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.