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. 2008 Dec;89(6):438–446. doi: 10.1111/j.1365-2613.2008.00598.x

Expression of galectins-1, -3 and -4 varies with strain and type of experimental colitis in mice

Anne Mathieu *, Nathalie Nagy *, Christine Decaestecker †, Liesbeth Ferdinande ‡, Klaas Vandenbroucke §, Pieter Rottiers §, Claude A Cuvelier ‡, Isabelle Salmon *, Pieter Demetter *
PMCID: PMC2669605  PMID: 19134053

Abstract

Galectins are increasingly the focus of biomedical research. Although they are involved at different stages in inflammation, data on galectins in colitis remain scarce. The aim of this study was to determine and compare the expression of galectins in acute and chronic experimental colitis in mice. Immunohistochemistry for galectins-1, -3 and -4 was performed on colon tissue from C57BL/6 and BALB/c mice with acute dextran sodium sulphate colitis and from 129 Sv/Ev IL-10 knock-out (IL-10−/−) mice. From these three mouse strains, we first detected major differences in galectin expression related to the genetic background in the control animals. With regard to inflammation, chronic colitis in IL-10−/− mice was associated with increased galectin-4 expression; in contrast with the two other models, no galectin-1 and -3 alterations were observed in IL-10−/− mice. Acute colitis in C57BL/6 and BALB/c mice showed increased galectin-3 expression in the lamina propria and the crypt epithelium, together with a decreased nuclear expression. These results suggest an involvement of galectins in the development and perpetuation of colonic inflammation and illustrate that the choice of the mouse strain for studying galectins might influence the outcome of the experiments.

Keywords: animal models, colitis, galectins, immunohistochemistry, inflammatory bowel disease

The soluble-type lectins or galectins are a family of proteins characterized by their binding affinity for β-galactosyl-containing glycoconjugates and by the conserved sequence of at least one characteristic carbohydrate domain (Barondes et al. 1994). Galectins play a role in cell–cell and cell–matrix adhesion (Hirabayashi 1997; Hughes 2001), growth regulation and internal processes such as premessenger ribonucleic acid splicing (Hirabayashi 1997); so, it is not surprising that they are involved in malignancy (Danguy et al. 2002; van den Brûle et al. 2004). Moreover, they have attracted the attention of immunologists as these molecules seem master regulators of immune cell homeostasis and inflammation, either by regulating cell survival and signalling, influencing chemotaxis or interfering with cytokine secretion (Liu 2000; Rabinovich et al. 2002a; Almkvist & Karlsson 2004; Rubinstein et al. 2004).

The galectin expression pattern varies among different adult tissues; although it is not yet clear whether the 15 galectins identified so far have functions in common, a striking feature of all of them is the strong modulation of expression during development and under different physiological or pathological conditions.

The mammalian colon is one of the organs rich in galectins, as seven subtypes (galectins-1, -2, -3, -4, -6, -8 and -9) have been identified by several assays (Jensen-Jarolim et al. 2002; Nagy et al. 2002; Hittelet et al. 2003; Hokama et al. 2004; Nio et al. 2005; Saal et al. 2005). With regard to inflammation in the digestive tract, data on galectins are, however, scarce.

Human recombinant galectin-1 exerts protective and immunomodulatory activity in 2,4,6-trinitrobenzene sulphonic acid-induced colitis in mice (Santucci et al. 2003) suggesting that it might be effective in the treatment of inflammatory bowel diseases. This molecule downregulates the immune response by induction of apoptosis of activated T cells and by other as yet unknown non-apoptotic mechanisms (Rabinovich et al. 2002b; Stillman et al. 2006).

Although galectin-3 can also act as an immunomodulator by inducing apoptosis in T cells (Stillman et al. 2006), it has been mainly described as an amplifier of the inflammatory cascade (Rabinovich et al. 2002a; Almkvist & Karlsson 2004). However, downregulation of galectin-3 in the intestinal epithelium of Crohn’s disease patients has been reported, possibly as a consequence of an enhanced production of tumour necrosis factor-alpha by inflammatory cells (Jensen-Jarolim et al. 2002; Muller et al. 2006).

Galectin-4, which is selectively produced by intestinal epithelial cells (Gitt et al. 1998), might also be involved in the pathogenesis of inflammatory bowel disease. Indeed, this galectin possesses immunogenic activity specifically stimulating interleukin-6 (IL-6) production under inflammatory conditions by interacting with the immunological synapse generated on colonic lamina propria CD4+ T cells. This leads to the exacerbation of chronic intestinal inflammation and delay in the recovery from acute inflammation (Hokama et al. 2004). It was postulated that the production of galectin-4 per epithelial cell is upregulated during intestinal inflammation, but this hypothesis was not confirmed (Hokama et al. 2004). How galectin-4, which is secreted at the apical side of the epithelial cells (Danielsen & van Deurs 1997), can exert a function on lamina propria cells in inflamed mucosa remains to be elucidated; it can be hypothesized that there is a passive release of galectin-4 because of epithelial cell damage and death under inflammatory conditions.

Systematic data on the expression of different galectins in animal models for colitis are lacking. This study aimed to determine the expression of galectins, supposed to be involved in colonic inflammation, in acute and chronic experimental colitis in mice.

Methods

Development of acute and chronic colitis in mice

Twenty female BALB/c and 20 C57BL/6 mice were obtained from Elevage Janvier (Le Genest Saint Isle, France). They were housed in a conventional animal facility. To induce acute colitis, mice weighing approximately 20 g were provided with a 5% (w/v) (for 10 BALB/c mice) or 4% (for 10 C57BL/6 mice) solution of dextran sodium sulphate (DSS) (Applichem, Darmstadt, Germany) ad libitum instead of water for 7 days. The 20 control mice received tap water ad libitum. On day 7, the mice were killed by cervical dislocation.

Eight IL-10 knockout mice (Kühn et al. 1993) (129Sv/Ev IL-10−/−) were housed and bred under specific pathogen-free conditions. The IL-10−/− mice were killed at 24 weeks of age, at which time chronic colitis had fully developed. These mice as well as their controls (eight wild-type 129Sv/Ev mice) were fed standard laboratory feed and tap water ad libitum.

Fragments of middle and distal colon were fixed in formalin, embedded in paraffin and sectioned longitudinally. Haematoxylin–eosin stainings of the slides were scored semiquantitatively in a blinded manner; the histological score is the sum of the epithelial damage and the inflammatory infiltration, each ranging from 0 to 4 as described (Kojouharoff et al. 1997). Histological scores for BALB/c mice provided with DSS varied from 6 to 8, for C57BL/6 mice provided with DSS from 7 to 8 and for IL-10−/− mice from 4 to 7. For all control mice, the histological score was 0. Myeloperoxidase activity in the middle colon was measured as described (Bradley et al. 1982) and the clinical and histological findings of colitis were confirmed (data not shown).

Immunohistochemistry

For immunohistochemistry, polyclonal antibodies to galectin-1 (goat IgG; R&D Systems, Minneapolis, MN, USA), galectin-3 (goat IgG; R&D Systems) and galectin-4 (goat IgG; R&D Systems) were used.

Briefly, 4-μm thick sections were deparaffinized in xylene and rehydrated. An antigen-retrieval microwave treatment in citrate buffer, pH 6.0 was only applied to slides for galectin-3 immunohistochemistry. Blocking of the endogenous peroxidase activity was performed by incubation with 0.3% hydrogen peroxide in methanol and the non-specific serum binding sites were saturated with normal horse serum (1/20; Vector Laboratories, Burlingame, CA, USA).

Slides were incubated with the primary antibodies at dilution 1/500, 1/300 and 1/500, respectively, for galectins-1, -3 and -4, followed by incubation with a biotinylated anti-goat serum. Negative control sections were immunostained under the same conditions, but with the substitution of anti-galectin antibodies by irrelevant antibodies (goat IgG). Staining was visualized using an indirect avidin–biotin complex immunoperoxydase method (Vectastain ABC Kit; Vector Laboratories) according to the supplier’s protocol. Finally, the slides were counterstained with haematoxylin.

Immunohistochemical expression analysis

Immunohistochemical stainings were assessed by means of standard light microscopy by two independent pathologists (A.M. and P.D.). Four slides for which no observers’ agreement could be reached were excluded. To each slide, the galectin-1, -3 and -4 expression levels were characterized in the superficial epithelium, the crypt epithelium and the lamina propria. This characterization consisted of an evaluation of (i) the number of positive cells (no staining, 0; <30%, 1; 30–60%, 2; >60%, 3) and (ii) the staining intensity (no staining, 0; weak staining, 1; moderate staining, 2; strong staining, 3). In addition, for the epithelial cells, the intracellular location (nuclear and/or cytoplasmic staining) of anti-galectin immunoreactivity was also determined (absence of nuclear staining, 0; nuclear staining lower than cytoplasmic staining, 1; nuclear staining equals cytoplasmic staining, 2).

Statistical analysis

Differences in galectin expression among the groups of mice were described by means of contingency tables crossing one of the staining features described above and the mice groups of interest, i.e. either the three control groups, or the control and the treated groups for each mouse strain. In view of the reduced sizes of the animal groups analysed and the fact that all the possible values of the galectin features were not always observed, we transformed all the galectin features into binary features (e.g. by opposing 0–1 scores to 2–3 scores of the staining intensity); this binarization was made in accordance with the observed value distributions (see details in the Results). This transformation also enabled (i) the assumption underlying the use of the chi-squared test to be satisfied (i.e. the expected frequencies are not too small) for the comparison of three mice groups and (ii) the Fisher’s exact test to be used for comparing two mice groups (controls vs. treated). All the statistical analyses were carried out using statistica (Statsoft, Tulsa, OK, USA).

Ethical considerations

The animal experiments were approved by the Ethics Committee of the Faculty of Medicine and Health Sciences of Ghent University (Belgium).

Results

Expression of galectins-1, -3 and -4 in control mice

A graphical display of the significant differences in epithelial expression of galectins-1, -3 and -4 observed among the three mouse strains is presented in Figure 1. The significance levels detailed below concerned three-group comparisons carried out by means of chi-squared tests applied on contingency tables crossing the three mouse strains and the galectin features (after grouping their scores into two categories for statistical reasons).

Figure 1.

Figure 1

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Differences in expression of galectins-1, -3 and -4 in the epithelium of the three groups of control mice. Differences in distributions of immunohistochemical scores between the strains were detected with regard to galectin-1 in superficial epithelium (a), galectin-3 in crypt epithelium (b) and galectin-4 in superficial epithelium (c). The first distribution corresponds to C57BL/6, the second to BALB/c and the third to 129Sv/Ev mice.

Galectin-1

In contrast to the other strains, galectin-1 expression in the superficial epithelium of the colonic mucosa was lacking in the C57BL/6 mice (Figures 1a and 2a,b). However, the other strains showed cytoplasmic superficial epithelial galectin-1 expression in at least 70% of the samples analysed. These differences in superficial epithelial cell staining among the three strains were evidenced as statistically significant with regard to both number of cells stained (scores 0–1 vs. 2–3; P = 0.03) and intensity of staining (score 0 vs. 1; P = 0.0001). Similarly, all the C57BL/6 mice showed the lowest number of cells expressing galectin-1 (scores 0–1) in the lamina propria, whereas at least 80% of cases from the other two strains exhibited high numbers of galectin-1 expressing cells (scores 2–3). This inter-group difference was evidenced as highly significant (P = 0.0002). There were no differences with regard to the intensity of staining in the lamina propria. Crypt epithelial cells were negative for galectin-1 immunohistochemistry in the three strains.

Figure 2.

Figure 2

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Differences in galectin expression related to genetic background or inflammation. Lack of galectin-1 expression in superficial epithelium of C57BL/6 mice (a) in contrast to the other strains (b). Control BALB/c mice presented relatively low numbers of crypt epithelial cells expressing galectin-3, with some cells showing nuclear expression (arrows) (c). In acute colitis in the BALB/c strain, the number of crypt epithelial cells expressing galectin-3 was higher with, however, lower nuclear expression (d). In 129Sv/Ev control mice, crypt epithelium did not express galectin-4 (e); a majority of IL-10−/− showed galectin-4 expression in the crypts, with some positive nuclei (arrows) (f).

Galectin-3

All mice presented strong galectin-3 expression in both the cytoplasm and the nucleus of a large number of superficial epithelial cells without difference among the three strains.

In contrast, galectin-3 expression in crypt epithelial cells exhibited differences among the three strains, as illustrated in Figure 1b. In comparison with the other strains, a majority of 129Sv/Ev mice showed a lower number of crypt epithelial cells with galectin-3 expression (scores 0–1 vs. 2–3; P = 0.003); this was associated with a lower number of samples with nuclear expression (P = 0.00007). There was also a difference in galectin-3 expression with regard to the intensity of the staining at crypt epithelium level. This time, a relatively similar proportion of cases from the BALB/c and the 129 Sv/Ev strain (60% and 50% respectively) exhibited low intensity scores (scores 0–1) in contrast with the 100% of C57BL/6 cases showing score 2 (P = 0.01).

The lamina propria showed an intense galectin-3 staining in numerous cells in all tissue samples without differences among the strains.

Galectin-4

Although there were no significant differences with regard to the number of superficial epithelial cells expressing galectin-4, strong staining intensity (score 3) was observed in seven of the eight 129Sv/Ev mice (Figure 1c). This significantly differed with the large proportion of cases from the other two strains showing a lower intensity (scores 1–2; P = 0.00006). In addition, the number of samples in which nuclear staining equals cytoplasmic staining (score 2) was the greatest among the BALB/c mice and strongly differed (P = 0.00006) from the profiles of the other two strains (all cases with score 1 or 0, i.e. nuclear staining lower than cytoplasmic staining or lack of nuclear staining).

The crypt epithelium and the lamina propria of all mice were negative for galectin-4 immunohistochemistry.

In summary, our data show that C57BL/6 mice exhibited low galectins-1 and -4 expression together with high galectin-3 one. The two other strains showed more variations in galectin expression depending on the type of cells (superficial epithelium vs. crypt epithelium) and subcellular location (cytoplasm vs. nucleus).

Alterations in galectins-1, -3 and -4 expression in experimental colitis

A graphical display of examples of alterations of galectin expression in acute DSS colitis in C57BL/6 as well as in BALB/c mice and in chronic colitis in IL-10−/− mice is presented in Figure 3. Fisher’s exact test was used to evaluate the significance levels characterizing the proportion differences (of low vs. high scores) observed between the control and the treated groups in each strain.

Figure 3.

Figure 3

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Examples of variations in distributions of immunohistochemical scores for galectins-1, -3 and -4 because of acute DSS colitis in C57BL/6 (a) as well as BALB/C mice (b) and chronic colitis in IL10−/− mice (c). For each feature, the first distribution represents control mice, the second distribution mice with colitis.

Acute DSS colitis in C57BL/6 mice

Whereas 50% of control C57BL/6 mice presented relatively low numbers (scores 1–2) of crypt epithelial cells positive for galectin-3 immunohistochemistry, all mice with DSS colitis showed high numbers of positive cells (score 3; P = 0.03) (Figure 3a). Moreover, intensity of galectin-3 staining in these crypt cells was higher in 100% of the colitis group (score 2 vs. 3; P = 0.00001); the nuclear expression, however, was lower in 90% of colitis cases (P = 0.0001).

No alterations were detected with regard to galectin-3 expression in the superficial epithelium or with regard to galectin-1 expression in superficial or crypt epithelium.

Higher proportions of mice with acute colitis presented high numbers of galectin-3 (score 3) and galectin-1 (scores 2–3) expressing cells in the lamina propria (P = 0.00001 and 0.0001 respectively). However, in the case of galectin-1, more mice with colitis featured a low staining intensity (scores 0–1 vs. 2–3; P = 0.02). For galectin-3, the staining intensity in the lamina propria did not differ between control mice and mice with colitis. For galectin-4 expression, no alterations were found.

Acute DSS colitis in BALB/c mice

Compared with the C57BL/6 strain, induction of acute DSS colitis in BALB/c mice caused more variations in galectin expression (Figure 3b). All the BALB/c mice with DSS colitis showed absence of galectin-1 expression (score 0) in the superficial epithelium contrasting with the scores 1–3 exhibited by a majority of cases in the control group (P = 0.03 for number of positive cells; P = 0.003 for staining intensity). There was no difference with regard to galectin-1 expression in the crypt epithelium and both groups did not present any nuclear galectin-1 expression. Also, at the level of the lamina propria, there was no difference for galectin-1 expression between both groups.

Although the number of crypt epithelial cells expressing galectin-3 was equal in both groups, the intensity of galectin-3 immunoreactivity in the crypts was low (scores 0–1) in a majority of control mice, but enhanced (scores 2–3) in all mice with colitis (P = 0.01) with the loss of nuclear expression (P = 0.00001) (Figure 2c,d). No differences were found for galectin-3 expression in the superficial epithelium. With regard to the number of galectin-3 expressing cells in the lamina propria, all control mice had relatively low scores (scores 1–2) whereas all mice with colitis had maximal scores (P = 0.00001). The intensity of galectin-3 staining in the lamina propria was equal in both groups.

In the superficial epithelium, there was no difference with regard to cytoplasmic galectin-4 expression, but the number of cell nuclei expressing galectin-4 decreased in inflammation (score 1 for all mice) compared with the number (score 2) observed in a large majority of controls (P = 0.0007). Whereas in all the control mice, all crypt cells were negative for galectin-4 immunohistochemistry, four of the nine inflammation cases exhibited a focal, weak-to-moderate cytoplasmic galectin-4 expression in the crypts accompanied by some positive nuclei (P = 0.03 for the three features). Galectin-4 expression was absent in the lamina propria in all mice.

Chronic colitis in IL-10−/− mice

No alterations were observed in chronic colitis with regard to galectins-1 and -3 in contrast to the variations exhibited by galectin-4 expression (Figure 3c). Although in the control group, the crypt epithelium was negative for galectin-4 immunohistochemistry, a large majority of IL-10−/− mice showed galectin-4 expression in terms of a focal, weak to moderate cytoplasmic expression (P = 0.007 for both number of cells and staining intensity) together with some positive nuclei (P = 0.007) (as also illustrated in Figure 2e,f). With regard to galectin-4 expression in the superficial epithelium and in the lamina propria, no alterations were detected.

In summary, our results show that during acute DSS colitis, both mouse strains exhibited strong variations in galectin-3 expression including an epithelial cytoplasmic upregulation accompanied by a decrease in nuclear expression and an upregulation in the lamina propria. This contrasts with the results for chronic colitis in the IL-10−/− mice where only upregulated epithelial galectin-4 expression was detected.

Discussion

A growing body of evidence indicates that galectins exert important functions in the initiation, amplification or resolution of inflammatory processes (Liu 2000; Rabinovich et al. 2002a; Almkvist & Karlsson 2004; Rubinstein et al. 2004). This study aimed to characterize the expression of galectins-1, -3 and -4 in murine colitis. However, by analysing three mouse strains, we also detected differences in galectin expression related to the genetic background because they were observed between the non-inflammatory control groups.

Concerning galectin-1 at the epithelial level, protein expression was restricted to superficial cells, which is consistent with results obtained by others (Santucci et al. 2003); it was of relevance that this expression was, however, lacking in C57BL/6 mice. With regard to galectin-3, we found no difference among the three strains at the superficial epithelial level; in crypts, however, the number of cells showing cytoplasmic and/or nuclear galectin-3 expression was lower in the 129Sv/Ev strain than in the other strains. For galectin-4 in superficial epithelial cells, the highest nuclear expression was present in the BALB/c strain. These results suggest that genetic heterogeneity plays a role in the expression of galectins-1, -3 and -4. Thus, this needs to be accounted for when designing and interpreting experiments using mice and when studying in vivo models of alterations in galectin expression. Strain differences are not new in biological studies (Johnson et al. 2006; McLin et al. 2006; Ryman & Lamb 2006), but have never been described before with regard to galectin expression.

It is widely accepted that galectin-3 exerts important functions in inflammatory disorders (Liu 2000; Rabinovich et al. 2002a; Almkvist & Karlsson 2004; Rubinstein et al. 2004). In contrast to the downregulation of epithelial galectin-3 in human inflammatory bowel disease (IBD) (Muller et al. 2006), acute colitis in C57BL/6 as well as in BALB/c mice was associated with an upregulated galectin-3 expression at the level of the crypt epithelium as well as in the lamina propria. However, it must be stressed that although DSS colitis remains an important tool to study particular aspects of intestinal inflammation, it clearly differs from human IBD, including the initiating events as well as the clinical course of disease (Pizarro et al. 2003). Galectin-3 mainly behaves as a pro-inflammatory cytokine, as has been demonstrated by the attenuated inflammatory response in galectin-3 knock-out mice (Hsu et al. 2000). This lectin promotes chemotaxis of neutrophils and monocytes (Sano et al. 2000), and has been shown to activate various inflammatory cells, including neutrophils (Yamaoka et al. 1995), monocytes/macrophages (Liu et al. 1995) and lymphocytes (Dong & Hughes 1996; Hsu et al. 1996). Thus, increased galectin-3 expression in acute DSS colitis may be involved in the pathogenesis of the disorder, promoting the recruitment of inflammatory cells. Even if galectin-3 upregulation only represents an epiphenomenon resulting from an as yet unknown mechanism, it can be hypothesized that increased galectin-3 levels contribute to the perpetuation of the inflammatory process. It must be mentioned that the nuclear galectin-3 expression was lower in the acute DSS colitis in C57BL/6 as well as in BALB/c mice. As the nuclear expression of galectin-3 has been shown to be higher in the nuclei of differentiated colonocytes (Lotz et al. 1993), this might reflect the variation in colonic epithelial functional phenotype depending on the type and phase of experimental colitis (Mizoguchi et al. 2003). Moreover, studies with murine and human fibroblasts revealed that both phosphorylated and unphosphorylated galectin-3 are present in the nucleus, but only the phosphorylated one in the cytoplasm (Cowles et al. 1990). Phosphorylation is required for its anti-apoptotic effect (Yoshii et al. 2002); therefore, altered galectin-3 cytolocation with an increase in cytoplasmic and phosphorylated galectin-3 may be involved in preservation of the epithelium under inflammatory conditions.

In acute colitis in BALB/c mice and in IL-10−/− mice, an increased galectin-4 expression was observed in crypt epithelial cells, at cytoplasmic as well as nuclear level. Galectin-4 acts as a stimulator of mucosal CD4+ T cells and contributes to the exacerbation of intestinal inflammation by stimulating IL-6 production that enhances the survival of intestinal CD4+ T cells (Hokama et al. 2004). Acquired immune responses, dysregulated by enhanced IL-6 production, play a critical role in the development and perpetuation of T-cell-mediated chronic colitis, including colitis in IL-10−/− mice, as well as in chemically induced colitis such as DSS colitis (Atreya et al. 2000; Yamamoto et al. 2000; Suzuki et al. 2001; Mizoguchi et al. 2002; Hokama et al. 2004). Therefore, the upregulation of galectin-4 in the colitis models may be a mediator for the induction as well as the progression of the inflammation. Although hitherto no studies have focused on possible functions for galectin-4 in the nucleus, galectin-4 labelling associated with the cell nucleus, which was also observed in crypt cells under inflammatory circumstances, could suggest a possible involvement of galectin-4 in the nuclear events that might be more important during inflammation. However, it must be mentioned that we detected a downregulation of nuclear galectin-4 expression at the level of the superficial epithelial cells in DSS colitis induced in BALB/c mice.

The loss of superficial epithelial cell expression of galectin-1 in DSS colitis in BALB/c mice confirms previous results on galectin-1 expression in experimental colitis induced by intrarectal administration of 2,4,6-trinitrobenzene sulphonic acid in mice from the same strain (Santucci et al. 2003). It is hypothesized that this decrease in galectin-1 expression increases the resistance of lamina propria T cells against apoptosis (Santucci et al. 2003), which is in line with the reduced expression of galectin-1 in synovium from patients with juvenile idiopathic arthritis, characterized by defective T-cell apoptosis (Harjacek et al. 2001). We did not observe an accompanying decrease in galectin-1 expression in the lamina propria; the possible consequences of galectin alterations in the epithelium compared with the lamina propria are, however, unknown and remain to be investigated.

In summary, in this pilot study, we have shown that the expression of galectins-1, -3 and -4 varies with strain and type of experimental colitis in mice. Our results suggest an involvement of galectins in the development and perpetuation of colonic inflammation, and illustrate that the mouse strain, chosen for studies on galectins, may influence the outcome of the experiments.

Acknowledgments

The authors thank Audrey Verrellen, Alix Berton and Benoît Martin (Department of Pathology, Erasme University Hospital, Université libre de Bruxelles, Belgium) for excellent technical assistance. C. Decaestecker is a Senior Research Associate with the ‘Fonds National de la Recherche Scientifique’ (Belgium). This work was supported by the ‘Found Yvonne Boël’ (Brussels, Belgium).

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