Biochimica et Biophysica Acta 1572 (2002) 274 284

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Review
Role of galectins in inflammatory and immunomodulatory processes
Gabriel A. Rabinovich *, Natalia Rubinstein, Marta A. Toscano
Division de Immunogenetica, Hospital de Clnicas Jose de San Martn, Facultad de Medicina, Universidad de Buenos Aires,
Cordoba 2351, 3er Piso, CP 1120 Buenos Aires, Argentina
Received 2 April 2002; accepted 19 June 2002

Abstract

Galectins are members of a highly conserved family of h-galactoside-binding animal lectins. Presently, more than 14 members have been
identified and additional homologues are likely to be discovered. Given their conservation throughout animal evolution, it is not surprising
that they could play key roles in innate and adaptive immune responses, through sugar-dependent and -independent mechanisms. Recently, it
has become increasingly clear that galectins can differentially affect cellular activation and function. These biological effects attracted
attention of researchers in cell biology, biochemistry, glycobiology and immunology, not only in the mode of action of galectins, but also in
their role as putative modulators of immune surveillance, apoptosis, cell adhesion and chemotaxis. Here we will summarize the state-of-the-
art of the effects of galectins in inflammatory and immunomodulatory processes. In addition, we will discuss in-depth the current knowledge
about the effects of this enigmatic family of animal lectins and their glycoligands in the progression, diagnosis and treatment of different
pathological processes such as autoimmunity, allergy, infection and chronic inflammation.
D 2002 Elsevier Science B.V. All rights reserved.

Keywords: Galectin; Apoptosis; Inflammation; Immunomodulation; Autoimmunity

1. Galectins as master regulators of immune cell
homeostasis
1.1. A brief introduction
The redundancy of biological systems minimizes the
probability that isolated molecular and cellular defects entail
deleterious consequences. This notion also applies to immune
regulation, inflammation and the establishment of immuno-
logical tolerance and privilege. Thus, immune homeostasis is
attributed to multiple distinct safety valves that are intercon-
nected and intervene at defined checkpoints of the life cycle
of immunocytes to guarantee clonal expansion, activation,
generation of immunological memory and functional inacti-
vation of self-reactive potentially autoaggressive lympho-
cytes [1].
Recently, a growing family of animal lectins, called
galectins, has attracted the interest of cell biologists and im-
munologists as master regulators of immune cell homeostasis
*
Corresponding author. Tel.: +54-11-5950-8755/8756/8757; fax: +54-
11-5950-8758.
E-mail address: gabyrabi@ciudad.com.ar (G.A. Rabinovich).
[2 5]. According to their structure, these sugar-binding
proteins have been classified into proto-type, chimera-type
and tandem-repeat-type. They share sequence similarities in
the carbohydrate recognition domain (CRD), as well as
specificity for galactoside-containing saccharide ligands.
For further information on galectin structure and biochemis-
try, see related articles in this issue by Gabius et al. [6],
Kilpatrick [7] and Loris [8]. Fourteen mammalian galectins
have been identified to date in a wide variety of tissues from
different species [5,9]. Analysis of GenBank databases has
led to the identification of an additional number of galectin-
like proteins in mammals, invertebrates, nematodes, plants
and viruses, suggesting that these sugar-binding proteins are
highly conserved throughout animal evolution (see related
articles in this issue by Cooper [9] and Hirabayashi et al.
[10]). Another common feature of galectins is intriguing;
although they are found both in the cytoplasm and extracell-
ularly, none of them has a secretion signal peptide. Instead,
several galectins are secreted by an unorthodox mechanism to
exert their extracellular functions [2,3,11].
In the present review, we will summarize the state-of-the-
art regarding the effects of this enigmatic family of animal
lectins in inflammatory episodes and immunoregulatory
processes. Despite extensive sequence homology and similar

0304-4165/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 3 0 4 - 4 1 6 5 ( 0 2 ) 0 0 3 1 4 - 8
 G.A. Rabinovich et al. / Biochimica et Biophysica Acta 1572 (2002) 274284
carbohydrate specificity, various members of this protein
family behave as amplifiers of the inflammatory cascade,
while others activate homeostatic signals to dampen down
potentially damaging immune responses and inhibit the
spread of inflammation [3]. We will analyze how different
members of the galectin family influence biological pro-
cesses such as cell growth regulation, apoptosis, cell adhe-
sion, cytokine production and chemotaxis, contributing to the
generation of immune tolerance and homeostasis (Table 1).
Furthermore, we will highlight the consequences of these
effects in the pathogenesis and treatment of immunological
disorders.
1.2. Galectins and the generation of central tolerance:
modulation of thymocyte survival
A pivotal process during lymphoid development is the
education of immature lymphoid populations to discriminate
between self and non-self. In the case of the T-cell lineage,
potentially autoagressive immature thymocytes are deleted
within the thymus by negative selection [12]. During the last
decade, it was demonstrated that clonal deletion occurs by
the induction of apoptosis and that this process requires new
gene and protein synthesis. Although many aspects of
apoptosis in the immune system rely on Fas/Fas ligand
interactions, there is compelling evidence that this system
does not play any role during positive and negative selection
Table 1
Immunomodulatory effects of individual members of the galectin family
NA: Function non-assigned. Little is known about other members, such as galectin-2, which is expressed by tumor cells, galectins-4 and -6 by gastrointestinal
epithelium, galectin-5 by rat erythrocytes, galectin-10 and -14 by eosinophils, galectin-11 (GRIFIN) by lens of the eye and galectin-13 by human placenta.
275
in the thymus [12]. So far, three distinct pathways leading to
apoptosis of thymocytes have been identified [1,12]. The
first is dependent on expression of the tumor suppressor gene
p53, the second is induced by glucocorticoid treatment and
the later involves T-cell receptor (TCR) engagement [12].
In this complex scenario, galectin-1, a proto-type mem-
ber of the galectin family has been shown to induce
apoptosis of immature thymocytes [13]. The first evidence
suggesting that galectin-1 could regulate T-cell apoptosis
was the detection of 10-fold upregulation of its gene
expression in a human leukemia cell line during gluco-
corticoid-induced cell death [14]. Baum et al. [15] further
showed that human thymic epithelial cells express galec-
tin-1, which binds to core 2-O-glycans on immature
cortical thymocytes and modulates their survival at differ-
ent checkpoints of thymocyte maturation [13,15]. Galec-
tin-1 binding correlated with the activation state of the
cells, as immature cortical thymocytes bound more galec-
tin-1 than did mature medullar thymocytes [15]. In this
sense, changes in thymocyte cell surface glycosylation
have been proposed to take place at specific stages of
thymocyte maturation [16].
Although lactosamine is the minimal oligosaccharide
structure recognized by galectin-1, a number of glycopro-
teins with multiple and complex sugar structures are likely
the candidate receptors for galectin-1 (for further informa-
tion, see Brewer and Dam [17] in this issue). Many glyco-
276 G.A. Rabinovich et al. / Biochimica et Biophysica Acta 1572 (2002) 274284
ligands are likely to be discovered in the near future by using
different strategies such as combinatorial libraries, as dis-
cussed by Ramstrom and Lehn [18]. In fact CD45, CD43,
CD2, CD3 and CD7 have been reported to be primary T-cell
glycoproteins bound by galectin-1 [15,19 23]. In this sense,
it has been also demonstrated that alterations at the level of
CD45 surface expression affects the outcome of thymic
selection [24]. Perillo et al. [13] demonstrated that galec-
tin-1 killed two subsets of CD4lo CD8lo thymocytes, repre-
senting non-selected and negatively selected immature
thymocytes. Galectin-1-induced apoptosis was independent
of that induced by steroids, but was synergistic with TCR
engagement [13,25]. Similarly to galectin-1, galectin-9 has
also been shown to induce apoptosis of murine immature
thymocytes [26]. In both cases, the apoptotic effect was dose
dependent and carbohydrate specific. Transgenic or knock-
out mice will be necessary to address the specific role of each
galectin in the maturation and education of developing
thymocytes.
1.3. Galectins and the generation of peripheral tolerance:
modulation of cell proliferation and T-cell death outside the
thymus
T cells that failed intrathymic negative selection may be
involved in the pathogenesis of various autoimmune diseases
if they escape to the periphery. Here, the induction of
antigen-specific unresponsiveness, immune deviation and
elimination after repeated activation, comprise the back-up
mechanisms that contribute to the maintenance of self-
tolerance [1]. To maintain cellular homeostasis and to protect
activated mature T cells from the continued secretion of
potentially harmful amounts of cytokines, activated cells
must be removed through the induction of apoptosis
[7,27]. Although death in the periphery has been reported
to occur through Fas Fas ligand interactions, it has been
proposed that other molecules may play a role in the complex
gear of interactions involved in peripheral T-cell homeostasis
[27]. An overview of the role of galectins at different levels
of the central and peripheral immune responses is shown in
Fig. 1.
Galectin-1 showed specific growth inhibitory properties
toward different cell types, such as phytohemagglutinin
(PHA)-activated human T cells [28,29], concanavalin A
(Con A)-stimulated rat T cells [30], chicken activated
lymphocytes [31], human leukemia T cells [32] and other
cell types [33,34]. It has been demonstrated that following
an antigenic challenge, galectin-1 is secreted from activated
T cells and reduces clonal expansion of antigen-stimulated
CD8 + T cells and IL-2 production in an autocrine-depend-
ent manner [25,28,29,35]. Interestingly, it has been con-
firmed that the homeostatic regulation of CD8 + T cells after
an antigenic challenge may be regulated by mechanisms that
do not require Fas, as shown by T cells from normal or Fas-
deficient (lpr/lpr) mice, which were equally susceptible to
activation-induced cell death (AICD) [36].
Investigation of the molecular mechanisms involved in
cell growth regulatory properties revealed that galectin-1
induced apoptosis not only of immature thymocytes, but
also of activated peripheral T-cells [21,37,38]. CD45 was
the first glycoprotein demonstrated to be a galectin-1
receptor in peripheral lymphocytes [15,20,21]. Keeping in
mind that CD45R0 is expressed in immature thymocytes
and activated T cells, which are the main target cells for this
carbohydrate-binding protein, it was tempting to speculate
that galectin-1-induced apoptosis might be regulated at the
post-transcriptional and post-translational levels by the
generation of distinct CD45 glycoforms [39]. Nguyen et
al. [39] recently demonstrated that CD45 can positively or
negatively regulate galectin-1-induced T cell death, depend-
ing on the glycosylation status of the cells. Hence, CD45 +
T cell lines lacking the core 2 beta-1,6 N-acetylglucosami-
nyltransferase (C2GnT) are resistant to galectin-1 death.
This enzyme is responsible for creating branched structure
on O-glycans of T-cell surface glycoproteins such as CD45.
Recently, other counter-receptors were demonstrated to bind
galectin-1, examples being CD43, CD2, CD3, CD7 and the
ganglioside GM1 [19 23,40]. Galectin-1 binding to T cells
resulted in a dramatic redistribution of these glycoproteins
into segregated membrane microdomains [22]. Since CD7
appears to be critical for galectin-1-induced cell death, the
loss of CD7 in some autoimmune diseases and T-cell
lymphomas may allow survival of autoreactive or neoplastic
T cells [23,41].
It has been clearly demonstrated that under certain inflam-
matory conditions, activated macrophages [37,42], antigen-
stimulated T cells [28], activated B cells [43] and alloreactive
T cells [44] secrete high levels of galectin-1 to kill effector T
cells after the completion of an immune response. Inves-
tigation of the intracellular signals involved in galectin-1-
induced apoptosis revealed activation of the AP-1 transcrip-
tion factor, downregulation of Bcl-2, activation of caspases
and enhancement of extracellular signal regulated kinase-2
(ERK-2) activation [25,38,44]. Moreover, Chung et al. [45]
reported that this lectin antagonizes IL-2 production by
inducing partial TCR-~ chain phosphorylation.
An attractive finding is that galectin-1 is overexpressed in
immune privileged tissues, such as retina, placenta, testis and
ovary [4,5,46 48]. Because immune privilege tissues have
been identified by their ability to prohibit the spread of
inflammation to protect their integrity and function [4,5],
this h-galactoside-binding protein might contribute to
immune privilege mechanisms, ensuring the rapid elimina-
tion of inflammatory T-cells by a novel apoptotic pathway.
Interestingly, the primary structure of the recently identified
placental tissue specific protein 13 (PP13) was found to be
highly homologous to several members of the galectin family,
and so-called galectin-13 [49]. Moreover, galectin-11 (also
called GRIFIN for galectin related interfiber protein) was
found to be present in the lens of the eye, suggesting a role for
this protein in the maintenance of immune privilege in this
vulnerable tissue [50].
 G.A. Rabinovich et al. / Biochimica et Biophysica Acta 1572 (2002) 274284 277

Fig. 1. Role of galectins at central and peripheral levels of the adaptive immune response.

While galectin-1 inhibits cell growth and triggers apopto-
sis, galectin-3 (a 29-kDa member of the same family),
promotes cell proliferation and prevents T-cell apoptosis
[51]. In contrast to the extracellular signal triggered by
galectin-1, the anti-apoptotic activity of galectin-3 seems to
be an intracellular function of this carbohydrate-binding
protein. For further information of the intracellular functions
of this lectin, see Liu et al. [52] in this issue. Human leukemia
T cells transfected with galectin-3 cDNA showed higher rates
of proliferation and were protected against apoptosis induced
278 G.A. Rabinovich et al. / Biochimica et Biophysica Acta 1572 (2002) 274284
by several stimuli [51]. Proliferation of anti-CD3-stimulated
T cells was almost completely blocked after inhibition of
endogenous galectin-3 by an oligonucleotide antisense [53].
Galectin-3 not only rescued T-cells from apoptosis, but also
protected breast carcinoma cells from nitric oxide-induced
apoptosis and prevented death induced by the loss of cell
anchorage (anoikis) [54,55]. Investigation of the mechanisms
responsible for these effects revealed that galectin-3 acts by
preventing alterations of the mitochondrial membrane and
formation of reactive oxygen species [56]. Moreover, very
recent observations suggest that galectin-3 phosphorylation
regulates the anti-apoptotic activity of this molecule [57].
Furthermore, Inohara et al. [58] provided evidence for an
extracellular function of this protein, showing that exoge-
nously added galectin-3 stimulates DNA synthesis and
growth of fibroblasts.
So far, most research has focused attention on galectins-1
and -3. However, it has been demonstrated that galectin-7
increases susceptibility of keratinocytes to UVB-induced
apoptosis [59]. Moreover, galectin-8 has been shown to
modulate tumor survival by binding to h-integrins [60], and
galectin-12 has recently been reported to induce cell cycle
arrest and apoptosis [61]. These results suggest that different
members of the galectin family might interact in vivo to
positively or negatively modulate survival of different cell
types in a tissue-specific manner. If these results could be
demonstrated in vivo, it will be a challenge in the near
future to manipulate expression of individual members of
the galectin family for gaining therapeutic benefits.
1.4. b-Galactoside-binding proteins modulate cell cell and
cell matrix interactions
The multivalent properties of galectins make these h-
galactoside-binding proteins suited for cell adhesion func-
tions, including cell-to-cell and cell-to-extracellular matrix
(ECM) interactions. Galectin-1 and -3 showed pro-adhesive
or anti-adhesive properties, regulated by binding to saccha-
ride ligands on cell surface receptors and ECM glycopro-
teins, such as fibronectin and laminin [4,62].
We have demonstrated that galectin-1 inhibits IL-2-
induced T-cell adhesion to ECM glycoproteins in a dose-
and carbohydrate-dependent manner [63]. The anti-adhesive
effect, which involves reorganization of the activated cells
actin cytoskeleton, is accompanied by impaired secretion of
pro-inflammatory cytokines and is independent of the pro-
apoptotic effects of this protein [63]. Moreover, this lectin has
also shown pro- or anti-adhesive effects toward other cell
types such as myoblasts, melanocytes, teratocarcinoma cells,
olfactory neurons, rhabdomiosarcoma cells and fibroblasts
[62,64].
On the other hand, galectin-3 has been reported to promote
or inhibit cell cell and cell matrix interactions. In the
context of an innate immune response, galectin-3 promotes
adhesion of neutrophils to laminin [65]. Moreover, this
endogenous lectin facilitates antigen presentation by media-
ting dendritic cell interactions with nave lymphocytes at the
level of T-cell-dependent areas of lymph nodes, thus contri-
buting to the initiation of an adaptive immune response [66]
(Fig. 1). However, galectin-3 also showed anti-adhesive
properties under different physiopathological circumstances,
such as tumor cell binding to basal membrane and ECM [67].
Regarding other members of this lectin family, galectin-8
has been shown to form complexes with members of the
integrin family to modulate cell adhesion and extravasation
through ECM glycoproteins [60]. It should be stressed that
most of the pro- or anti-adhesive effects of the galectin
family of sugar-binding proteins have been demonstrated
during cancer progression and metastasis. For further infor-
mation of the role of galectins in tumor biology, see Danguy
et al. [68] in this issue. In addition, a pivotal role in cell
adhesion and trafficking has also been reported for other
lectins with different carbohydrate specificities, such as
selectins [69] and I-type lectins (syaloadhesins) as discussed
in this issue by Angata and Brinkman-van der Linden [70].
1.5. Galectins as novel chemoattractants
The migration of immune cells to sites of inflammation
requires mobilization of functional adhesion receptors and
the combination of proinflammatory signals in the forms of
cytokines and chemokines. Galectins also possess chemo-
tactic activity. While galectin-9 functions as a selective
eosinophil chemoattractant [71], galectin-3 provides chemo-
tactic signals to monocytes and macrophages [72]. Similarly
to chemokines, the chemotactic activity of galectin-3 is
abolished by pertussis toxin [72], suggesting the involve-
ment of G-proteins in this biological effect.
1.6. Galectins in innate immunity and acute inflammation
The inflammatory response involves the sequential
release of soluble mediators and the recruitment of circulat-
ing leukocytes, which become activated at the inflammatory
sites. This response is self-limiting and resolves through the
release of endogenous anti-inflammatory products and the
clearance of inflammatory cells. In addition to the role of
galectins in adaptive immune response, different members
of this family have been reported to play key roles in innate
immunity by modulating several steps of the inflammatory
cascade.
We have shown that galectin-1 ameliorates phospholi-
pase A2-induced edema in a selective and dose-dependent
manner, when pre-injected or co-injected together with the
enzyme [73]. Moreover, this lectin inhibits arachidonic acid
release and prostaglandin production from lipopolysacchar-
ide (LPS)-stimulated macrophages and blocks neutrophil
extravasation, mast cell degranulation and nitric oxide syn-
thesis [73].
In contrast, a growing body of experimental evidence
supports the role of galectin-3 as a pro-inflammatory medi-
ator. This lectin activates mast cells and basophils [74],
 G.A. Rabinovich et al. / Biochimica et Biophysica Acta 1572 (2002) 274284
stimulates superoxide production from neutrophils [75],
activates the NADPH oxidase [76], potentiates LPS-induced
IL-1 production from monocytes [77] and induces monocyte
chemotaxis [72]. Definitive evidence of the pro-inflamma-
tory role of galectin-3 was provided by in vivo studies using
galectin-3-deficient mice. Targeted mutation of the galectin-
3 gene resulted in less inflammatory cells following an
immunological challenge and reduced levels of cytokine-
induced NFkB activation [78,79]. Finally, expression of
different members of this protein family has been shown to
be modulated by several inflammatory agents, cytokines and
immunomodulators, such as PMA, FMLP, thioglicolate,
butiric acid, IL-1h, TNF-a and cyclophosphamide [42,43,
80 83], supporting the role of these endogenous animal
lectins during inflammatory episodes. A comprehensive
overview of the functions of individual members of the
galectin family is shown in Table 1.
In addition to galectins, a growing body of experimental
evidence supports a role for other sugar-binding proteins
such as collectins, ficollins and mannan-binding lectins in
vertebrate innate immunity, as described by Lu et al. [84]
and Kilpatrick [85] in this issue. On the other hand, a novel
family of lectins called tachylectins has been shown to play
a crucial role in invertebrate natural defenses (for further
information, see Kawabata [86] in this issue).
2. Galectins and immunopathology
2.1. Galectins in the pathogenesis and treatment of auto-
immune and chronic inflammatory disorders: cellular and
molecular mechanisms
Potentially autoaggressive clones will cause autoimmune
disease if only a series of dysfunctions, and not an isolated
defect, is disrupted [1]. In other words, lymphocytes that
express self-specific clonotipic receptors will mediate auto-
immune lesions if they either: (a) escape clonal deletion in
Table 2
Role of galectins in the modulation of experimental autoimmune and inflammatory disorders
Experimental model Animal and strain
Experimental autoimmune Lewis rats
encephalomyelitis (EAE)
Collagen-induced arthritis (CIA) DBA/1 mice
Experimental autoimmune New Zealand rabbits
myasthenia gravis (EAMG)
Experimental nephrotoxic nephritis by Wistar Kyoto rats
anti-basement membrane antibodies
Con A-induced hepatitis BALBc mice
Phospholipase A2-induced edema Wistar rats
Peritoneal inflammation in the C57BL/6 Galectin-3
absence of galectin-3 knock out mice
279
central organs; (b) do not receive any of the multiple anergy-
inducing or suppressive signals; (c) express the appropriate
combination of adhesion receptors that will allow for
migration to the target tissue containing the auto-antigen;
and (d) once activated, are not counterbalanced by immu-
nosuppression and activation-induced apoptosis [1,27]. The
redundancy of several homeostatic systems might explain
why autoimmune diseases are rarely acute, but follow a
chronic, slowly progressive inflammatory course. Galectin-
1 has been shown to be a powerful homeostatic signal,
probably by influencing all the described mechanisms:
central clonal deletion, cell adhesion, clonal suppression
and peripheral T-cell death.
The immunosuppressive and anti-inflammatory effects of
galectin-1 have been demonstrated in several experimental
models of autoimmunity and chronic inflammation (Table
2). Regarding T-cell-dependent autoimmune disorders, Off-
ner et al. [87] demonstrated that galectin-1 prevents clinical
and histopathological manifestations of autoimmune ence-
phalomyelitis (EAE), an experimental model of multiple
sclerosis in Lewis rats.
We have recently shown using gene and protein therapy
strategies that galectin-1 ameliorates the inflammatory and
autoimmune response in collagen-induced arthritis (CIA), an
experimental model of rheumatoid arthritis [35]. Immortal-
ized syngeneic embryonic fibroblasts were transfected with a
plasmid expressing galectin-1 from a CMV promoter. Per-
manently transfected cells were implanted intraperitoneally at
onset of CIA and the progression of the disease was moni-
tored and compared with the effect of daily injections of
recombinant galectin-1 [35]. Although both treatments ame-
liorated paw swelling, reduced the clinical score and blocked
the production of anti-collagen antibodies, the gene transfer
strategy was overall more protective to joint structure than
administration of the recombinant protein. Investigation of
the mechanisms involved in the anti-inflammatory effects of
galectin-1 revealed that this h-galactoside-binding protein
increases T-cell susceptibility in vivo to AICD [35]. This
Human correlate Galectin involved
Multiple sclerosis Galectin-1
Rheumatoid arthritis Galectin-1
(gene and protein
therapy strategies)
Myasthenia gravis 14-kDa electrolectin
(galectin-1-like)
Human nephritis Galectins 1, 3 and 9
(Goodpastures syndrome)
T-cell mediated Galectin-1
human liver disorders
Acute edema Galectin-1
Peritonitis or other acute Galectin-3
inflammatory responses
280 G.A. Rabinovich et al. / Biochimica et Biophysica Acta 1572 (2002) 274284
effect was antigen specific and required signalling via the
TCR. In addition to triggering apoptosis in activated T cells,
immunosuppression by galectin-1 can come about by pre-
venting synthesis and/or release of proinflammatory and Th1
cytokines [35,63]. Within the arthritogenic process, galectin-
1 treatment skewed the overall balance toward a Th2 profile
with reduction of the level of IFN-g and a clear increase in IL-
5 production [35]. In this regard, a relationship between
lectins and cytokines has been well established, and certain
cytokines have been also proposed to have carbohydrate-
binding properties, as described by Cebo et al. [88] in this
issue.
An inhibitory effect of galectin-1 has also been reported
on Con A-induced hepatitis, a T-cell dependent model of
liver injury in mice [89]. Galectin-1 pretreatment prevented
both liver injury and T-cell liver infiltration induced by Con
A. This immunosuppressive effect was also associated with
inhibition of TNF-a and IFN-g production [89].
In addition to the role of galectin-1 in T-cell dependent
autoimmune disorders, a h-galactoside-binding lectin puri-
fied from the fish electric eel prevented the development of
experimental autoimmune myasthenia gravis (EAMG) in
rabbits, a model of an antibody-mediated autoimmune
disorder [90]. Furthermore, galectins-1, -3 an -9 were also
tested for their ability to modulate the progression of
nephrotoxic nephritis induced by injection of antiglomerular
basement membrane serum in Wistar Kyoto rats [91].
Recently, in studying TCR-mediated responses in mice
deficient in N-acetyl-glucosaminyl-transferase V (Mgat5),
Demetriou et al. [92] have identified galectin-3 as one of the
endogenous lectins that possibly play a role in restricting
TCR complex recruitment to the site of antigen presentation.
The absence of the enzyme in Mgat-5 knock-out mice
resulted in enhanced delayed-type hypersensitivity (DTH)
responses and increased susceptibility to autoimmune dis-
orders [92]. The hypothesis proposed by the authors is that
galectin-3 forms multivalent lattice with glycoproteins of
the TCR and thereby restrains the lateral mobility of TCR
complexes. In Mgat-5-deficient mice, dysregulation of
galectin glycoproteins associations will increase TCR acti-
vation and the threshold of susceptibility to autoimmune
disease. However, one might also speculate that the absence
of this enzyme might render autoreactive T cells resistant to
the pro-apoptotic effect of galectin-1. Further experiments
using galectin knock-out mice will support the relevance of
the immunosuppressive and therapeutic effects.
Regarding human autoimmune disorders, we have
recently shown that defective mononuclear apoptosis in
synovial inflammatory infiltrates occurs with decreased
galectin-1 and increased galectin-3 expression [93]. More-
over, the presence of anti-galectin autoantibodies has been
described in several autoimmune, inflammatory and neuro-
logical disorders [94 96]. Whether these autoantibodies
could be reliable markers of progression or whether they
could play any role in the pathogenesis of autoimmune
disorders still remain to be investigated.
2.2. Galectins during allergic inflammation
Type-1 hypersensitivity reactions are triggered by allergen
cross-linking of preformed IgE antibody that is bound to Fcq
receptors on the surface of mast cells. Allergic reactions,
such as rhynitis, asthma and systemic anaphylaxis vary in
their severity and are associated with increased Th2 cytokine
production, eosinophilia and increased mast cell activation.
Galectin-3 was first reported as an IgE-binding protein (so
called qBP) able to interact with some IgE glycoforms [74].
Whilst galectin-1 promoted a shift toward a Th2-cytokine
profile, galectin-3 has been shown to block transcription of
the IL-5 gene from human eosinophils and allergen-specific
T cell lines [97,98]. This protein was able to interfere at the
level of the REIII site, a negative regulatory transcription
element [98]. At first sight, it seems contradictory that a pro-
inflammatory protein such as galectin-3 could silence an
allergic Th2-dependent inflammatory reaction by reducing
the levels of IL-5. However, it may be possible that galectin-
3 could act as a pro-inflammatory or anti-inflammatory
signal depending on the physiopathological situation (Th1
or Th2 responses), kinetic of the immune response, cell
activation status or the glycosylation state of counter-recep-
tors.
As mentioned before, galectin-9 is overexpressed in
peripheral blood mononuclear cells from allergic patients
and acts as a selective T-cell-derived eosinophil chemoat-
tractant [71]. Moreover, galectin-10 is selectively expressed
in eosinophils and basophils [99] and galectin-14 has been
recently found to be released from eosinophils in response to
an allergen challenge [100]. These observations suggest that
these family members might be also relevant in the context of
allergic episodes.
2.3. Galectins and microbial infection
The immunomodulatory properties of galectin-1 have
been recently studied in the context of a parasite infection.
Addition of increasing concentrations of galectin-1 induced a
biphasic modulation of parasite replication and cell survival
in macrophages isolated from Trypanosoma cruzi-infected
mice [101]. The same effect was observed when the J774
macrophage cell line was infected with living trypomasti-
gotes. While low concentrations of this protein increased
parasite replication and did not affect cell survival, high
inflammatory doses of galectin-1 promoted macrophage
apoptosis and decreased the number of intracellular amasti-
gotes and extracellular trypomastigotes [101]. Interestingly,
low concentrations of this sugar-binding protein were suffi-
cient to downregulate critical mediators for parasite killing
such as IL-12 and nitric oxide, while did not affect IL-10
production. Moreover, transcription of endogenous galectin-
1 gene was found to be upregulated after T. cruzi infection of
B cells and macrophages [43,101].
On the other hand, recent evidence indicates that galec-
tin-3 plays a key role in h2 integrin-independent neutrophil
 G.A. Rabinovich et al. / Biochimica et Biophysica Acta 1572 (2002) 274284
extravasation, which occurs during alveolar infection with
Streptococcus pneumoniae [102]. Moreover, this animal
lectin has been shown to specifically recognize bacterial
LPSs [103]. Finally, expression of this protein was modu-
lated after infection with the HTLV-1 retrovirus [104] or
transfection of the TAT protein of HIV-1 [105]. Further
experiments in vivo are required to validate a definitive role
for galectins during infectious processes.
3. Concluding remarks and future directions
In summary, we conclude that galectins play key roles in
immune cell homeostasis during innate and adaptive
immune responses by modulating T-cell apoptosis, prolifer-
ation, cell adhesion, chemotaxis and synthesis of inflamma-
tory mediators such as cytokines, nitric oxide and pros-
taglandins (a summary is shown in Table 1). The key
question that remains is how different galectins with similar
carbohydrate specificities might trigger opposite effects
toward the same cell types. The pre-clinical data on auto-
immune disease and inflammatory processes may mark the
beginning of a new era of therapeutic strategies, using en-
dogenous non-toxic sugar-binding proteins or their antag-
onists for the treatment of inflammatory and immunological
disorders.
Acknowledgements
We apologize that we could not cite many excellent
studies on galectins because of the limited space. We thank
Prof. Fu-Tong Liu for critical reading of the manuscript and
Drs. L. Fainboim, O. Podhajcer and J. Geffner for continuous
support.
Our work is supported by grants to G.A. Rabinovich from
Fundacion Sales for Science and Technology and Fundacion
Roemmers. G.A. Rabinovich is an associate research member
of the scientific career of CONICET. N.R and M.A.T. thank
CONICET, Fundacion Sales and CEDIQUIFA for the
fellowships granted.
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