Introduction
Inflammatory bowel disease (IBD), which encompasses ulcerative colitis
(UC) and Crohn’s disease (CD), comprises a group of intestinal chronic
disorders characterized by inflammation and periods of remission and
relapse[1]. The populations of western countries
are more likely to suffer from IBD than those in Asia. However, recent
studies have shown that the incidence and prevalence rates in some Asian
countries are rapidly increasing[2-4].
Numerous studies have indicated that genetic factors play important
roles in the pathogenesis of IBD, with involvement of some of these
genes in multiple autoimmune disorders. Leukocyte immunoglobulin like
receptors (LILRs ; synonyms: ILT, LIR, CD85) are the most
conserved genes among those located within the leukocyte receptor
cluster on human chromosome 19. The family includes 13 members with
activating or inhibiting capacity[5]: LILRs with
long cytoplasmic tails bearing tyrosine-based inhibitory motifs are
inhibitory receptors (LILRBs ), whereas LILRs with short
cytoplasmic tails have activating functions
(LILRAs )[6,7]. LILRA3 (ILT-6,
CD85e), located in the centromeric ILT cluster, is a special member of
the LILR family. Genomic sequencing of LILRA3 has revealed that LILRA3
is highly homologous to other LILRs such as LILRB1 and
LILRB2[8], suggesting that LILRA3 might act by
impairing the function of these LILRBs. In addition, LILRA3 shows
presence-absence variation, as opposed to other LILRs, which are
conserved genetically[9]. For example, some
individuals may carry an aberrant deletion of a 6.7-kb fragment
encompassing the first seven exons[8,10], and this
variation has been proven to be associated with many autoimmune
diseases, such as Sjögren’s syndrome (SS), multiple sclerosis (MS) and
rheumatoid arthritis (RA)[11-14].
rs103294 and rs410852 are two single-nucleotide polymorphisms (SNPs) of
the LILRA3 gene. In a case-control study among the Chinese population,
rs103294 was reported to be associated with benign prostatic
hyperplasia[15]. A genome-wide association study
(GWAS) also identified rs103294 as a new risk locus for prostate
cancer[16]. This GWAS also revealed that
polymorphism of this locus affects LILRA3 expression. Many recent
articles have demonstrated that the 6.7-kb deletion affects LILRA3 mRNA
and protein expression, with individuals carrying the wild type (+/+)
having much higher levels than those with the homozygous deletion
(-/-)[17-19]. Nonetheless, increased LILRA3 is
detected in many diseases, such as MS and systemic lupus erythematosus
(SLE)[18,19], both of which are autoimmune
disorders characterized by excessive inflammation. These findings
indicate that LILRA3 is a novel susceptibility gene for autoimmune
diseases and might play a crucial role in the pathogenesis of chronic
inflammatory diseases. Additionally, it has been reported that
interleukin 10 (IL-10 ) or interferon-γ (IFN-γ ) sharply
upregulates LILRA3 expression in human monocytes, whereas tumor necrosis
factor-α (TNF-α ) exhibits the opposite
effect[20]. Furthermore, LILRA3 induces
proliferation of CD8+ T-cells and NK cells in the
presence of pro-inflammatory cytokines[21],
suggesting an anti-inflammatory effect of LILRA3. Apart from
inflammation, LILRA3 is also reported to function as an antagonist of
LILRB2 and to promote synapse formation through the Erk/MEK
pathway[22].
Because IBD is an autoimmune disorder characterized by recurrent
intestinal inflammation, we hypothesized that LILRA3 might play a role
in IBD pathogenesis. Accordingly, in this study, we investigated the
interaction between LILRA3 polymorphisms and IBD development. Although
no significant association was found, we surprisingly observed increased
LILRA3 in IBD patients. LILRA3 is mainly expressed in mono-myeloid
cells, such as monocytes, macrophages (Mø) and dendritic cells
(DCs)[21,23-25]. Monocytes are critical regulators
in immune responses and have important roles in immune surveillance by
directly phagocytizing pathogens in
circulation[26]. Monocytes secrete many cytokines
such as IFN-γ, TNF-α, interleukin 6 (IL-6 ), and IL-10. As these
cells also exert many of their functions outside the vascular system,
crossing the blood vessel wall and migrating to the site of injury are
required[27]. The effects of LILRA3 on monocytes
have not been systematically reported. We employed the U937 human
monocyte cell line to establish LILRA3-overexpressing cells and then
explored the effects of LILRA3 on the above functions of monocytes as
well as other biological behaviors such as apoptosis and proliferation.