Alternative titles; symbols
HGNC Approved Gene Symbol: IL10
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38) : 1:206,767,602-206,772,494 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.1 | {Graft-versus-host disease, protection against} | 614395 | 3 | |
| {HIV-1, susceptibility to} | 609423 | 3 | ||
| {Rheumatoid arthritis, progression of} | 180300 | 3 |
IL10 is a key antiinflammatory cytokine produced by activated immune cells. It plays a critical role in the control of immune responses (summary by Ip et al., 2017).
Immune responses are specific for both the antigen against which they are mounted and the class of response that is induced. For example, humoral (antibody-mediated) and delayed-type hypersensitivity (DTH) responses can be mutually exclusive. Tuberculoid leprosy is accompanied by a strong DTH response that ultimately kills and clears the bacilli, while in lepromatous leprosy, with weak cell-mediated immunity, the organisms multiply and the disease persists. In mice there is a cytokine synthesis inhibitory factor suggested by studies of helper T-cell clones that differ in their effector functions and cytokine secretion patterns. Vieira et al. (1991) demonstrated the existence of human cytokine synthesis inhibitory factor, which is also called interleukin-10. By study of cDNA clones encoding human IL10 isolated from a tetanus toxin-specific human T-cell clone, they found that, like mouse IL10, the human homolog exhibits strong DNA and amino acid sequence homology to an open reading frame in the Epstein-Barr virus.
Gesser et al. (1997) identified 2 functional domains of IL10 exerting different IL10-like activities, an observation that suggested that relatively small segments of these signal proteins are responsible for particular biologic functions.
Pinderski Oslund et al. (1999) found that IL10 blocks atherosclerotic events in vitro and in vivo. Terkeltaub (1999) suggested that IL10 may arrest and reverse the chronic inflammatory response in established atherosclerosis.
Franchimont et al. (1999) examined the ability of tumor necrosis factor-alpha (TNFA; 191160) and IL10 to differentially regulate the sensitivity of human monocytes/macrophages to glucocorticoids. Dexamethasone had different effects on lipopolysaccharide-induced TNFA and IL10 secretion; whereas it suppressed TNFA in a dose-dependent fashion, its effect on IL10 secretion was biphasic, producing stimulation at lower doses and inhibition at higher doses. The concentration of lipopolysaccharide employed influenced the effect of dexamethasone on IL10 secretion (P less than 0.001). Pretreatment with TNFA diminished, and with IL10 improved, the ability of dexamethasone to suppress IL6 (147620) secretion in whole-blood cell cultures (P less than 0.01 for both) and to enhance IL1 receptor antagonist (IL1RN; 147679) secretion by U937 cells (P less than 0.05 for both). TNFA decreased (P less than 0.001), while IL10 increased (P less than 0.001), the concentration of dexamethasone binding sites in these cells, with no discernible effect on their binding affinity. The authors concluded that glucocorticoids differentially modulate TNFA and IL10 secretion by human monocytes in a lipopolysaccharide dose-dependent fashion, and that the sensitivity of these cells to glucocorticoids is altered by TNFA or IL10 pretreatment; TNFA blocks their effects, whereas IL10 acts synergistically with glucocorticoids.
IL10 mediates its antiinflammatory effects independently of IL10R (see IL10RB, 123889) or its activation of PIK3 (PIK3CG, 601232) or the p70 S6 kinase (see 608938) (Crawley et al., 1996). Lee and Chau (2002) showed that IL10, but not IL6, induces expression of Hmox1 (141250) in mouse macrophages through the p38 MAP kinase (MAPK14; 600289), but not the ERK (176948) or JNK (601158), pathway. Western blot analysis showed that treatment with Hmox1 antisense or hemoglobin (HBG1; 142200), a carbon monoxide scavenger, attenuated the IL10-mediated suppression of lipopolysaccharide-induced TNFA, INOS (NOS2B; 600719), and MMP9 (120361) production, suggesting that carbon monoxide mediates the inhibitory effect of IL10 on inflammatory mediator production. Administration of IL10 to mice also induced Hmox1 and protected mice from lipopolysaccharide-induced septic shock. The protection was reversed in mice also receiving an Hmox1 inhibitor, zinc protoporphyrin IX. In these mice, protection was restored by carbon monoxide treatment.
Kitagawa et al. (2000) found that the Epstein-Barr virus (EBV)-encoded RNAs (EBERs) of EBV-positive Akata and Mutu Burkitt lymphoma (BL; 113970) cell lines activated higher levels of IL10 expression than EBV-negative cells and enabled growth of BL cells. RT-PCR analysis revealed that EBV-positive but not EBV-negative BL tumors expressed both EBERs and IL10, suggesting that BL cells use IL10 as an autocrine growth factor. IL10 enhanced the growth of EBV-negative cells in culture, but transfection of IL10 into such cells did not confer tumorigenicity in SCID mice. Kitagawa et al. (2000) proposed that RNA molecules can regulate cell growth.
Akbari et al. (2002) noted that Th1 cells secreting IFNG (147570) regulate Th2 cells and may be involved in downregulating Th2-driven airway hyperreactivity and asthma. However, IFNG may also contribute to the severity of disease by exacerbating pulmonary inflammation. After exposure of mice to allergen by the respiratory route, regulatory CD4 (186940)-positive T cells (Tr) developed, producing high levels of IL10, typically considered a Th2 cytokine. The Tr cells downmodulated allergen-induced airway hyperreactivity in previously sensitized mice. Both development and function of the Tr depend on the presence of IL10 and interaction with ICOS (604558) expressed on dendritic cells. These dendritic cells also express B7-1 (CD80; 112203) and B7-2 (CD86; 601020). Akbari et al. (2002) suggested that IL10 may initially be involved in the polarization of Th2 responses but plays a regulatory role late in immune responses to attenuate Th2-driven inflammatory activity.
Kemper et al. (2003) examined the requirements for activation of T-regulatory-1 (Tr1) cells, which are defined as CD4-positive T lymphocytes that secrete IL10 and suppress T-helper cells. Stimulation of purified CD4-positive T cells with monoclonal antibodies to CD3 (see 186740) and CD46 (120920) in the presence of IL2 (147680) or anti-CD28 (186760) induced the secretion of large amounts of IL10 and sustained proliferation, as measured by flow cytometric analysis for expression of PCNA (176740). CD45RA-positive/CD45RO-negative (naive) T cells and CD45RA-positive/CD45RO-positive (high-responding) T cells produced IL10 in response to these agonists, while CD45RA-negative/CD45RO-positive (memory) T cells did not. After primary anti-CD3/anti-CD46 activation, however, both naive and high-responding CD4-positive T cells acquired an IL10-producing memory phenotype (CD45RA-negative/CD45RO-positive). Stimulation of CD4-positive T cells with anti-CD3/anti-CD28 without anti-CD46 failed to induce IL10 production and caused the production of large amounts of IL2. Stimulation with anti-CD3/anti-CD28 in the presence of complement factor C3b (120700) dimers resulted in IL10 secretion comparable to that of anti-CD3/anti-CD28/anti-CD46-activated T cells. Supernatants of the anti-CD3/anti-CD46-activated T cells induced IL10-mediated suppression of proliferation by bystander T cells. Kemper et al. (2003) concluded that CD46 has a role in human T-cell regulation and that these findings establish a link between the complement system and adaptive immunity. They proposed that Tr1 cells are essential for maintaining peripheral tolerance and preventing autoimmunity, as well as for responses to many pathogens.
Esposito et al. (2003) tested the hypothesis that low serum IL10 concentrations associate with the metabolic syndrome (see 605552) in obese women. Compared with 50 matched nonobese women, the prevalence of the metabolic syndrome (3 or more of the following abnormalities: waist circumference greater than 88 cm; triglycerides greater than 1.69 mmol/liter; high density lipoprotein cholesterol less than 1.29 mmol/liter; blood pressure greater than 130/85 mm Hg; glucose greater than 6.1 mmol/liter) was higher in 50 obese women (52% vs 16%; P less than 0.01). As a group, obese women had higher circulating levels of IL6, C-reactive protein (123260), and IL10 than nonobese women. In both obese and nonobese women, IL10 levels were lower in those with than in women without the metabolic syndrome. These results showed that circulating levels of the antiinflammatory cytokine IL10 are elevated in obese women and that low IL10 levels are associated with the metabolic syndrome.
Ma et al. (2005) analyzed B-cell development in 14 patients with X-linked lymphoproliferative syndrome (XLP; 308240) and identified an extrinsic block in differentiation that was improved by the provision of exogenous IL10 or by ectopic expression of SH2D1A (300490), which increased IL10 production by T cells. Ma et al. (2005) suggested that insufficient IL10 production may contribute to hypogammaglobulinemia in XLP.
An increase of IL10 levels has been reported in the vitreous of patients with primary intraocular lymphoma (PIOL) (Chan et al., 1995), a disease with a poor prognosis that frequently masquerades as posterior uveitis. Diagnosis of PIOL is often made months or years after the initial onset of ocular symptoms. Cassoux et al. (2007) determined that IL10 measurements in the aqueous humor after an anterior chamber paracentesis is a good screening test that may reduce diagnostic delays.
Mazmanian et al. (2008) reported that the prominent human symbiont Bacteroides fragilis protects mice from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A). In animals harboring B. fragilis not expressing polysaccharide A, H. hepaticus colonization led to disease and proinflammatory cytokine production in colonic tissues. Purified polysaccharide A administered to animals was required to suppress proinflammatory Il17 (see 603149) production by intestinal immune cells and also inhibited in vitro reactions in cell cultures. Furthermore, polysaccharide A protected from inflammatory disease through a functional requirement for Il10-producing Cd4+ T cells. Mazmanian et al. (2008) concluded that molecules of the bacterial microbiota can mediate the critical balance between health and disease.
Dardalhon et al. (2008) showed that Il4 (147780) blocked the generation of Tgfb (190180)-induced Foxp3 (300292)-positive T-regulatory (Treg) cells in mice and instead induced a population of T-helper cells lacking Foxp3 and producing Il9 (146931) and Il10. These Il9-positive/Il10-positive T cells lacked regulatory activity. Adoptive transfer of Il9-positive/Il10-positive T cells into Rag1 (179615)-deficient mice resulted in colitis and peripheral neuritis. Dardalhon et al. (2008) proposed that, depending on the context in which IL10 is produced by T cells, that T cells can inhibit or promote inflammation and tissue destruction.
Nemeth et al. (2009) observed that bone marrow stromal cell (BMSC) treatment of septic mice reduced mortality and improved organ function, and that this beneficial effect was eliminated by macrophage depletion or pretreatment with IL10- or IL10R (see 146933)-specific antibodies. Monocytes and macrophages from BMSC-treated mice produced more IL10 than those from untreated mice, and lipopolysaccharide (LPS)-stimulated macrophages produced more IL10 when cultured with BMSCs. Increased IL10 production was eliminated if BMSCs lacked the genes encoding TLR4 (603030), MYD88 (602170), TNFR1A (see 191190), or COX2 (600262). The authors suggested that BMSCs, activated by LPS or TNFA, reprogram macrophages by releasing prostaglandin E2, which acts on macrophages through the EP2 (PTGER2; 176804) and EP4 (PTGER4; 601586) receptors. In turn, these macrophages produce large amounts of IL10, an antiinflammatory cytokine that decreases levels of circulating TNFA and IL6, thus reducing harm caused to host tissues by unbridled immune responses.
Using flow cytometric analysis, Said et al. (2010) found that expression of PD1 (600244) was upregulated on CD16 (146740)-positive and CD16-negative monocytes, but not on dendritic cells, in viremic human immunodeficiency virus (HIV; see 609423)-positive patients, but not in highly active antiretroviral therapy (HAART)-treated HIV-positive patients. PD1 upregulation in monocytes was induced by microbial TLR ligands and inflammatory cytokines. In HIV-positive patients, PD1 expression on CD16-positive or CD16-negative monocytes correlated with blood IL10 concentrations. Furthermore, triggering of PD1 by PDL1 (PDCD1LG1; 605402), but not by PDL2 (PDCD1LG2; 605723), induced monocyte IL10 production. PD1 triggering inhibited CD4-positive T-cell responses. IL10 stimulation increased STAT3 (102582) phosphorylation in CD4-positive T cells, and both CD4-positive and CD8 (see 186910)-positive T lymphocytes showed increased PD1 expression in viremic HIV patients. Said et al. (2010) proposed that both IL10-IL10R and PD1-PDL1 interactions need to be blocked to restore the immune response during HIV infection.
Using RT-PCR and immunohistochemistry, Teles et al. (2013) demonstrated increased expression of the type I interferon IFNB (IFNB1; 147640) in lesions of lepromatous leprosy (i.e., multibacillary, or L-lep) patients compared with tuberculoid leprosy (i.e., paucibacillary, or T-lep) patients (see 609888). Expression of an IFNB receptor, IFNAR1 (107450), was also increased in L-lep lesions. Increased expression of IFNB was associated with increased expression of IL10, and IFNB alone induced IL10 expression in mononuclear cells in vitro. There was an inverse correlation between IL10 expression and expression of the antimicrobial peptides CAMP (600474) and DEFB4 (DEFB4A; 602215). Measurement of uncultivable Mycobacterium leprae viability based on the ratio of M. leprae 16S rRNA to M. leprae repetitive element DNA indicated that IFNG induced antimicrobial activity against M. leprae in monocytes by about 35%, which was abrogated by the addition of either IFNB or IL10. Teles et al. (2013) concluded that the type I interferon gene expression program prominently expressed in L-lep lesions inhibits the IFNG-induced antimicrobial response against M. leprae through an intermediary, IL10.
In mice, Olszak et al. (2014) showed that while bone marrow-derived Cd1d (188410) signals contribute to natural killer T (NKT) cell-mediated intestinal inflammation, engagement of epithelial Cd1d elicits protective effects through the activation of Stat3 and Stat3-dependent transcription of Il10, Hsp110 (610703), and Cd1d itself. All of these epithelial elements are critically involved in controlling CD1D-mediated intestinal inflammation. This was demonstrated by severe NKT cell-mediated colitis upon intestinal epithelial cell-specific deletion of IL10, CD1D, and its critical regulator microsomal triglyceride transfer protein (MTP; 157147), as well as deletion of HSP110 in the radioresistant compartment. Olszak et al. (2014) concluded that these studies uncovered a novel pathway of intestinal epithelial cell-dependent regulation of mucosal homeostasis as well as highlighted a critical role for IL10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
Tanaka et al. (2018) showed that conditional knockout of Trim33 (605769) in T cells of mice resulted in decreased Il17 and Ccr6 (601835) expression, but enhanced Il10 production, leading to protection against experimental autoimmune encephalitis (EAE). Further examination revealed that Trim33 played a crucial role in differentiation of Th17 cells, but not inducible Treg cells. Microarray and real-time RT-PCR analyses confirmed downregulation of Il17 and Ccr6 and upregulation of Il10 in the absence of Trim33. Il17 and Ccr6 downregulation was not due to enhanced Il10 expression, as Il10 blockade did not restore Il17 and Ccr6 expression in Trim33-knockout T cells. Genomewide analysis of Trim33-bound genes showed that Il17 and Il10 were collaboratively regulated by Trim33 and Ror-gamma (RORC; 602943) at the transcriptional level. Trim33 controlled Il17 and Il10 expression at the chromatin level through regulation of histone modifications. Smad2 (601366) was crucial for binding of Trim33 to Il17 and Il10 loci, and the Trim33/Smad2/Ror-gamma complex was necessary for optimal expression of Il17 and repression of Il10 in Th17 cells. Moreover, enhanced expression of Il10 in Trim33-knockout T cells was almost completely suppressed by deletion of Smad4 (600993), indicating that Trim33 suppresses Il10 expression by reduction of Smad4 protein in T cells. The authors concluded that TRIM33 promotes the proinflammatory function of Th17 cells by inducing IL17 and suppressing IL10 expression.
By comparing lipid profiles, York et al. (2024) found that Il10 functioned downstream of Tlr2 (603028) activation to regulate sphingolipid metabolism in mouse bone marrow-derived macrophages (BMDMs). Il10 knockout in macrophages and in mice showed that accumulation of saturated very long chain (VLC) ceramides enhanced cytokine and chemokine gene expression in TLR-activated macrophages, suggesting that dysregulation of VLC ceramide homeostasis contributes to exacerbated inflammation in IL10 deficiency. Accordingly, knockout of CERS2 (606920), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression program associated with IL10 deficiency in macrophages in vitro and in mice in vivo. Monounsaturated fatty acid (MUFAs) content was altered in Il10-deficient BMDMs, and altered MUFA synthesis limited ceramide production and affected the associated inflammation, because accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo MUFA synthesis pathway. Further analysis demonstrated that VLC ceramides did not activate the inflammasome to enhance inflammation. Instead, persistent inflammation mediated by VLC ceramides was largely dependent on sustained activity of REL (164910), an immunomodulatory transcription factor.
Kim et al. (1992) showed that the mouse Il10 gene contains 5 exons and spans about 5.2 kb of genomic DNA.
Kim et al. (1992) mapped the IL10 gene to mouse chromosome 1 by interspecific backcross analysis and to human chromosome 1 by PCR analysis of DNAs from a panel of hamster-human somatic cell hybrids.
Eskdale et al. (1997) mapped the IL10 gene to the junction between 1q31 and 1q32. For this they used 2 dinucleotide repeats that lie in the 5-prime flanking region of the IL10 gene to analyze its position on the Whitehead Institute Radiation Hybrid map of human chromosome 1. (The theory of radiation hybrid mapping was reviewed by Cox et al. (1990). The human genome is fragmented by irradiation, with the degree of fragmentation being dependent on the radiation dose. Chromosomal fragments are then randomly inserted into hamster cell lines where they often become integrated into the hamster genome, thereby creating radiation hybrids. Examining a panel of such hybrids by PCR generates a pattern of positive and negative hybrid clones. The distance between test markers and known standards is given in centi-Rays (cR).)
Stimulation of human blood cultures with bacterial lipopolysaccharide (LPS) showed large interindividual variation in IL10 secretion, which has been shown to have a genetic component of over 70% (Westendorp et al., 1997). Eskdale et al. (1998) undertook to determine the extent to which the structure of the IL10 promoter contributed to the genetic variation in LPS-induced secretion of IL10. Turner et al. (1997) had demonstrated a difference in IL10 secretion, in association with the presence or absence of an 'A' at position -1082 of the human IL10 promoter, following concanavalin-A stimulation of peripheral blood mononuclear cells. Eskdale et al. (1998) defined alleles at 2 microsatellite loci in the 4 kb immediately upstream of the human IL10 transcription initiation site in 132 individuals from 56 Dutch families and assigned the alleles as haplotypes. LPS-induced IL10 secretion was measured by ELISA and related to the IL10 promoter haplotypes present in 78 unrelated individuals from these families. Analysis showed that LPS-induced IL10 secretion from unrelated individuals varied with IL10 promoter haplotypes (P = 0.024). Those haplotypes containing the allele IL10.R3 were associated with lower IL10 secretion than haplotypes containing any other IL10.R allele; the haplotype IL10.R2/IL10.G14 was associated with highest IL10 secretion overall, whereas the haplotype IL10.R3/IL10.G7 was associated with lowest IL10 secretion. Monocytes are the main source of IL10, although many cell types can be stimulated to IL10 secretion. The results indicate that genetic heterogeneity not only controls whether antigen responsiveness occurs (via the major histocompatibility complex) but also, through cytokines and their receptors, the extent and direction in which that response may develop once antigen recognition has occurred.
Grove et al. (2000) examined the potential role for polymorphism in the IL10 gene in the pathogenesis of alcoholic liver disease. The allele frequencies for 2 single basepair substitutions at positions -627(C to A) and -1117(A to G) in the IL10 promoter region were determined in 287 heavy alcohol drinkers with biopsy-proven advanced liver disease, 107 heavy drinkers with no evidence of liver disease, and 227 healthy volunteers. Fifty percent of patients with alcoholic liver disease possessed the A allele at position -627, compared with 33% of normal individuals (p less than 0.0001) and 34% of drinkers with no or mild disease (p = 0.017). No significant difference in allele frequencies was noted at position -1117. The authors concluded that the -627A allele is associated with an increased risk of advanced liver disease in alcohol abusers. This appeared to be consistent with reports elsewhere that the -627A allele is associated with low levels of IL10 expression, a situation which favors inflammatory, immune-mediated, and profibrotic mechanisms of tissue injury.
High IL10 production is associated with autoimmune diseases such as rheumatoid arthritis (180300) and systemic lupus erythematosus (SLE; 152700). In addition, IL10 production levels are concordant in monozygotic twins (Westendorp et al., 1997). The IL10 promoter is polymorphic and may account for different levels of cytokine production. Gibson et al. (2001) identified 7 novel SNPs in the distal region of the IL10 promoter and found that certain haplotypes are significantly associated with high or low IL10 production and with SLE in African Americans.
Using short tandem repeat polymorphism (i.e., microsatellite) analysis, Shin et al. (2000) identified significant genotype associations for human immunodeficiency virus-1 (HIV-1) infection and progression to acquired immunodeficiency syndrome (AIDS) (see 609423) with markers adjacent to and tracking common single nucleotide polymorphic variants in the IL10 promoter region. Individuals carrying the 5-prime -592A promoter allele (124092.0001) were at increased risk for HIV-1 infection, and once infected they progressed to AIDS more rapidly than homozygotes for the alternative -592C/C genotype. Approximately 25 to 30% of long-term nonprogressors (i.e., those who avoid clinical AIDS for 10 or more years after HIV-1 infection) carried the -592C/C promoter genotype. Additional protection or susceptibility was associated with the relevant CCR5 (601373.0001) and CCR2 (601267.0001) alleles. EMSA analysis indicated that the -592A allele, but not the 592C/C allele, retains a binding site for ETS (see 164720) family DNA-binding proteins, whereas both alleles interact with SP1 (189906). Shin et al. (2000) noted studies (e.g., Rosenwasser and Borish (1997)) that showed that the -592A allele is associated with diminished IL10 production. They suggested that progression to AIDS might be retarded by immunotherapeutic strategies mimicking or enhancing the natural inhibitory role of IL10.
After organ transplantation, susceptibility to cancer is multifactorial, especially for skin carcinomas. Risk factors may include genetic susceptibilities, such as the control of cytokine production. IL10 is a cytokine that is implicated in tumorigenesis, and polymorphisms in its gene promoter correlate with differential amounts of production. Alamartine et al. (2003) investigated a possible association between IL10 gene promoter polymorphisms and the occurrence of skin carcinomas after renal transplantation. Seventy kidney transplant recipients who developed a squamous cell carcinoma or a basal cell carcinoma were examined for polymorphisms in the IL10 gene promoter using PCR-based methods. Single-basepair mutations were studied at positions -1082, -819, and -592 (124092.0001). These patients were compared to 70 healthy controls and to 70 matched renal transplant recipients without cancer. The IL10 secretion capability was tested in a subgroup of 40 of these patients by in vitro stimulation of peripheral mononuclear cells. IL10 genotypes and haplotypes were differently distributed in kidney transplant recipients who developed a skin carcinoma, but especially a squamous cell carcinoma, with an increased frequency of the GCC haplotype and a decreased frequency of the ATA haplotype. Alamartine et al. (2003) found a shift in the predicted phenotypes from the low production phenotype to the high production phenotype. Secretion of IL10 was strongly correlated to the production predicted phenotype, and tended to be higher in patients who developed a squamous cell carcinoma than in the others. These results indicated that IL10 gene polymorphisms and IL10 production capability may contribute to the development of skin squamous cell carcinomas after renal transplantation.
IL10 is thought to play a key role in psoriasis (see 177900). Its highly polymorphic promoter contains 2 informative microsatellites, IL10.G and IL10.R. Asadullah et al. (2001) analyzed IL10 promoter polymorphisms in 78 patients and 80 healthy controls. The distribution of IL10.G and IL10.R microsatellite alleles did not vary between patients and controls. In addition, when the psoriasis patients were stratified according to age of onset (younger than 40, or 40 and older), no difference in allele distribution was observed; however, a clear differential distribution was revealed at the IL10.G locus when patients were stratified according to whether they had a positive family history of psoriasis (p = 0.04). This difference was due to an overrepresentation of the IL10.G13 allele in those patients with familial disease (40.4% vs 19.6%, chi square = 7.292, p = 0.007). The positive association of allele IL10.G13 with familial psoriasis was especially strong when patients with early onset were compared with those with early onset against a nonfamilial background (39.6% vs 14.5%, chi square = 8.959, p = 0.003). Patients with age of onset of less than 40 were 4-fold more likely to have a psoriatic family background if they carried the IL10.G13 allele. These data suggested that the IL10 locus contributes to the heritability of psoriasis susceptibility.
By means of genetic association analysis, Shin et al. (2003) showed that the IL10 haplotype IL10-ht2 was strongly associated with hepatocellular carcinoma (HCC; 114550) in a well-characterized hepatitis B virus (HBV; see 610424) cohort. The frequency of susceptible IL10-ht2 was much higher in HCC patients and significantly increased in order of susceptibility to HBV progression from chronic hepatitis to liver cirrhosis and HCC among hepatitis B patients. In addition, survival analysis clearly showed that the onset age of HCC was also accelerated among chronic hepatitis B patients who were carrying IL10-ht2. Shin et al. (2003) suggested that increased IL10 production mediated by IL10-ht2 accelerates progression of chronic HBV infection, especially to HCC development.
Summers et al. (2000) hypothesized that higher or lower production of IL10 could affect the production of inflammatory cytokines associated with SIDS (272120). The IL10 promoter SNPs -1082A, -819T, and -592A define the low IL10 producer haplotype, or ATA. Summers et al. (2000) found that the ATA haplotype, and specifically the -592A allele, were significantly more frequent in a group of 23 SIDS cases compared with controls. There was no association between SIDS and a TNF (191160) promoter polymorphism or a TGFB1 (190180) coding region polymorphism. Summers et al. (2000) noted that the -592 allele is associated with IL10 production by monocytes and macrophages. They proposed that a deficit in IL10 may contribute to SIDS either by a tardy initiation of protective antibody production or by a lower capacity to inhibit inflammatory cytokine production.
In a larger study than that of Summers et al. (2000), Opdal et al. (2003) found that the ATA haplotype of IL10 was associated with sudden unexpected infant death due to infection. However, they found no association between the SNPs that define the ATA haplotype and SIDS.
Centenarians escape, or at least delay, age-associated diseases that normally cause mortality at earlier ages. Considerable evidence supports involvement of genetic components to longevity (152430). The major trait of the offspring of centenarians is a significantly reduced prevalence of cardiovascular diseases. Patients with atherosclerosis have a proinflammatory genotype. Gene polymorphisms for proinflammatory cytokines seem to contribute significantly to the risk of coronary heart disease. In 2 different populations from north and south Italy, Lio et al. (2004) found a significantly higher frequency of the IL10 -1082G/G genotype (which is associated with increased production of IL10) among oldest old participants than in controls and patients with acute myocardial infarction. Conversely, the frequency of the -1082A/A genotype, associated with low production of IL10, was significantly higher in patients with acute myocardial infarction than in controls and oldest old participants. Thus, high production of IL10 was protective for acute myocardial infarction and a determinative parameter for longevity. A genetic background protective against cardiovascular disease appeared to be a component of longevity. Lio et al. (2004) reasoned that since the human immune system evolved to control pathogens, proinflammatory responses were likely to be programmed by evolution to resist fatal infections; they also noted that low production of interleukin-10 is associated with an increased resistance to pathogens. Increased concentration of interleukin-10, however, might better control inflammatory responses induced by chronic vessel damage and reduce the risk of atherogenic complications. Lio et al. (2004) concluded that these conditions might result in an increased chance of long life in an environment with a reduced load of antigens (i.e., pathogens).
In a case-control study of 304 Australian patients with Crohn disease (see IBD23, 612381) and 231 healthy controls, Fowler et al. (2005) found a significant association of the higher-producing IL10 -1082G and TNF-alpha -857C alleles with stricturing disease. The association was strongest when these alleles were combined and persisted after multivariate analysis.
IL10 promoter SNPs were defined as markers for leprosy susceptibility (see 246300) and severity in a Brazilian population by Moraes et al. (2004) and in an Indian population by Malhotra et al. (2005).
As a follow-up to their studies examining TNF levels in response to M. tuberculosis culture filtrate antigen as an intermediate phenotype model for tuberculosis (TB) susceptibility in a Ugandan population (see 607948), Stein et al. (2007) studied genes related to TNF regulation by positional candidate linkage followed by family-based SNP association analysis. They found that the IL10, IFNGR1 (107470), and TNFR1 (191190) genes were linked and associated to both TB and TNF. These associations were with active TB rather than susceptibility to latent infection.
Using multivariate logistic regression and multiplex cytokine analysis, Ouma et al. (2008) determined that the -1082G/-819C/-592C (GCC) IL10 promoter haplotype was associated with increased IL10 production and with protection from severe malaria anemia (SMA; see 611162) in parasitemic children in Kisumu, Kenya. Individuals having the -1082A/-819T/-592A (ATA) promoter haplotype had increased susceptibility to SMA and reduced circulating IL10 levels. The ratio of IL10 to TNF was higher in GCC and lower in ATA individuals, while the ratio of IL10 to IL12 (see 161560) was higher in ATA children. Ouma et al. (2008) concluded that common IL10 promoter haplotypes influence susceptibility to SMA and functional changes in circulating IL10, TNF, and IL12 levels in children with falciparum malaria.
Trachoma, an infectious disease of the conjunctiva caused by Chlamydia trachomatosis, causes scarring and blindness in some infected individuals but not others. Natividad et al. (2008) noted that a particular IL10 haplotype (H-RISK) consisting of 3 SNPs in the promoter (-3575T-A, -1082T-C , and -592T-G) and 1 SNP in the 3-prime UTR (5009A-G) is associated with increased risk of scarring trachoma in Gambians. Using allele-specific transcript quantification, Natividad et al. (2008) found that there was allelic variation in cis regulation of IL10 in the conjunctiva during active trachoma in a Gambian population, with individuals with H-RISK generating more IL10 transcripts than those with other haplotypes. Natividad et al. (2008) concluded that their findings provide a functional explanation for the genetic association of H-RISK with scarring trachoma and suggested that an excess IL10 response to Chlamydia trachomatis infection is a risk factor for scarring and blindness.
Keratinocytes have been demonstrated to be suitable target cells for gene therapy. Keratinocyte gene therapy may be appropriate for treating diseases caused by genetic defects that result in keratinocytes with abnormal proteins. Keratinocytes are relatively easy to obtain and can easily be monitored by the expression of transgenes. Keratinocytes can be used as bioreactors releasing the transgenic protein into the circulation, and the endocrine and systemic effects of the protein required for therapy can be monitored. IL10 plays a major role in suppressing immune and inflammatory responses by inhibiting the production of proinflammatory cytokines. Meng et al. (1998) examined the systemic effects of IL10 released from transduced keratinocytes. An expression vector was constructed for human IL10 and was injected into the dorsal skin of hairless rats. Local expression of IL10 mRNA and protein was detected by RT-PCR and immunohistochemical staining, respectively. Enzyme-linked immunosorbent assay showed that the amount of IL10 in the local keratinocytes and in the circulation increased with the dose of vector transferred. To determine whether circulating IL10 could inhibit the effector phase of contact hypersensitivity at a distant area of the skin, various doses of the vector were injected into the dorsal skin of sensitized rats before challenge on the ears. The results showed that the degree of swelling of the ears of treated rats was significantly lower than that in the negative control animals. These results suggested that the IL10 released from transduced keratinocytes can enter the bloodstream and cause biologic effects at distant areas of the skin. It may therefore be possible to treat systemic disease such as hemophilia B by use of keratinocyte gene therapy.
Targeted mutations in a variety of mouse genes produce colitis. Mice homozygous for a disrupted interleukin-10 gene (Kuhn et al., 1993) supported the hypothesis that a dysregulated immune response to enteric flora can trigger inflammatory bowel disease (see 266600). The severity of the colitis depends on the inbred strain background in which the disrupted gene is placed. Colitic lesions are much more severe in C3H mice than in B6 mice. Farmer et al. (2001) identified modifiers of cytokine deficiency-induced colitis susceptibility (Cdcs) by using quantitative trait locus (QTL) analysis. A major C3H-derived colitogenic QTL on mouse chromosome 3 contributed to lesions in both cecum and colon, as well as colitis-related phenotypes such as spleen/body weight ratio, mesenteric lymph node/body weight ratio, and secretory IgA levels. Evidence for other C3H QTLs on chromosomes 1 and 2 was obtained. The resistant B6 background also contributed colitogenic QTLs.
Treatment with the immunoregulatory cytokines IL4 (147780) or IL10 can inhibit the development of type I diabetes mellitus (see 222100) in nonobese diabetic (NOD) mice, a model of the human disease. Such treatment can also inhibit the recurrence of disease, whether alloimmune and/or autoimmune, in mice receiving islet transplants. Goudy et al. (2001) tested the feasibility of muscle-directed gene therapy to prevent autoimmune diabetes in NOD mice. They developed recombinant adeno-associated virus (rAAV) vectors containing murine cDNAs for immunomodulatory cytokines IL4 or IL10. Skeletal muscle transduction of female NOD mice with IL10, but not IL4, completely abrogated diabetes. Recombinant AAV-IL10 transduction attenuated the production of insulin autoantibodies, quantitatively reduced pancreatic insulitis, maintained islet insulin content, and altered splenocyte cytokine responses to mitogenic stimulation. These results indicated the utility for rAAV, a vector with advantages for therapeutic gene delivery, to transfer immunoregulatory cytokines capable of preventing type I diabetes. In addition, these studies provided foundational support for the concept of using immunoregulatory agents delivered by rAAV to modulate a variety of disorders associated with deleterious immune responses, including allergic reactions, transplantation rejection, immunodeficiencies, and autoimmune disorders.
Lee et al. (2002) generated transgenic mice overexpressing Il10 in lung. In these mice, Il10 inhibited Tnf production and neutrophil accumulation, induced mucus metaplasia, B- and T-cell-rich inflammation, and subepithelial fibrosis, and augmented expression of Gob5 (CLCA1; 603906), mucins (see 158371), and Il13 (147683) mRNA. In mice lacking Il13, Il4ra (IL4R; 147781), or Stat6 (601512), transgenic Il10 induced inflammation and fibrosis, but not mucus metaplasia. Lee et al. (2002) concluded that IL10 induces airway remodeling accompanied by mucus metaplasia and tissue inflammation through multiple IL13-dependent and -independent mechanisms.
Using semiquantitative RT-PCR analysis, Singh et al. (2003) detected increased expression of Ip10 (147310) and its receptor, Cxcr3 (300574), in mesenteric lymph nodes and inflamed colons of Il10 -/- mice. The Crohn disease-like colitis in Il10 -/- mice was associated with increased serum amyloid A (SAA; 104750), Il6, and Th1 cytokine levels and weight loss, all of which could be abrogated by anti-Ip10 treatment. Singh et al. (2003) concluded that anti-IP10 treatment can successfully impede development of inflammatory bowel disease, and that SAA levels can reveal the intensity of colitis.
Froicu et al. (2006) compared mice lacking Il10 with double-knockout (DKO) mice lacking Il10 and vitamin D receptor (VDR; 601769). They observed normal thymic development and peripheral T-cell numbers in DKO mice up to 3 weeks of age. However, following onset of IBD, the thymus became dysplastic with reduced cellularity and increased apoptosis. Spleen weight increased due to red blood cell accumulation, but there was a 50% reduction in lymphocytes. In contrast, mesenteric lymph nodes of DKO mice were enlarged and had increased lymphocyte numbers. DKO T cells were hyporesponsive. RT-PCR detected overexpression of inflammatory cytokines (e.g., IL1B; 147720) in DKO colon. Froicu et al. (2006) concluded that Vdr expression is required for T-cell control of inflammation in Il10-deficient mice.
Like HIV (see 609423) and hepatitis B and C viruses in humans, lymphocytic choriomeningitis virus (LCMV) can cause a persistent infection associated with loss of T-lymphocyte function in rodents. The LCMV variant Armstrong (Arm) induces a robust T-cell response and is cleared within 10 days, whereas the LCMV variant clone 13, which has an amino acid change in its glycoprotein that enables high-affinity binding to dendritic cells, generates a persistent infection. Using ribonuclease protection and flow cytometric analyses, Brooks et al. (2006) showed that mice infected with clone 13 had enhanced expression of Il10 compared with mice infected with Arm. Mice lacking Il10 and mice treated with anti-Il10r had increased anti-LCMV virus-specific T cells and could clear the persistent viral infection, facilitating development of memory T cells. Brooks et al. (2006) concluded that IL10 induces immunosuppression leading to viral persistence, and they proposed that IL10 neutralization early after HIV or HCV exposure may have a therapeutic benefit.
Sun et al. (2009) found that immune Cd8-positive and Cd4-positive effector T (Teff) cells were the primary source of Il10 during acute influenza virus infection in mice, with Cd8-positive cells contributing a larger fraction of the Il10 produced. The Teff cells produced Il10 and proinflammatory cytokines simultaneously. Inhibition of Il10 by Il10r blockade in sublethally infected animals resulted in enhanced pulmonary inflammation, injury, and accelerated death with no change on the rate of viral clearance. Lethal injury could be attenuated by corticosteroid administration. Sun et al. (2009) concluded that IL10 produced by Teff cells may have a significant role in regulating the magnitude of inflammation during acute virus infection.
Kane et al. (2011) demonstrated that transmission of the retrovirus mouse mammary tumor virus (MMTV) required commensal intestinal microbiota and that MMTV was bound to LPS. Mice lacking Tlr4, Il6, Il10, or Cd14 (158120), but not those lacking Tlr2 (603028), eliminated MMTV in successive generations. Kane et al. (2011) concluded that LPS-induced TLR4 signaling drives a viral 'subversion' pathway via IL6-dependent IL10 production that promotes viral transmission to successive generations.
In the mdx mouse model of Duchenne muscular dystrophy (DMD; 310200), M1 macrophages play a major role in worsening muscle injury. However, mdx muscle contains M2c macrophages that promote tissue repair. Villalta et al. (2011) investigated factors regulating the balance between M1 and M2c macrophages in mdx mice. Ablation of Il10 expression in mdx mice increased muscle damage in vivo and reduced mouse strength. Treatment of mdx muscle macrophages with Il10 reduced activation of the M1 phenotype, as assessed by iNOS (see NOS2A, 163730) expression. Macrophages from mice lacking Il10 were more cytolytic than macrophages from wildtype mice. Real-time PCR and immunohistochemical analysis detected expression of Il10r (146933) in mdx muscle. Ablation of Il10 expression in mdx mice did not affect satellite cell numbers, but it increased myogenin (MYOG; 159980) expression in vivo during the acute and regenerative phases of mdx pathology. Villalta et al. (2011) concluded that IL10 plays a significant role in muscular dystrophy by reducing M1 macrophage activation and cytotoxicity, increasing M2c macrophage activation, and modulating muscle differentiation.
Devkota et al. (2012) showed that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulfite-reducing pathobiont, Bilophila wadsworthia. This was associated with a proinflammatory T helper type-1 (TH1) immune response and increased incidence of colitis (see 266600) in genetically susceptible Il10 -/-, but not wildtype, mice. These effects were mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increase the availability of organic sulfur used by sulfite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10 -/- mice. Devkota et al. (2012) concluded that, taken together, their data showed that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. Devkota et al. (2012) further suggested that their data provided a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.
By generating mice lacking Il10 or Il10ra in Cx3cr1 (601470)-expressing macrophages residing in intestinal lamina propria, Zigmond et al. (2014) found that Il10 was dispensable for gut homeostasis and maintenance of colonic regulatory T cells. In contrast, loss of Il10ra expression impaired conditioning of these macrophages and resulted in spontaneous development of severe colitis. Zigmond et al. (2014) concluded that IL10 is a critical homeostatic macrophage-conditioning agent in colon and that high CX3CR1-expressing macrophages are key drivers in determining gut health or inflammation.
Ip et al. (2017) found that LPS-stimulated mouse Il10 -/- BMDMs showed increased glycolysis and decreased oxidative phosphorylation that was not due to nitric oxide production. The wildtype phenotype could be restored in Il10 -/- BMDMs by exogenous Il10, and wildtype BMDMs had a similar phenotype if treated with anti-Il10r. The reduced oxidative phosphorylation phenotype in Il10 -/- BMDMs appeared to be due to reduced mitochondrial fitness. Il10 -/- BMDMs also showed sustained glucose uptake when stimulated with LPS. Immunofluorescent microscopy demonstrated translocation of Glut1 (SLC2A1; 138140) from intracellular vesicles to plasma membrane upon LPS stimulation in Il10 -/- BMDMs. Treatment with Il10 prevented accumulation of dysfunctional mitochondria in Il10 -/- BMDMs and promoted induction of autophagy. Il10 maintained mitochondrial integrity and function through induction of Ddit4 (607729), which inhibited Mtor (601231). Inhibition of Mtor negatively regulated Nlrp3 (606416) inflammasome activation. Activation of macrophage inflammasome was aberrant in both Il10 -/- mice and in patients with IBD and IL10R null mutations. Ip et al. (2017) concluded that IL10 has a key role in controlling cellular metabolism and inflammation via inhibition of MTOR. In a commentary on the work of Ip et al. (2017), Kabat and Pearce (2017) proposed that IL10 reduces LPS-induced IL1B production by preventing release of reactive oxygen species by damaged mitochondria and through the induction of mitophagy.
Shin et al. (2000) reported an increased susceptibility to HIV-1 infection (609423) and more rapid progression to AIDS in patients with a C-to-A polymorphism at position -592 of the IL10 promoter. The -592A allele reduces IL10 transcription by a factor of 2 to 4. The authors found that -592A allele-specific synthetic oligonucleotides did not bind certain ETS family transcription factors, which recognize the wildtype IL10 allele sequence. Heterozygosity and homozygosity with respect to the -592A allele was associated with accelerated AIDS progression, probably owing to downregulation of the inhibitory IL10 cytokine.
In 993 transplant recipients, Lin et al. (2003) found that the IL10 -592A/A genotype, as compared with the C/C genotype, was associated with a decreased risk of acute graft-versus-host disease (GVHD; 614395) and death in remission. A haplotype analysis showed that the -592A allele was a specific marker for a promoter haplotype, T-C-A-T-A, defined by 5 polymorphisms at positions -3575, -2763, -1082, -819, and -592, respectively. Among recipients of hematopoietic cells from an HLA-identical sib, the -592A allele was shown to be a marker of a favorable outcome after transplantation. Cooke and Ferrara (2003) commented on the usefulness of information on IL10 genotype in clinical practice.
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