal respectively. Heterozygous Sepp1 mice or Sepp1{Delta}240-361 mice that had been backcrossed 10 times with C57BL/6 mice were mated, and female wild-type, Sepp1 KO, and Sepp1{Delta}240-361 offspring were selected for study by genotyping as reported (20, 21). Wild-type Sepp1 KO and Sepp1{Delta}240-361 mice were fed from the time of weaning Torula yeast-based diet (22) supplemented with 1 mg selenium/kg as sodium selenite (prepared by Harlan Sprague Dawley). Mice were kept under filter barrier and used at 8–12 wk of age. As controls, noninfected age matched mice were used.

T. congolense variant Ag type 13 (Tc13) (23) was provided by Dr. H. Tabel (University of Sakatchewan, Canada). Parasites stored at –80°C were used to infect cyclophosphamide-treated (C57BL/6 x BALB/C) mice bred in house by i.p. inoculation. At day 4 post infection, mice were bled, and parasites were purified by diethyl-aminoethyl-cellulose chromatography (24). C57BL/6 strains were then infected with 2000 purified parasites. Parasitemia was monitored by tail blood puncture. Gadolinium chloride was injected through the tail vein at a dose of 5 mg/kg. Experiments were performed in compliance with the relevant laws and institutional guidelines.

MC isolation

Liver non-parenchymal cells were isolated as follows: animals were euthanized (CO2) and livers were perfused through the portal vein with 10 ml of 100 U/ml collagenase type III (Worthington Biochemical Corporation) in HBSS supplemented with 2 mM EDTA. Then, the liver was minced and incubated in 10 ml of 100 U/ml collagenase III (20 min, 37°C). The resulting cell suspension was passed through a 100 µm nylon mesh filter and then centrifuged (300 g, 10 min, 4°C). After erythrocyte lysis, the pellet was resuspended in 10 ml of HBSS supplemented with 2 mM EDTA, 10% FCS, and overlayed on 10 ml of Lymphoprep (Lucron Bioproducts). After centrifugation (430 g, 25 min, 17°C), the layer of low-density cells at the interface containing non-parenchymal cells was harvested. MCs were isolated by incubation of non-parenchymal cells with MACS CD11b Microbeads (Miltenyi Biotech; 10 µl/107 cells) in MACS buffer (Ca2+/Mg2+ free HBSS, 2 mM EDTA, and 0.5% BSA) and passage through two consecutive positive LS selection columns (Miltenyi Biotech). The CD11b– cell fraction was collected as flow-through during washing of the columns with ice-cold MACS buffer. Purity of isolated MCs checked by flow cytometry, on FACSCanto II using the FlowJo program, always exceeded 95%.

Cytokines and nitrite determination

Blood collected by heart puncture on heparin (20 U/ml) was centrifuged (10 000 g, 10 min) and stored at –80°C. Cytokines were quantified in the plasma using ELISAs for IFN-{gamma}, IL-10 (Pharmingen), or TNF-{alpha} (R&D Systems) according to the manufacturer’s protocols. NO level was determined by quantifying the accumulation of nitrate and nitrite in plasma as in Ref. 13 .

Differential gene expression analysis

Gene expression was analyzed by quantitative real time PCR using the conditions and primers described in Ref. 2 . Results of the PCR analyses were normalized against the house-keeping gene S12, in at least two independent experiments involving at least five mice per condition.

Reactive oxygen species (ROS)

ROS production was measured using H2DCFDA as a probe. Briefly, cells (106) were incubated in serum-free DMEM containing 2 µM H2DCFDA (30 min, 37°C), washed twice with excess cold RPMI 1640, and analyzed by flow cytometry.

Apoptosis

Cells were incubated with FITC-Annexin V (BD Biosciences; 4 µl/105 cells, 15 min, room temperature) in binding buffer (10 mM HEPES, 140 mM NaCl, and 2.5 mM CaCl2 (pH 7.4)). After washing with binding buffer, cells were analyzed by flow cytometry.

Flow cytometry

After blocking FcR with 2.4G2 anti-CD16/32 Abs (BD Biosciences), cells were incubated with PE-anti-CD11b Abs (BD Biosciences; 1 µg/106 cells, 30 min, 4°C, in the dark). After washing with ice-cold RPMI 1640, cells were analyzed on FACSVantage station (BD Biosciences) using CellQuest software.

Alanine aminotransferase (ALT) levels

Liver glutamic pyruvic transaminase/alanine aminotransferase (ALT) levels were measured in individual serum samples, using a commercial kit (Boehringer Mannheim).

Statistical analysis

Results are presented as mean ± SEM. All comparisons were tested for statistical significance (p < 0.05) using the unpaired t test from GraphPad Prism 4.0 software. Studies were performed on 3–5 independent experiments.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
1. M2-associated genes Ctss, F13a1, Sepp1, and Ngfb are up-regulated upon T. congolense infection in C57BL/6 mice but not in relatively susceptible IL-10 KO C57BL/6 mice

To envisage a potential role of M2 in the outcome of African trypanosomiasis, the expression of 30 recently identified M2-associated genes (2) was addressed in CD11b+ MC fraction from the liver of T. congolense-infected C57BL/6 mice that gradually expanded in the course of infection (Table I). Genes were considered significantly induced if the expression in CD11b+ myeloid cells from all infected mice tested (n ≥ 5) was >3-fold higher than in all noninfected mice (n ≥ 5). Twelve genes were found using real time PCR to be preferentially induced in M2 expanding in the liver of T. congolense-infected C57BL/6 mice (Pla2g7, phospholipase A2, group VII; Psap, prosaposin; Sepp1, selenoprotein P, plasma, 1; Trem2, triggering receptor expressed on MC 2; Ngfb, nerve growth factor β; F13a1, coagulation factor XIII, A1 subunit; Pmp22, peripheral myelin protein; Chi3l3/4, Ym(1/2); Mrc1, mannose receptor C, type 1; Folr2, folate receptor 2 (fetal); Lrg1, leucine-rich {alpha}-2-glycoprotein 1; and Ctss, cathepsin S).


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  		Table I. Number and percentage of CD11b+ cells in the liver at different times post T. congolense infection in wild-type C57BL/6 micea

 
A kinetic of expression revealed that most of the above mentioned M2-associated genes were significantly induced from days 21–28 post T. congolense infection (not shown), with the exception of the genes coding for selenoprotein P (Sepp1), nerve growth factor β (Ngfb), cathepsin S (Ctss), and coagulation factor XIIIa (F13a1) that appeared significantly induced as soon as the first peak of parasitemia was controlled (day 9 post infection) (Table II). Of note, the induction of the latter four genes coincided with the time at which the IFN-{gamma} titer in the plasma of T. congolense-infected C57BL/6 mice returned to normal values coupled to a gradual increase of the IL-10 titer (18, 25). The early induction of expression of these genes coinciding with the time of emergence of IL-10 suggests their IL-10 dependence.


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  		Table II. Gene expression level of M2-associated genes Sepp1, Ngfb, F13a1, and Ctss in the liver of T. congolense-infected wild-type KO C57BL/6 mice

 
To address the mechanisms by which the subset of M2 triggered in an IL-10 environment limit the pathogenicity and render the host relatively resistant to the disease, the level of expression of the M2-associated genes Ctss, F13a1, Sepp1, and Ngfb was determined in T. congolense-infected IL-10 KO C57BL/6 mice and compared with the level of expression observed in wild-type C57BL/6 mice. This analysis was performed at day 9 post infection considering the short survival of IL-10 KO mice (Table III). The level of expression of all genes tested in infected IL-10 KO mice returned to the level of noninfected wild-type mice. Thus, the induction of Ctss, F13a1, Sepp1, and Ngfb can be considered as IL-10 dependent in T. congolense-infected C57BL/6 animals. This observation is highly suggestive for a role of the respective gene products in the IL-10-dependent control of disease symptoms in African trypanosomiasis.


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  		Table III. Gene expression level of M2-associated genes Sepp1, Ngfb, F13a1, and Ctss in the liver of T. congolense-infected IL-10 KO C57BL/6 mice

 
2. Sepp1 KO mice are more susceptible to T. congolense infection

Sepp1 was selected to test whether the IL-10-induced, M2-associated genes limit the pathogenicity and favor the resistance to T. congolense infection. Selenoprotein P, the gene product of Sepp1, is postulated to be an antioxidant molecule (26, 27, 28), and ROS, including peroxynitrite, are formed during African trypanosomiasis (29, 30). However, since ROS also cause liver injury (31), we hypothesized that an increased production of selenoprotein P in liver MCs limits the pathogenicity of African trypanosomiasis by detoxifying ROS.

To test this possibility, the course of T. congolense infection was compared in Sepp1 KO and wild-type C57BL/6 mice. Sepp1 KO mice controlled the first peak of parasitemia less efficiently than did wild-type animals, exhibiting higher parasite burden and impaired parasite clearance capacity (Fig. 1). Approximately 50% of Sepp1 KO mice died around 9 days post infection, i.e., 3 days after the first peak of parasitemia was reached. Yet, Sepp1 KO mice that overcame the early wave of parasitemia died significantly earlier than wild-type mice (around 95 days post infection vs 163 ± 12 days post infection). Thus, in the absence of Sepp1 gene expression, the host becomes more susceptible to T. congolense infection, in terms of parasite control ability and survival.


Figure 1
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  		FIGURE 1. (A) Parasitemia and (B) survival at different times post T. congolense infection of wild-type, Sepp1{Delta}240-361, and Sepp1 KO C57BL/6 mice (n = 6). Beyond day 10 post infection, minor but similar waves of parasitemia were observed until the animals died in all experimental groups. *, higher (p < 0.05) than in wild-type- and Sepp1{Delta}240-361-infected mice.

 
Selenoprotein P has two domains with respect to selenium content and functions. The N-terminal, selenium poor domain, encompassing two potential redox motifs, was predicted to have enzymatic (peroxidase) properties, while the C-terminal, selenium rich domain plays a role in selenium transport (21). To distinguish the function of the selenoprotein P domains during trypanosome infection, C57BL/6 mice with a deletion of the C-terminal domain of Sepp1 gene (Sepp1{Delta}240-361 mice) that have been recently generated (21) were used (Fig. 1). In contrast to Sepp1 KO mice, Sepp1{Delta}240-361 mice controlled T. congolense parasitemia as efficiently and survived as long as wild-type animals, suggesting that the enzymatic activity of selenoprotein P, and not its selenium transporter function, is important for African trypanosomiasis control.

3. Increased necrosis/apoptosis and oxidative stress occur in MCs from T. congolense-infected Sepp1 KO mice

Pathogenic insults in African trypanosome-infected mice result in necrosis/apoptosis in the liver, including Kupffer cells (17). In agreement, the shorter survival of T. congolense-infected Sepp1 KO C57BL/6 mice correlated with higher serum ALT values than in wild-type mice (Fig. 2A), indicating that hepatocytes from the former animals were more damaged. Moreover, the percentage of liver CD11b+ MCs and of CD11b– cells undergoing apoptosis, as evidenced in flow cytometry by Annexin V staining, was higher in Sepp1 KO than in wild-type animals, both at the peak of parasitemia (day 7 post infection) and later on (day 90) during infection (Fig. 2, B and C). The difference in apoptosis levels between infected wild-type and Sepp1 KO mice correlated with an increased accumulation of ROS within liver CD11b+ MCs (Fig. 2, D and E). In contrast, T. congolense-infected Sepp1{Delta}240-361 mice had similar levels of ALT (Fig. 2A), of apoptotic CD11b+ and CD11b– cells (Fig. 2, B and C), and of ROS accumulation within CD11b+ MCs (Fig. 2, F and G) as infected wild-type mice. Thus, selenoprotein P may play a role in reducing pathogenicity of T. congolense infection by protecting liver parenchymal and non-parenchymal cells from apoptosis/necrosis via its N-terminal domain-mediated enzymatic function. That the increased apoptosis/necrosis of liver MCs in Sepp1 KO mice affected the control of T. congolense growth was supported by the observation that treatment of wild-type mice at day 18 post infection with gadolinium chloride (32), which eliminates 90% of liver MCs (Fig. 3) but only 20% of spleen MCs (not shown), abolished its ability to control the parasitemia and severely shortened its survival (22 ± 1 days vs 165 ± 25 days in nontreated mice; p < 0.01) (Fig. 3).


Figure 2
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  		FIGURE 2. A, ALT level at different times post T. congolense infection in the serum of wild-type, Sepp1{Delta}240-361, and Sepp1 KO C57BL/6 mice (n = 5). B and C, Level of apoptosis at days 7 and 90 post T. congolense infection within CD11b+ and CD11b– liver cells from wild- type, Sepp1{Delta}240-361, and Sepp1 KO C57BL/6 mice. Percentage of Annexin V+ cells within gated CD11b+ or CD11b– cells were determined by flow cytometry (n = 9). *, higher (p < 0.05) than in wild-type- and Sepp1{Delta}240-361-infected mice. D–G, ROS production at days 7 and 90 post T. congolense infection within CD11b+ liver cells from wild-type, Sepp1{Delta}240-361, and Sepp1 KO C57BL/6 mice. ROS production was measured using H2DCFDA oxidation within gated CD11b+ cells by flow cytometry. Profiles are representative of one individual mouse of nine investigated in three independent experiments. For clarity, ROS production in noninfected wild-type mice, which was similar to noninfected Sepp1 KO and Sepp1{Delta}240-361 mice, is not shown. D and E, Light line, noninfected Sepp1 KO mice; shaded line, infected wild-type mice; bold line, infected Sepp1 KO mice; F and G, Light line, noninfected Sepp1{Delta}240-361 mice; shaded line, infected wild-type mice; bold line, infected Sepp1{Delta}240-361 mice.

 

Figure 3
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  		FIGURE 3. A, Percentage of CD11b+ cells determined by flow cytometry in the liver of wild-type C57BL/6 mice treated or not treated (PBS) with gadolinium chloride at day 18 post T. congolense infection (n = 5). Cells from nontreated mice were analyzed at the same time as cells from mice treated since 24 h with gadolinium chloride. B, parasitemia in wild-type C57BL/6 mice treated ({downarrow}) or not treated (PBS) with gadolinium chloride at day 18 post T. congolense infection (n = 5). Treated mice survived 22 ± 1 days post infection vs 165 ± 25 days post infection for not treated mice. #, lower (p < 0.05) than in control infected mice. *, higher (p < 0.05) than in control infected mice.

 
4. Absence of Sepp1 does not affect cytokine environment and expression of other M2-associated, IL-10-dependent genes

Cytokine levels in the plasma and the expression of Ngfb, F13a1, and Ctss in MCs were measured during T. congolense infection in Sepp1 KO and Sepp1{Delta}240-361 mice and compared with wild-type C57BL/6 mice. The IFN-{gamma} and IL-10 titers were similar in all experimental groups both at the peak of parasitemia (day 7 post infection) and later on (day 90) during infection (Fig. 4). Moreover, no significant difference in the production of TNF-{alpha} and NO, that are known to contribute to the control of trypanosome growth (8, 33), was observed between infected Sepp1 KO, Sepp1{Delta}240-361, and wild-type mice (not shown). The expression in the liver MCs of Ngfb, F13a1, and Ctss was similar in infected Sepp1 KO, Sepp1{Delta}240-361, and wild-type mice at days 9 and 90 post infection (not shown). Together, these data suggest that the increased susceptibility of T. congolense-infected Sepp1 KO mice is not reflected by a change in the immune environment or in the expression of the M2 genes potentially associated with lower severity of the disease tested.


Figure 4
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  		FIGURE 4. Plasma concentration of (A) IFN-{gamma} and (B) IL-10 in wild-type, Sepp1{Delta}240-361, and Sepp1 KO C57BL/6 mice at days 7 and 90 post T. congolense infection (n = 5). IFN-{gamma} (*) or IL-10 (#) level higher (p < 0.05) than in non infected mice (day 0 post infection).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
The gene expression profile of both human and mouse M2 is now relatively well studied. Yet, the mechanisms and downstream effector molecules by which these cells contribute to protective (34, 35) or detrimental (36, 37) type II immune response are poorly characterized. In contrast, it is clearly established that IL-10 is a major and multifunctional regulator of innate and adaptive immunity. By controlling the immune response, IL-10 creates an environment that favors the persistence of microbes and the development of chronic diseases. However, IL-10 can protect the host from the pathogenicity of diseases caused by exacerbated immune responses and, as such, avoids tissue or systemic lesions (38). Consequently, IL-10 inducible genes represent novel and more specific therapeutic options to intervene in the host’s ability to mount a protective immune response during inflammatory/anti-inflammatory processes. In the present study, African trypanosome infection was used as a model to identify IL-10-dependent, M2-associated genes that could contribute to protection of the host against the pathogenicity associated with the disease.

Limited tissue damages and long survival in a host relatively resistant to African trypanosome infection result from a balance between (i) an inflammatory immune response that associates with the production of IFN-{gamma}, TNF-{alpha}, and NO as well as with the development of M1, and (ii) a counteracting anti-inflammatory response that includes IL-10, the development of M2, and the expansion of Tregs. Both M2 (not shown) and Tregs (18) have been found to contribute to IL-10 production. Genetic polymorphism in host populations influences the progression both of natural (39, 40, 41, 42, 43, 44) and experimental (45) African trypanosomiasis. Moreover, increased resistance is under the control of multiple genes that relate to the control of either the parasitemia or the pathogenic effects of the parasite. These genes remain largely unknown (46, 47, 48). However, quantitative trait loci studies performed in mice and cattle have revealed chromosomal regions linked to control of African trypanosomiasis. In particular in mice infected with T. congolense, 5 quantitative trait loci Tir1 on chromosome 17, Tir2 on chromosome 5 and Tir3a, Tir3b, and Tir3c on chromosome 1 have been identified (49, 50), among which one, Tir3b, maps close to the location of the IL-10 gene (51).

Herein, by comparing the expression of 12 M2 gene markers in MCs isolated from the liver of T. congolense-infected wild-type and IL-10 C57BL/6 KO mice, four genes (Sepp1, Ngfb, F13a1, and Ctss) that are expressed in relatively resistant wild-type animals, but not in highly susceptible IL-10 KO mice, have been identified. Thus, Sepp1, Ngfb, F13a1, and Ctss can be considered as in vivo IL-10-dependent, M2-associated genes, the respective gene products of which could favor the control of the pathogenicity and hereby the resistance of C57BL/6 mice to T. congolense infection. With the exception of the gene product of Ctss, which contributes to Ag presentation and matrix degradation (52, 53), the other genes encode proteins controlling inflammatory/anti-inflammatory processes (54, 55, 56, 57, 58).

Despite producing higher levels of IL-10 than C57BL/6 mice, BALB/C mice, that are highly susceptible to T. congolense infection and die within 10 ± 0.3 days post infection, did not up-regulate the expression of Sepp1, Ngfb, F13a1, and Ctss in MCs (not shown). It has been suggested that infected BALB/C mice are not responsive to the effect of IL-10 (17). In fact, T. congolense-susceptible BALB/c mice, that do not control the first peak of parasitemia, produce simultaneously IFN-{gamma} and IL-10 in the early stage of infection while resistant C57BL/6 mice change from a predominant IFN-{gamma} environment to a predominant IL-10 environment after the control of the first peak of parasitemia (59). Thus, we cannot exclude that the mixed IFN-{gamma} and IL-10 response in BALB/C mice in the early stage of infection impairs the efficient activation of MCs, including up-regulation of Sepp1, Ngfb, F13a1, and Ctss expression.

Selenoprotein P is the major transporter of selenium, a trace element required for normal development (60, 61). This secreted glycoprotein is almost exclusively synthesized by the liver, but local production in virtually all tissues has been described (62, 63, 64), including M2 elicited in several infection and cancer models (2). Selenoprotein P plasma level is depressed in a number of human pathologies including cirrohsis and Crohn’s disease (65, 66). Moreover, human and/or murine Sepp1 gene promoter activity is impaired by IFN-{gamma}, TNF-{alpha}, and IL-1β (67) while induced by TGF-β (68) and IL-10 (2) suggesting a differential regulation of selenoprotein P expression during type 1 or 2 inflammatory reactions. In addition, selenoprotein P was proposed to function in anti-oxidant defense, as a scavenger of peroxynitrite or as a phospholipid hydroperoxide thiol peroxidase (26, 28, 69). Accordingly, selenoprotein P expressed in human pancreatic cancer cells associates with resistance to chemotherapy by suppressing the induction of ROS (70). Hereby, its pH-dependent heparin-binding property suggests that selenoprotein P binds to host cell membranes in areas of inflammation that typically have low pH, preventing cell injury induced by ROS (70, 71, 72).

Currently, a documented role for selenoprotein P in M2 and in infectious diseases is lacking. In an attempt to validate our approach to identify IL-10-dependent, M2-associated genes contributing to the control of the severity of African trypanosomiasis, Sepp1 KO mice, and Sepp1{Delta}240-361 mice-expressing selenoprotein P truncated of the selenium transporter domain but retaining the domain exerting anti-oxidant activity-in the resistant C57BL/6 background were infected with T. congolense. It has been shown that in Sepp1 KO or Sepp1{Delta}240-361 mice, severe neurological dysfunction occurs in animals fed a selenium-deficient diet. Yet, feeding 0.25 mg selenium/kg largely prevents this phenotype in Sepp1 KO or Sepp1{Delta}240-361 mice (20, 21, 22, 73). In this context, it is important that in our experiments, Sepp1 KO and Sepp1{Delta}240-361 mice were supplied with 10 times the normal nutritional requirement, 1 mg selenium/kg, preventing pathological phenotype and selenium depletion in most tissues including the liver. Our data show that in T. congolense-infected wild-type animals, the expression of Sepp1 mRNA gradually increased in liver CD11b+ MCs after the clearance of the first peak of parasitemia. Concomitantly, it was not affected in CD11b– cells. Of interest, the mRNA expression level of other selenoproteins tested (thioredoxin reductases 1–3 and glutathione peroxidases 1–4) in CD11b– cells and CD11b+ MCs from the liver was not up-regulated in T. congolense infected wild-type and Sepp1 KO mice (not shown). These data suggest that selenoprotein P is the major selenoprotein induced in infected mice and that none of the other selenoproteins tested compensates, in MCs, for the loss of selenoprotein P in Sepp1 KO mice. T. congolense infection is more pathogenic in Sepp1 KO mice. The increased parasitemia and reduced survival of these animals as compared with wild-type mice correlate with increased liver injury, including apoptosis/necrosis of hepatocytes and non-parenchymal cells. Of note, the increased susceptibility of Sepp1 KO mice to T. congolense infection does not associate with a change in cytokine environment or in the expression of IL-10-dependent M2 genes associated with resistance to the disease (Ngfb, F13a1, and Ctss). In addition, while all IL-10 KO mice died after the first peak of parasitemia, only half of the Sepp1 KO mice died at that moment, suggesting that the effect of IL-10 on resistance to T. congolense is not restricted to the sole induction of IL-10-dependent genes identified in the present study.

In contrast to Sepp1 KO mice, Sepp1{Delta}240-361 mice controlled T. congolense infection as efficiently as wild-type animals, suggesting that the anti-oxidant activity of selenoprotein P is important to avoid tissue damage and ensure survival. In agreement, in T. congolense-infected mice, liver MCs from Sepp1 KO mice, but not from Sepp1{Delta}240-361 mice, accumulate more ROS than wild-type mice. Although ROS can limit trypanosome growth (29, 30), parasitemia increases in Sepp1 KO-infected mice during the first, most aggressive wave of parasitemia. Since liver MCs were more prone to undergo apoptosis/necrosis in the latter animals, and since gadolinium chloride treatment, which eliminates 90% of liver MCs in wild-type mice, results in loss of parasite control and early death of the host, selenoprotein P may contribute to trypanosomiasis control by preserving the integrity/viability of MCs. Yet, Sepp1 KO mice that survived the first peak of parasitemia succumbed earlier than wild-type and Sepp1{Delta}240-361 mice, suggesting that MCs contribute to resistance to trypanosomiasis by more than their parasite clearance function. African trypanosome infection perturbs the triglyceride metabolism (74) and the release of acute phase proteins (25), two major functions of hepatocytes. Because ALT level was increased in infected Sepp1 KO mice, a role for selenoprotein P and MCs in the protection of hepatocytes from apoptosis/necrosis cannot be excluded.

In summary, by analyzing the gene profile in M2-oriented MCs in T. congolense-infected mice, we have identified IL-10-dependent genes that could prevent the pathogenicity and, thus, contribute to the resistance of the host to the disease. These genes code for proteins potentially involved in the control of inflammatory processes. One of these genes coding for selenoprotein P was found essential to control the pathogenic effect of the parasite including excessive production of ROS as well as destruction of liver MCs and hepatocytes. In a more general context, M2 genes that contribute to the limitation of severity of African trypanosome infection may represent targets for therapeutic intervention aiming to limit potentially harmful inflammatory responses.


   Acknowledgments
 
We thank Drs. Patrizia Loi and Véronique Flamand (Institut de Biologie et Médecine Moléculaires, Université Libre de Bruxelles, Belgium) for measuring ALT/aspartate aminotransferase levels.


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


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

1 This work, performed in frame of an Interuniversity Attraction Pole Program, was supported by grants from the Institute for Promotion of Innovation by Science and Technology in Flanders and the Fund for Scientific Research Flanders, and by a grant from Institute for Promotion of Innovation by Science and Technology in Flanders for Generisch Basisonderzoek aan de Universiteiten. R.F.B. and K.E.H. are supported by National Institutes of Health Grant ES02497. Back

2 Address correspondence and reprint requests to Dr. Alain Beschin, Department of Molecular and Cellular Interactions, Vrije Universiteit Brussel, Laboratory of Cellular and Molecular Immunology, Pleinlaan 2, 1050 Brussels, Belgium. E-mail address: abeschin{at}vub.ac.be Back

3 Abbreviations used in this paper: MC, myeloid cell; ROS, reactive oxygen species; Sepp1, selenoprotein P; Sepp1{Delta}240-361, selenoprotein P truncated of amino acids 240–361; Ctss, cathepsin S; Ngfb, nerve growth factor β; F13a1, coagulation factor XIII, A1 subunit; Treg, T regulatory cell; KO, knockout. Back

Received for publication July 16, 2007. Accepted for publication February 20, 2008.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

  1. Mantovani, A., A. Sica, M. Locati. 2007. New vistas on macrophage differentiation and activation. Eur. J. Immunol. 37: 14-16. [Medline]
  2. Ghassabeh, G. Hassanzadeh, P. De Baetselier, L. Brys, W. Noel, J. A. Van Ginderachter, S. Meerschaut, A. Beschin, F. Brombacher, G. Raes. 2006. Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. Blood 108: 575-583. [Abstract/Free Full Text]
  3. Biswas, S. K., L. Gangi, S. Paul, T. Schioppa, A. Saccani, M. Sironi, B. Bottazzi, A. Doni, B. Vincenzo, F. Pasqualini, et al 2006. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-{kappa}B and enhanced IRF-3/STAT1 activation). Blood 107: 2112-2122. [Abstract/Free Full Text]
  4. Loke, P., M. G. Nair, J. Parkinson, D. Guiliano, M. Blaxter, J. E. Allen. 2002. IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype. BMC Immunol. 3: 7[Medline]
  5. Brys, L., A. Beschin, G. Raes, G. H. Ghassabeh, W. Noel, J. Brandt, F. Brombacher, P. De Baetselier. 2005. Reactive oxygen species and 12/15-lipoxygenase contribute to the antiproliferative capacity of alternatively activated myeloid cells elicited during helminth infection. J. Immunol. 174: 6095-6104. [Abstract/Free Full Text]
  6. Van Ginderachter, J. A., S. Meerschaut, Y. Liu, L. Brys, K. De Groeve, G. Hassanzadeh Ghassabeh, G. Raes, P. De Baetselier. 2006. Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands reverse CTL suppression by alternatively activated (M2) macrophages in cancer. Blood 108: 575-583. [Abstract/Free Full Text]
  7. Noel, W., G. Raes, G. Hassanzadeh Ghassabeh, P. De Baetselier, A. Beschin. 2004. Alternatively activated macrophages during parasite infections. Trends Parasitol. 20: 126-133. [Medline]
  8. Magez, S., M. Radwanska, M. Drennan, L. Fick, T. N. Baral, F. Brombacher, P. De Baetselier. 2006. Interferon-{gamma} and nitric oxide in combination with antibodies are key protective host immune factors during Trypanosoma congolense Tc13 infections. J. Infect. Dis. 193: 1575-1583. [Medline]
  9. Kaushik, R. S., J. E. Uzonna, Y. Zhang, J. R. Gordon, H. Tabel. 2000. Innate resistance to experimental African trypanosomiasis: differences in cytokine (TNF-{alpha}, IL-6, IL-10, and IL-12) production by bone marrow-derived macrophages from resistant and susceptible mice. Cytokine 12: 1024-1034. [Medline]
  10. Flynn, J. N., M. Sileghem. 1991. The role of the macrophage in induction of immunosuppression in Trypanosoma congolense-infected cattle. Immunology 74: 310-316. [Medline]
  11. Iraqi, F., K. Sekikawa, J. Rowlands, A. Teale. 2001. Susceptibility of tumour necrosis factor-{alpha} genetically deficient mice to Trypanosoma congolense infection. Parasite Immunol. 23: 445-451. [Medline]
  12. Taiwo, V. O., J. O. Adejinmi, J. O. Oluwaniyi. 2002. Non-immune control of trypanosomosis: in vitro oxidative burst of PMA- and trypanosome-stimulated neutrophils of Boran and N'Dama cattle. Onderstepoort J. Vet. Res. 69: 155-161. [Medline]
  13. Namangala, B., W. Noel, P. De Baetselier, L. Brys, A. Beschin. 2001. Relative contribution of interferon-{gamma} and interleukin-10 to resistance to murine African trypanosomosis. J. Infect. Dis. 183: 1794-1800. [Medline]
  14. Schleifer, K. W., H. Filutowicz, L. R. Schopf, J. M. Mansfield. 1993. Characterization of T helper cell responses to the trypanosome variant surface glycoprotein. J. Immunol. 150: 2910-2919. [Abstract]
  15. Magez, S., M. Radwanska, A. Beschin, K. Sekikawa, P. De Baetselier. 1999. Tumor necrosis factor {alpha} is a key mediator in the regulation of experimental Trypanosoma brucei infections. Infect. Immun. 67: 3128-3132. [Abstract/Free Full Text]
  16. Namangala, B., P. de Baetselier, L. Brijs, B. Stijlemans, W. Noel, E. Pays, M. Carrington, A. Beschin. 2000. Attenuation of Trypanosoma brucei is associated with reduced immunosuppression and concomitant production of Th2 lymphokines. J. Infect. Dis. 181: 1110-1120. [Medline]
  17. Shi, M., W. Pan, H. Tabel. 2003. Experimental African trypanosomiasis: IFN-{gamma} mediates early mortality. Eur. J. Immunol. 33: 108-118. [Medline]
  18. Guilliams, M., G. Oldenhove, W. Noel, M. Hérin, L. Brys, P. Loi, V. Flamand, M. Moser, P. De Baetselier, A. Beschin. 2007. African trypanosomiasis: naturally occuring regulatory T cells favor trypanotolerance by limiting pathology associated with sustained type 1 inflammation. J. Immunol. 179: 2748-2757. [Abstract/Free Full Text]
  19. Dempsey, W. L., J. M. Mansfield. 1983. Lymphocyte function in experimental African trypanosomiasis: V. Role of antibody and the mononuclear phagocyte system in variant-specific immunity. J. Immunol. 130: 405-411. [Abstract]
  20. Hill, K. E., J. Zhou, W. J. McMahan, A. K. Motley, J. F. Atkins, R. F. Gesteland, R. F. Burk. 2003. Deletion of selenoprotein P alters distribution of selenium in the mouse. J. Biol. Chem. 278: 13640-13646. [Abstract/Free Full Text]
  21. Hill, K. E., J. Zhou, L. M. Austin, A. K. Motley, A. J. Ham, G. E. Olson, J. F. Atkins, R. F. Gesteland, R. F. Burk. 2007. The selenium-rich C-terminal domain of mouse selenoprotein P is necessary for the supply of selenium to brain and testis but not for the maintenance of whole body selenium. J. Biol. Chem. 282: 10972-10980. [Abstract/Free Full Text]
  22. Hill, K. E., J. Zhou, W. J. McMahan, A. K. Motley, R. F. Burk. 2004. Neurological dysfunction occurs in mice with targeted deletion of the selenoprotein P gene. J. Nutr. 134: 157-161. [Abstract/Free Full Text]
  23. Otesile, E. B., M. Lee, H. Tabel. 1991. Plasma levels of proteins of the alternative complement pathway in inbred mice that differ in resistance to Trypanosoma congolense infections. J. Parasitol. 77: 958-964. [Medline]
  24. Lanham, S. M., D. G. Godfrey. 1970. Isolation of salivarian trypanosomes from man and other mammals using DEAE-cellulose. Exp. Parasitol. 28: 521-534. [Medline]
  25. Kitani, H., Y. Yagi, J. Naessens, K. Sekikawa, F. Iraqi. 2004. The secretion of acute phase proteins and inflammatory cytokines during Trypanosoma congolense infection is not affected by the absence of the TNF-{alpha} gene. Acta Trop. 92: 35-42. [Medline]
  26. Saito, Y., T. Hayashi, A. Tanaka, Y. Watanabe, M. Suzuki, E. Saito, K. Takahashi. 1999. Selenoprotein P in human plasma as an extracellular phospholipid hydroperoxide glutathione peroxidase: isolation and enzymatic characterization of human selenoprotein p. J. Biol. Chem. 274: 2866-2871. [Abstract/Free Full Text]
  27. Burk, R. F., K. E. Hill, J. A. Awad, J. D. Morrow, P. R. Lyons. 1995. Liver and kidney necrosis in selenium-deficient rats depleted of glutathione. Lab. Invest. 72: 723-730. [Medline]
  28. Arteel, G. E., V. Mostert, H. Oubrahim, K. Briviba, J. Abel, H. Sies. 1998. Protection by selenoprotein P in human plasma against peroxynitrite-mediated oxidation and nitration. Biol. Chem. 379: 1201-1205. [Medline]
  29. Gobert, A. P., S. Semballa, S. Daulouede, S. Lesthelle, M. Taxile, B. Veyret, P. Vincendeau. 1998. Murine macrophages use oxygen- and nitric oxide-dependent mechanisms to synthesize S-nitroso-albumin and to kill extracellular trypanosomes. Infect. Immun. 66: 4068-4072. [Abstract/Free Full Text]
  30. Vincendeau, P., S. Daulouede, B. Veyret. 1989. Role of hypochlorous acid in Trypanosoma musculi killing by phagocytes. Parasitology 98: 253-257. [Medline]
  31. Cesaratto, L., C. Vascotto, S. Calligaris, G. Tell. 2004. The importance of redox state in liver damage. Ann. Hepatol. 3: 86-92. [Medline]
  32. Hardonk, M. J., F. W. Dijkhuis, C. E. Hulstaert, J. Koudstaal. 1992. Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation. J. Leukocyte Biol. 52: 296-302. [Abstract]
  33. Tabel, H., R. S. Kaushik, J. Uzonna. 1999. Experimental African trypanosomiasis: differences in cytokine and nitric oxide production by macrophages from resistant and susceptible mice. Pathobiology 67: 273-276. [Medline]
  34. Herbert, D. R., C. Holscher, M. Mohrs, B. Arendse, A. Schwegmann, M. Radwanska, M. Leeto, R. Kirsch, P. Hall, H. Mossmann, et al 2004. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20: 623-635. [Medline]
  35. Anthony, R. M., J. F. Urban, Jr, F. Alem, H. A. Hamed, C. T. Rozo, J. L. Boucher, N. Van Rooijen, W. C. Gause. 2006. Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat. Med. 12: 955-960. [Medline]
  36. Hesse, M., M. Modolell, A. C. La Flamme, M. Schito, J. M. Fuentes, A. W. Cheever, E. J. Pearce, T. A. Wynn. 2001. Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J. Immunol. 167: 6533-6544. [Abstract/Free Full Text]
  37. Holcomb, I. N., R. C. Kabakoff, B. Chan, T. W. Baker, A. Gurney, W. Henzel, C. Nelson, H. B. Lowman, B. D. Wright, N. J. Skelton, et al 2000. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 19: 4046-4055. [Medline]
  38. Mege, J. L., S. Meghari, A. Honstettre, C. Capo, D. Raoult. 2006. The two faces of interleukin 10 in human infectious diseases. Lancet Infect. Dis. 6: 557-569. [Medline]
  39. MacLean, L., J. E. Chisi, M. Odiit, W. C. Gibson, V. Ferris, K. Picozzi, J. M. Sternberg. 2004. Severity of human african trypanosomiasis in East Africa is associated with geographic location, parasite genotype, and host inflammatory cytokine response profile. Infect. Immun. 72: 7040-7044. [Abstract/Free Full Text]
  40. Courtin, D., L. Argiro, V. Jamonneau, L. N'Dri, P. N'Guessan, L. Abel, A. Dessein, M. Cot, C. Laveissiere, A. Garcia. 2006. Interest of tumor necrosis factor-{alpha}-308 G/A and interleukin-10–592 C/A polymorphisms in human African trypanosomiasis. Infect. Genet. Evol. 6: 123-129. [Medline]
  41. Courtin, D., J. Milet, V. Jamonneau, C. S. Yeminanga, V. K. Kumeso, C. M. Bilengue, C. Betard, A. Garcia. 2007. Association between human African trypanosomiasis and the IL6 gene in a Congolese population. Infect. Genet. Evol. 7: 60-68. [Medline]
  42. Naessens, J.. 2006. Bovine trypanotolerance: a natural ability to prevent severe anaemia and haemophagocytic syndrome?. Int. J. Parasitol. 36: 521-528. [Medline]
  43. Hanotte, O., Y. Ronin, M. Agaba, P. Nilsson, A. Gelhaus, R. Horstmann, Y. Sugimoto, S. Kemp, J. Gibson, A. Korol, et al 2003. Mapping of quantitative trait loci controlling trypanotolerance in a cross of tolerant West African N'Dama and susceptible East African Boran cattle. Proc. Natl. Acad. Sci. USA 100: 7443-7448. [Abstract/Free Full Text]
  44. Hill, E. W., G. M. O’Gorman, M. Agaba, J. P. Gibson, O. Hanotte, S. J. Kemp, J. Naessens, P. M. Coussens, D. E. MacHugh. 2005. Understanding bovine trypanosomiasis and trypanotolerance: the promise of functional genomics. Vet. Immunol. Immunopathol. 105: 247-258. [Medline]
  45. Morrison, W. I., G. E. Roelants, K. S. Mayor-Withey, M. Murray. 1978. Susceptibility of inbred strains of mice to Trypanosoma congolense: correlation with changes in spleen lymphocyte populations. Clin. Exp. Immunol. 32: 25-40. [Medline]
  46. Maillard, J. C., D. Berthier, S. Thevenon, D. Piquemal, I. Chantal, J. Marti. 2005. Efficiency and limits of the serial analysis of gene expression (SAGE) method: discussions based on first results in bovine trypanotolerance. Vet. Immunol. Immunopathol. 108: 59-69. [Medline]
  47. Trail, J. C., N. Wissocq, G. D. d’Ieteren, O. Kakiese, M. Murray. 1994. Quantitative phenotyping of N'Dama cattle for aspects of trypanotolerance under field tsetse challenge. Vet. Parasitol. 55: 185-195. [Medline]
  48. d’Ieteren, G. D., E. Authie, N. Wissocq, M. Murray. 1998. Trypanotolerance, an option for sustainable livestock production in areas at risk from trypanosomosis. Rev. Sci. Tech. 17: 154-175. [Medline]
  49. Iraqi, F., S. J. Clapcott, P. Kumari, C. S. Haley, S. J. Kemp, A. J. Teale. 2000. Fine mapping of trypanosomiasis resistance loci in murine advanced intercross lines. Mamm. Genome 11: 645-648. [Medline]
  50. Kemp, S. J., F. Iraqi, A. Darvasi, M. Soller, A. J. Teale. 1997. Localization of genes controlling resistance to trypanosomiasis in mice. Nat. Genet. 16: 194-196. [Medline]
  51. Tabel, H., R. S. Kaushik, J. E. Uzonna. 2000. Susceptibility and resistance to Trypanosoma congolense infections. Microbes Infect. 2: 1619-1629. [Medline]
  52. Bania, J., E. Gatti, H. Lelouard, A. David, F. Cappello, E. Weber, V. Camosseto, P. Pierre. 2003. Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs. Proc. Natl. Acad. Sci. USA 100: 6664-6669. [Abstract/Free Full Text]
  53. Hou, W. S., W. Li, G. Keyszer, E. Weber, R. Levy, M. J. Klein, E. M. Gravallese, S. R. Goldring, D. Bromme. 2002. Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum. 46: 663-674. [Medline]
  54. la Sala, A., S. Corinti, M. Federici, H. U. Saragovi, G. Girolomoni. 2000. Ligand activation of nerve growth factor receptor TrkA protects monocytes from apoptosis. J. Leukocyte Biol. 68: 104-110. [Abstract/Free Full Text]
  55. Wei, R., G. M. Jonakait. 1999. Neurotrophins and the anti-inflammatory agents interleukin-4 (IL-4), IL-10, IL-11 and transforming growth factor-β1 (TGF-β1) down-regulate T cell costimulatory molecules B7 and CD40 on cultured rat microglia. J. Neuroimmunol. 95: 8-18. [Medline]
  56. Stief, T. W.. 1991. Factor XIII of blood coagulation inhibits the oxidative phagocyte metabolism and suppresses the immune response in vivo. Thromb. Res. 63: 227-238. [Medline]
  57. Torocsik, D., H. Bardos, L. Nagy, R. Adany. 2005. Identification of factor XIII-A as a marker of alternative macrophage activation. Cell Mol. Life Sci. 62: 2132-2139. [Medline]
  58. D’Argenio, G., A. Grossman, V. Cosenza, N. D. Valle, G. Mazzacca, P. D. Bishop. 2000. Recombinant factor XIII improves established experimental colitis in rats. Dig. Dis. Sci. 45: 987-997. [Medline]
  59. Noel, W., G. Hassanzadeh, G. Raes, B. Namangala, I. Daems, L. Brys, F. Brombacher, P. D. Baetselier, A. Beschin. 2002. Infection stage-dependent modulation of macrophage activation in Trypanosoma congolense-resistant and -susceptible mice. Infect. Immun. 70: 6180-6187. [Abstract/Free Full Text]
  60. Olson, G. E., V. P. Winfrey, S. K. Nagdas, K. E. Hill, R. F. Burk. 2005. Selenoprotein P is required for mouse sperm development. Biol. Reprod. 73: 201-211. [Abstract/Free Full Text]
  61. Brown, K. M., J. R. Arthur. 2001. Selenium, selenoproteins, and human health: a review. Public Health Nutr. 4: 593-599. [Medline]
  62. Dreher, I., C. Schmutzler, F. Jakob, J. Kohrle. 1997. Expression of selenoproteins in various rat and human tissues and cell lines. J. Trace Elem. Med. Biol. 11: 83-91. [Medline]
  63. Moschos, M. P.. 2000. Selenoprotein P. Cell Mol. Life Sci. 57: 1836-1845. [Medline]
  64. Burk, R. F., K. E. Hill. 2005. Selenoprotein P: an extracellular protein with unique physical characteristics and a role in selenium homeostasis. Annu. Rev. Nutr. 25: 215-235. [Medline]
  65. Burk, R. F., D. S. Early, K. E. Hill, I. S. Palmer, M. E. Boeglin. 1998. Plasma selenium in patients with cirrhosis. Hepatology 27: 794-798. [Medline]
  66. Andoh, A., M. Hirashima, H. Maeda, K. Hata, O. Inatomi, T. Tsujikawa, M. Sasaki, K. Takahashi, Y. Fujiyama. 2005. Serum selenoprotein-P levels in patients with inflammatory bowel disease. Nutrition 21: 574-579. [Medline]
  67. Dreher, I., T. C. Jakobs, J. Kohrle. 1997. Cloning and characterization of the human selenoprotein P promoter: response of selenoprotein P expression to cytokines in liver cells. J. Biol. Chem. 272: 29364-29371. [Abstract/Free Full Text]
  68. Mostert, V., I. Dreher, J. Kohrle, S. Wolff, J. Abel. 2001. Modulation of selenoprotein P expression by TGF-β(1) is mediated by Smad proteins. Biofactors 14: 135-142. [Medline]
  69. Burk, R. F., K. E. Hill, M. E. Boeglin, F. F. Ebner, H. S. Chittum. 1997. Selenoprotein P associates with endothelial cells in rat tissues. Histochem. Cell Biol. 108: 11-15. [Medline]
  70. Maehara, S., S. Tanaka, M. Shimada, K. Shirabe, Y. Saito, K. Takahashi, Y. Maehara. 2004. Selenoprotein P, as a predictor for evaluating gemcitabine resistance in human pancreatic cancer cells. Int. J. Cancer 112: 184-189. [Medline]
  71. Steinbrenner, H., E. Bilgic, L. Alili, H. Sies, P. Brenneisen. 2006. Selenoprotein P protects endothelial cells from oxidative damage by stimulation of glutathione peroxidase expression and activity. Free Radic. Res. 40: 936-943. [Medline]
  72. Hondal, R. J., S. Ma, R. M. Caprioli, K. E. Hill, R. F. Burk. 2001. Heparin-binding histidine and lysine residues of rat selenoprotein P. J. Biol. Chem. 276: 15823-15831. [Abstract/Free Full Text]
  73. Schweizer, U., M. Michaelis, J. Kohrle, L. Schomburg. 2004. Efficient selenium transfer from mother to offspring in selenoprotein-P-deficient mice enables dose-dependent rescue of phenotypes associated with selenium deficiency. Biochem. J. 378: 21-26. [Medline]
  74. Nakamura, Y.. 1998. Alterations of serum lipid, lipoprotein and inflammatory cytokine profiles of rabbits infected with Trypanosoma brucei brucei. Vet. Parasitol. 80: 117-125. [Medline]



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M. Guilliams, K. Movahedi, T. Bosschaerts, T. VandenDriessche, M. K. Chuah, M. Herin, A. Acosta-Sanchez, L. Ma, M. Moser, J. A. Van Ginderachter, et al.
IL-10 Dampens TNF/Inducible Nitric Oxide Synthase-Producing Dendritic Cell-Mediated Pathogenicity during Parasitic Infection
J. Immunol., January 15, 2009; 182(2): 1107 - 1118.
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