IL10

Gene Summary

Gene:IL10; interleukin 10
Aliases: CSIF, TGIF, GVHDS, IL-10, IL10A
Location:1q31-q32
Summary:The protein encoded by this gene is a cytokine produced primarily by monocytes and to a lesser extent by lymphocytes. This cytokine has pleiotropic effects in immunoregulation and inflammation. It down-regulates the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. This cytokine can block NF-kappa B activity, and is involved in the regulation of the JAK-STAT signaling pathway. Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. Mutations in this gene are associated with an increased susceptibility to HIV-1 infection and rheumatoid arthritis.[provided by RefSeq, May 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-10
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: IL10 (cancer-related)

Kucera R, Topolcan O, Treskova I, et al.
Evaluation of IL-2, IL-6, IL-8 and IL-10 in Malignant Melanoma Diagnostics.
Anticancer Res. 2015; 35(6):3537-41 [PubMed] Related Publications
AIM: The aim of the present study was to evaluate the usefulness of four interleukins (IL-2, IL-6, IL-8 and IL-10) for melanoma detection and correlate these interleukins with sentinel node metastasis positivity.
PATIENTS AND METHODS: A group of 236 persons was assessed: 175 patients with melanomas and 61 healthy persons. Melanoma patients were divided to four groups according to Breslow score. We determined IL-2, IL-6, IL-8 and IL-10 in each plasma sample. Interleukin plasma levels were assayed using a Human Cytokine Milliplex Map kit. Measurements were performed using the Bio-Plex MAGPIX Multiplex Reader. Plasma samples were collected prior to surgery or any other form of treatment. All melanoma diagnoses were histologically verified.
RESULTS: We compared interleukin plasma levels in the healthy group and plasma levels in each Breslow score stage. In the first Breslow score stage, IL-2 (p<0.0001), IL-6 (p=0.0004) and IL-10 (p<0.0001) were positive. In the second Breslow score, stage IL-2 (p<0.0001), IL-6 (p<0.0001), IL-8 (p=0.0017) and IL-10 (p<0.0001) were positive. By comparing the group of positive and negative sentinel node metastasis, we observed a statistically significant difference in two interleukins: The median of IL-2 levels in the negative group was 5.88 pg/ml compared to 32.57 pg/ml in the positive group (p=0.0005). The median of IL-6 levels in the negative group was 4.80 pg/ml compared to 32.02 pg/ml in the positive group (p=0.0048).
CONCLUSION: Interleukins IL-2, IL-6 and IL-10 are promising biomarkers of early-stage melanoma. IL-2 and IL-6 appear to be prognostic biomarkers.

Savitri E, Haryana MS
Expression of interleukin-8, interleukin-10 and Epstein-Barr viral-load as prognostic indicator in nasopharyngeal carcinoma.
Glob J Health Sci. 2015; 7(3):364-72 [PubMed] Related Publications
Interleukin-8 (IL-8) is angiogeneic chemokine that plays a potential role in both development and progression of many human malignancies including nasopharyngeal carcinoma (NPC). Epstein- Barr virus (EBV) is recognized to be an important etiologic agent of NPC as the viral gene products are frequently detected in NPC tissue along with the elevation of antibody titre to the viral protein (VCA-p18+ EBNA1) of IgA in the majority of patients. Elevated plasma of Viral Load is regarded as an important marker for the presence of the disease and for the monitoring of disease progression. However, other serum /plasma parameters such as the level of certain interleukins (IL-8 and IL-10) has also been implicated in NPC progression. The study aimed to investigate the correlations between plasma Viral Load and the level of interleukin (IL-8) and Interleukin (IL-10) in relating these parameters to the stages of NPC. In addition of Viral Load (VCA-p18+EBNA1) IgA, Interleukin-8 and Interleukin-10 before and after therapy will be investigated to seek the possible marker for disease progression. A total of 39 NPC patients and 29 healthy control individuals enrolled in this study. Plasma Viral Load was quantified using real-time quantitative PCR. The Level of plasma interleukins both IL-8 and IL-10 were analyzed using ELISA methods. Results indicated there was a significant decrease in viral load was detected in plasma of NPC patients following therapy. Plasma of viral load was shown to be a good prognosticator for disease progression. There were positive correlation between plasma of viral load and IL-8. These non invasive parameters expressed in blood, could be substitutes of viral load using brushing method, which is invasive. In conclusion that: Viral Load, (VCA-p18+EBNA1) IgA and IL-8 levels are promising markers for the presence of NPC and progression of the disease.

Okada K, Kawai M, Hirono S, et al.
Perioperative administration of Daikenchuto (TJ-100) reduces the postoperative paralytic ileus in patients with pancreaticoduodenectomy.
Hepatogastroenterology. 2015 Mar-Apr; 62(138):466-71 [PubMed] Related Publications
BACKGROUND/AIMS: No study has reported whether perioperative administration of Daikenchuto (TJ-100) reduced paralytic ileus after pancreaticoduodenectomy (PD).
METHODOLOGY: Forty-five consecutive patients that were scheduled to undergo PD at Wakayama Medical University Hospital between August 2010 and August 2011 were enrolled in this study including the first cohort (n = 15) as the control group and the subsequent cohort (n = 30) as the TJ-100 group. This trial was registered at UMIN-CTR ID# 000005056.
RESULTS: Postoperative paralytic ileus occurred more frequently in the control group (73.3% of the control group and 20.0% of the TJ-100 group; p = 0.001). The first passages of flatus significantly improved earlier in the TJ-100 group than in the control group (p = 0.014). A multiple cytokine assay of the drainage and serum showed that IL-9 and IL-10 in the drainage was significantly higher on postoperative day 1 in the TJ-100 group. There were no complications associated with the preoperative administration of TJ-100 before surgery, and no significant differences were observed between the two groups in the incidence of postoperative Gradel-2 diarrhea (CTCAE4.0).
CONCLUSIONS: Perioperative administration of TJ-100 was feasible and reduced the incidence of paralytic ileus in PD, and further randomized controlled trials should be conducted.

Chang X, Wang L, Zang M, et al.
[Relationship between CCL20/CCR6/Th17 axis and vascular invasion and metastasis in patients with primary hepatocellular carcinoma].
Zhonghua Zhong Liu Za Zhi. 2015; 37(1):5-10 [PubMed] Related Publications
OBJECTIVE: To investigate the role of CCL20/CCR6/Th17 axis in vascular invasion and metastasis of primary hepatocellular carcinoma (HCC).
METHODS: Expression levels of CCL20 mRNA in the normal human liver cell line L-02, and human hepatocellular carcinoma cell lines Hep3B, Huh7 and HepG2 were quantified by using SYBR green real time PCR. CCL20 secretions from these cell lines were quantified by using ELISA. The chemotactic effect of HCC cell line Hep3B on human peripheral blood mononuclear cells was determined by using transwell chemotaxis assay. Pre-therapy serum levels of IL-1α, IL-1β, IL-6, IL-8, IL-10, IL-17, IL-23, IFN-γ, TNF-α and CCL20 in 93 patients with HCC were measured by using 9-plex array and ELISA. All the patients were chronic hepatitis B virus associated HCC, and 51 cases were those with vascular invasion and metastasis (metastasis group) and 42 cases were not (non-metastasis group). CCL20 and CCR6 mRNA expressions in the HCC and tumor-adjacent tissues were determined by using SYBR Green real time PCR in 41 patients, among them, 20 cases were from the group of patients with metastasis and 21 cases were from the group of patients without metastasis. The CCL20 expression was further determined by immunohistochemistry.
RESULTS: The HCC cell lines expressed and secreted higher amount of CCL20, which effectively recruited CCR6(+) T cells. Pre-therapy serum levels of CCL20 in 93 HCC patients were (38.2 ± 28.4)pg/ml, significantly increased than those with benign hepatic hemangiomas [(7.8 ± 17.8)pg/ml, P < 0.01]. In addition, the serum levels of CCL20 were positively correlated with the tumor diameters in HCC patients (r = 0.32, P = 0.0018). CCL20 was dominantly expressed in the cytoplasm in HCC cells, and it was also expressed by some infiltrating immune cells. The mRNA expression levels of CCL20 of the tumor tissues were significantly higher than that in the tumor-adjacent tissues (P < 0.05). Multivariate logistic regression analysis showed that serum levels of IL-17 and CCL20 were independent risk factors of metastasis in HCC patients (P < 0.05 for both). CCL20 mRNA showed no statistically significant differences between patients with metastasis and without metastasis in both tumor tissues and tumor-adjacent tissues (P > 0.05 for both). But the patients with metastasis showed significantly higher expressions of CCR6 both in their tumor [5.75 (1.79, 19.13)]and tumor-adjacent tissues [7.99 (4.49, 19.54)] than those with non-metastasis [1.69 (0.76, 2.87) and 3.58 (1.84, 4.32), P < 0.05 for both].
CONCLUSION: CCL20/CCR6/Th17 axis may promote vascular invasion and metastasis hepatocellular carcinoma.

Liu X, Song N, Liu Y, et al.
Efficient induction of anti-tumor immune response in esophageal squamous cell carcinoma via dendritic cells expressing MAGE-A3 and CALR antigens.
Cell Immunol. 2015; 295(2):77-82 [PubMed] Related Publications
Despite advances in the various treatment options for esophageal squamous cell carcinoma (ESCC), its prognosis is still very poor with a 5-year survival rate of only 14-22%. Recently, among the various therapeutic approaches, the focus has shifted to immunotherapy, specifically immunotherapy involving dendritic cells (DCs), which depends on their maturation and antigen presentation to effector immune cells. Recent studies have suggested that melanoma-associated antigen 3 (MAGE-A3) is a potential immunotherapeutic target and also a candidate for the development of an anti-tumor vaccine. Calreticulin (CALR) has been shown to support induction of DC maturation. Therefore, in this study, we overexpressed MAGE-A3 and CALR on DCs and studied their potential to generate anti-tumor immune responses. We observed that adenovirus (Ad)-infected DCs overexpressing CALR and MAGE-A3 showed enhanced expression of CD80, CD83, CD86, and HLA-DR markers. Also, these DCs secreted higher levels of interleukin (IL)-12, which induces the T helper type 1 cell (Th1) response, and a lower level of IL-10, a negative regulator of the Th1 response. Furthermore, CALR/MAGE-A3-infected DCs stimulated CD8(+) cytotoxic T lymphocytes, which in turn secreted higher levels of interferon-γ, which induced cytotoxic effects on ESCC cells expressing MAGE-A3. In conclusion, our results revealed the potential of CALR/MAGE-A3-infected DCs to elicit a MAGE-A3-specific anti-tumor immunogenic response in ESCC. This proof-of-principle study may promote the future design and development of DC-based effective immunotherapy against ESCC.

Shi Y, Song Q, Hu D, et al.
Tumor-infiltrating lymphocyte activity is enhanced in tumors with low IL-10 production in HBV-induced hepatocellular carcinoma.
Biochem Biophys Res Commun. 2015; 461(1):109-14 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most common cancers and can be induced by chronic HBV infection. The role of HBV-specific immune responses in mediating tumorigenesis and HCC prognosis is debated. The effect of intratumoral microenvironment on tumor-infiltrating lymphocytes (TILs) is also unclear. Here, we examined resected tumor tissue from 36 patients with HBV-induced HCC. We categorized study cohort based on ex vivo IL-10 secretion by tumor cells into high IL-10-secreting (Hi10) and low IL-10-secreting (Lo10) groups, and found that the Lo10 group was less sensitive to TLR ligand stimulation. TILs from the Lo10 group contained higher frequencies of HBV-specific IFN-g-producing cells and total IFN-g-producing cells, and possessed higher proliferative capacity. Moreover, the proliferative capacity of TILs from the Hi10 group was negatively correlated with IL-10 secretion from tumor cells. Together, our data demonstrated that low IL-10-producing capacity in HBV-induced HCC tumors is associated with enhanced TIL activity.

Karakhanova S, Ryschich E, Mosl B, et al.
Prognostic and predictive value of immunological parameters for chemoradioimmunotherapy in patients with pancreatic adenocarcinoma.
Br J Cancer. 2015; 112(6):1027-36 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
BACKGROUND: Chemoradioimmunotherapy of patients with pancreatic adenocarcinoma from the CapRI trial did not show any benefit of interferon-α in addition to a 5-fluorouracil (5FU)-based treatment. The aim of this study was to identify immunological parameters in patients from this trial to be used for predictive and/or prognostic purposes.
METHODS: The following methods were used: tumour immunohistology, FACS analyses, cytokine measurement, as well as cytotoxicity and ELIspot. Immunological parameters were correlated with patients' survival using the Kaplan-Meier method.
RESULTS: Irrespective of therapy type, high lymphocyte accumulation in tumours and frequencies of NK cells and effector (eff) CD8(+) T cells in peripheral blood of the patients were associated with patients' survival. Amount of CD3(+) and effector-memory CD8(+) blood lymphocytes, expression of CD152 and interleukin (IL)-2 serum level showed a predictive value for chemoradioimmunotherapy. Tumoural accumulation of CD3(+) and CD8(+) cells was predictive for outcome of chemotherapy alone. Besides, we identified the frequencies of CD3(+) lymphocytes, effCD8(+) T cells and NK cells in the peripheral blood of the patients, and IL-10 amount in serum, to be predictive values for 5FU-based chemotherapy.
CONCLUSIONS: Immunological parameters, identified in this trial as possible markers, may be of interest in personalized medicine towards the improvement of the treatment and prognosis of pancreatic carcinoma patients.

Fu C, Liang X, Cui W, et al.
β-Catenin in dendritic cells exerts opposite functions in cross-priming and maintenance of CD8+ T cells through regulation of IL-10.
Proc Natl Acad Sci U S A. 2015; 112(9):2823-8 [PubMed] Article available free on PMC after 03/09/2015 Related Publications
Recent studies have demonstrated that β-catenin in DCs serves as a key mediator in promoting both CD4(+) and CD8(+) T-cell tolerance, although how β-catenin exerts its functions remains incompletely understood. Here we report that activation of β-catenin in DCs inhibits cross-priming of CD8(+) T cells by up-regulating mTOR-dependent IL-10, suggesting blocking β-catenin/mTOR/IL-10 signaling as a viable approach to augment CD8(+) T-cell immunity. However, vaccination of DC-β-catenin(-/-) (CD11c-specific deletion of β-catenin) mice surprisingly failed to protect them against tumor challenge. Further studies revealed that DC-β-catenin(-/-) mice were deficient in generating CD8(+) T-cell immunity despite normal clonal expansion, likely due to impaired IL-10 production by β-catenin(-/-) DCs. Deletion of β-catenin in DCs or blocking IL-10 after clonal expansion similarly led to reduced CD8(+) T cells, suggesting that β-catenin in DCs plays a positive role in CD8(+) T-cell maintenance postclonal expansion through IL-10. Thus, our study has not only identified mTOR/IL-10 as a previously unidentified mechanism for β-catenin-dependent inhibition of cross-priming, but also uncovered an unexpected positive role that β-catenin plays in maintenance of CD8(+) T cells. Despite β-catenin's opposite functions in regulating CD8(+) T-cell responses, selectively blocking β-catenin with a pharmacological inhibitor during priming phase augmented DC vaccine-induced CD8(+) T-cell immunity and improved antitumor efficacy, suggesting manipulating β-catenin signaling as a feasible therapeutic strategy to improve DC vaccine efficacy.

Sun Z, Fourcade J, Pagliano O, et al.
IL10 and PD-1 Cooperate to Limit the Activity of Tumor-Specific CD8+ T Cells.
Cancer Res. 2015; 75(8):1635-44 [PubMed] Article available free on PMC after 15/04/2016 Related Publications
Immune checkpoint inhibitors show great promise as therapy for advanced melanoma, heightening the need to determine the most effective use of these agents. Here, we report that programmed death-1(high) (PD-1(high)) tumor antigen (TA)-specific CD8(+) T cells present at periphery and at tumor sites in patients with advanced melanoma upregulate IL10 receptor (IL10R) expression. Multiple subsets of peripheral blood mononucleocytes from melanoma patients produce IL10, which acts directly on IL10R(+) TA-specific CD8(+) T cells to limit their proliferation and survival. PD-1 blockade augments expression of IL10R by TA-specific CD8(+) T cells, thereby increasing their sensitivity to the immunosuppressive effects of endogenous IL10. Conversely, IL10 blockade strengthened the effects of PD-1 blockade in expanding TA-specific CD8(+) T cells and reinforcing their function. Collectively, our findings offer a rationale to block both IL10 and PD-1 to strengthen the counteraction of T-cell immunosuppression and to enhance the activity of TA-specific CD8(+) T cell in advanced melanoma patients.

Wang SS, Vajdic CM, Linet MS, et al.
Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci.
Am J Epidemiol. 2015; 181(6):406-21 [PubMed] Article available free on PMC after 15/03/2016 Related Publications
Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04).

Chang TP, Poltoratsky V, Vancurova I
Bortezomib inhibits expression of TGF-β1, IL-10, and CXCR4, resulting in decreased survival and migration of cutaneous T cell lymphoma cells.
J Immunol. 2015; 194(6):2942-53 [PubMed] Article available free on PMC after 15/03/2016 Related Publications
Increased expression of the immunosuppressive cytokines, TGF-β1 and IL-10, is a hallmark of the advanced stages of cutaneous T cell lymphoma (CTCL), where it has been associated with suppressed immunity, increased susceptibility to infections, and diminished antitumor responses. Yet, little is known about the transcriptional regulation of TGF-β1 and IL-10 in CTCL, and about their function in regulating the CTCL cell responses. In this article, we show that TGF-β1 and IL-10 expression in CTCL cells is regulated by NF-κB and suppressed by bortezomib (BZ), which has shown promising results in the treatment of CTCL. However, although the TGF-β1 expression is IκBα dependent and is regulated by the canonical pathway, the IL-10 expression is IκBα independent, and its inhibition by BZ is associated with increased promoter recruitment of p52 that characterizes the noncanonical pathway. TGF-β1 suppression decreases CTCL cell viability and increases apoptosis, and adding exogenous TGF-β1 increases viability of BZ-treated CTCL cells, indicating TGF-β1 prosurvival function in CTCL cells. In addition, TGF-β1 suppression increases expression of the proinflammatory cytokines IL-8 and IL-17 in CTCL cells, suggesting that TGF-β1 also regulates the IL-8 and IL-17 expression. Importantly, our results demonstrate that BZ inhibits expression of the chemokine receptor CXCR4 in CTCL cells, resulting in their decreased migration, and that the CTCL cell migration is mediated by TGF-β1. These findings provide the first insights into the BZ-regulated TGF-β1 and IL-10 expression in CTCL cells, and indicate that TGF-β1 has a key role in regulating CTCL survival, inflammatory gene expression, and migration.

Huang WJ, Wan Q, Xu TS
[Effect of moxa-grain-moxibustion on serum Th 1/Th 2 type cytokines in Lewis tumor-bearing mice].
Zhen Ci Yan Jiu. 2014; 39(6):477-81 [PubMed] Related Publications
OBJECTIVE: To observe the effect of moxa-grain-moxibustion on serum IL-2 and IL-10 levels and T-lymphocyte proliferation activity in Lewis tumor-bearing mice, so as to reveal its mechanism underlying improvement of immune function under lung cancer condition.
METHODS: Thirty Lewis tumor-bearing mice were randomly divided into control group, tumor-bearing model group and moxibustion group (n = 10 in each group). Lung tumor model was established by subcutaneous inoculation of Lewis tumor cell suspension (0. 2 mL). The ignited moxa-grain was applied to bilateral "Housanli" (ST 36) one session a day for 10 sessions. The animals' daily life activity and the lung tumor growing status were observed every day. MTT [3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyl tetrazolium bromide] colorimetry was used to determine T lymphocyte proliferation activity, and serum IL-2 and IL-10 contents were detected by ELISA.
RESULTS: Following moxibustion, no statistical differences were found in the gross tumor volume and body weight between tumor-bearing model and moxibustion groups and between pre-moxibustion and post-moxibustion in the same one group (P>0.05). Compared with the blank control group, serum IL-2 content in the model group were significantly decreased (P<0. 05),while serum IL-10 level was significantly increased in the model group (P<0. 05). After moxibustion, the T-lymphocyte proliferation rate and serum IL-2 were markedly increased(P<0. 05), but serum IL-10 level was considerably decreased in the moxibustion intervention group in comparison with the tumor-bearing model group(P<0. 05).
CONCLUSION: Moxa-grain-moxibustion can effectively up-regulate T lymphocyte proliferation activity and balance Th 1/Th 2 in tumor-bearing mice, suggesting an enhancement of the body's anti-tumor ability after moxibustion.

Lin HH, Chiang MT, Chang PC, Chau LY
Myeloid heme oxygenase-1 promotes metastatic tumor colonization in mice.
Cancer Sci. 2015; 106(3):299-306 [PubMed] Related Publications
Heme oxygenase-1 (HO-1) is a heme degradation enzyme with antioxidant and immune-modulatory functions. HO-1 promotes tumorigenesis by enhancing tumor cell proliferation and invasion. Whether HO-1 has an effect on cancer progression through stromal compartments is less clear. Here we show that the growth of tumor engrafted subcutaneously in syngeneic mice was not affected by host HO-1 expression. However, lung metastasis arisen from subcutaneous tumor or circulating tumor cells was significantly reduced in HO-1(+/-) mice comparing to wild type (WT) mice. The reduced lung metastasis was also observed in B6 mice bearing HO-1(+/-) bone marrow as comparing to WT chimeras, indicating that HO-1 expression in hematopoietic cells impacts tumor colonization at the metastatic site. Further experiments demonstrated that the numbers of myeloid cells recruited to pulmonary premetastatic niches and metastatic loci were significantly lower in HO-1(+/-) mice than in WT mice. Likewise, the extents of tumor cell extravasation and colonization at the metastatic loci in the early phase of metastasis were significantly lower in HO-1(+/-) mice. Mechanistic studies revealed that HO-1 impacted chemoattractant-induced myeloid cell migration by modulating p38 kinase signaling. Moreover, myeloid HO-1-induced expressions of vascular endothelial growth factor and interleukin-10 promoted tumor cell transendothelial migration and STAT3 activation in vitro. These data support a pathological role of myeloid HO-1 in metastasis and suggest a possibility of targeting myeloid HO-1 for cancer treatment.

Jiang X
Macrophage-produced IL-10 limits the chemotherapy efficacy in breast cancer.
J Zhejiang Univ Sci B. 2015; 16(1):44-5 [PubMed] Article available free on PMC after 15/03/2016 Related Publications

Wang Z, Liu QL, Sun W, et al.
Genetic polymorphisms in inflammatory response genes and their associations with breast cancer risk.
Croat Med J. 2014; 55(6):638-46 [PubMed] Article available free on PMC after 15/03/2016 Related Publications
AIM: To explore the association of NFKB1 c.-798_-795delATTG (rs28362491), NFKBIA c.-949C>T (rs2233406), IL-8 c.-352A>T (rs4073), IL-10 c.-854T>C (rs1800871), TNF c.-418G>A (rs361525), and TNF c.-488G>A (rs1800629) polymorphisms with breast cancer risk in an East Chinese population.
METHODS: We conducted a case-control study including 975 study participants (474 breast cancer patients and 501 female controls without cancer) and genotyped the polymorphisms employing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Logistic regression was used to assess the association of the polymorphisms with breast cancer risk.
RESULTS: We found that the ins/del and del/del genotypes of NFKB1 polymorphism and TT genotype of IL-10 polymorphism significantly increased breast cancer risk (NFKB1 ins/del odds ratio [OR] 1.69, 95% [CI] 1.23-2.33, P=0.001; NFKB1 del/del OR 2.42, 95% CI 1.72-3.42, P<0.001; IL-10 TT OR 2.36, 95% CI 1.58-3.52, P<0.001). On the other hand, the TT genotype of IL-8 polymorphism, GA and AA genotypes of TNF c.-418G>A polymorphism, and GA genotype of TNF c.-488G>A polymorphism significantly reduced breast cancer risk (IL-8 TT OR 0.48, 95% CI 0.33-0.72, P<0.001; TNF c.-418 GA OR 0.58, 95% CI 0.41-0.80, P=0.001; TNF c.-418 AA OR 0.38, 95% CI 0.14-0.98, P=0.044; TNF c.-488 GA OR 0.68, 95% CI 0.48-0.96, P=0.029). When stratified by menopausal status, the CT genotype of NFKBIA polymorphism significantly reduced the risk among pre-menopausal women (OR 0.63, 95% CI 0.40-0.99, P=,043), but not among post-menopausal women.
CONCLUSIONS: NFKB1, NFKBIA, IL-8, IL-10, and TNF polymorphisms could serve as useful predictive biomarkers for breast cancer risk among women in East China.

Doulberis M, Angelopoulou K, Kaldrymidou E, et al.
Cholera-toxin suppresses carcinogenesis in a mouse model of inflammation-driven sporadic colon cancer.
Carcinogenesis. 2015; 36(2):280-90 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Human studies and clues from animal models have provided important links between gastrointestinal (GI) tract bacteria and colon cancer. Gut microbiota antigenic stimuli play an important role in shaping the intestinal immune responses. Therefore, especially in the case of inflammation-associated colon cancer, gut bacteria antigens may affect tumorigenesis. The present study aimed to investigate the effects of the oral administration of a bacterial product with known immunomodulatory properties on inflammation-driven colorectal neoplasmatogenesis. For that, we used cholera-toxin and a well-established mouse model of colon cancer in which neoplasia is initiated by a single dose of the genotoxic agent azoxymethane (AOM) and subsequently promoted by inflammation caused by the colitogenic substance dextran sodium sulfate (DSS). We found that a single, low, non-pathogenic dose of CT, given orally at the beginning of each DSS treatment cycle downregulated neutrophils and upregulated regulatory T-cells and IL-10 in the colonic mucosa. The CT-induced disruption of the tumor-promoting character of DSS-induced inflammation led to the reduction of the AOM-initiated colonic polypoidogenesis. This result adds value to the emerging notion that certain GI tract bacteria or their products affect the immune system and render the microenvironment of preneoplastic lesions less favorable for promoting their evolution to cancer.

Tao H, Lu L, Xia Y, et al.
Antitumor effector B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10.
Eur J Immunol. 2015; 45(4):999-1009 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
We have previously reported that adoptive transfer of tumor-draining lymph node (TDLN) B cells confers tumor regression in a spontaneous pulmonary metastasis mouse model of breast cancer. In this study, we identified IL-10-producing cells within these B cells, and found that IL-10 removal, either by using IL-10(-/-) TDLN B cells or by systemic neutralization of IL-10, significantly augmented the therapeutic efficacy of adoptively transferred TDLN B cells. Depletion of IL-10 in B-cell adoptive transfers significantly increased CTLs and B-cell activity of PBMCs and splenic cells in the recipient. Activated TDLN B cells express Fas ligand, which was further enhanced by coculture of these TDLN B cells with 4T1 tumor cells. Effector B cells killed tumor cells directly in vitro in an antigen specific and Fas ligand-dependent manner. Trafficking of TDLN B cells in vivo suggested that they were recruited to the tumor and lung as well as secondary lymphoid organs. These findings further define the biological function of antitumor effector B cells, which may offer alternative cellular therapies to cancer.

Foucher ED, Blanchard S, Preisser L, et al.
IL-34- and M-CSF-induced macrophages switch memory T cells into Th17 cells via membrane IL-1α.
Eur J Immunol. 2015; 45(4):1092-102 [PubMed] Related Publications
Macrophages orchestrate the immune response via the polarization of CD4(+) T helper (Th) cells. Different subsets of macrophages with distinct phenotypes, and sometimes opposite functions, have been described. M-CSF and IL-34 induce the differentiation of monocytes into IL-10(high) IL-12(low) immunoregulatory macrophages, which are similar to tumor-associated macrophages (TAMs) in ovarian cancer. In this study, we evaluated the capacity of human macrophages induced in the presence of M-CSF (M-CSF macrophages) or IL-34 (IL-34 macrophages) and ovarian cancer TAMs to modulate the phenotype of human CD4(+) T cells. Taken together, our results show that M-CSF-, IL-34 macrophages, and TAMs switch non-Th17 committed memory CD4(+) T cells into conventional CCR4(+) CCR6(+) CD161(+) Th17 cells, expressing or not IFN-gamma. Contrary, the pro-inflammatory GM-CSF macrophages promote Th1 cells. The polarization of memory T cells into Th17 cells is mediated via membrane IL-1α (mIL-1α), which is constitutively expressed by M-CSF-, IL-34 macrophages, and TAMs. This study elucidates a new mechanism that allows macrophages to maintain locally restrained and smoldering inflammation, which is required in angiogenesis and metastasis.

Yu T, Lu Q, Ou XL, et al.
Clinical study on gastric cancer susceptibility genes IL-10-1082 and TNF-α.
Genet Mol Res. 2014; 13(4):10909-12 [PubMed] Related Publications
TNF 308 gene polymorphism and IL-10 polymorphism provided evidence in diagnosing some types of cancer. We aimed to explore the relation of gene polymorphism with gastric cancer. A total of 360 cases of gastric cancer patients were included in the study. The genotypes GG, GA, and AA of the interleukin-10-1082 gene (IL-10-1082) and the tumor necrosis factor-alpha gene (TNF-α) 308 polymorphism were examined by chromogenic detection. Three hundred healthy individuals' gene as control group were also examined. The GA 308 genotype of TNF-α differed significantly between the control group and the gastric cancer group (X(2) = 9.32, P < 0.05). Genotype frequencies of A/A (17.2%), A/G (26.2%), and G/G (9.1%) of the IL-10-1082 gene polymorphism in the gastric cancer group differed significantly compared to those of the control group (X(2) = 20.32, P < 0.05). The IL-10-1082 gene and the GA 308 genotype of the TNF-α gene were found to be susceptibility genes for gastric cancer.

Zitvogel L, Kroemer G
CD103+ dendritic cells producing interleukin-12 in anticancer immunosurveillance.
Cancer Cell. 2014; 26(5):591-3 [PubMed] Related Publications
The mechanisms through which tumor antigen-specific T cells are elicited in natural or chemotherapy-induced immunosurveillance have been elusive. In this issue of Cancer Cell, two papers by Broz and colleagues and Ruffell and colleagues delineate an important role for a specific dendritic cell subset characterized by CD103 expression, dependence on transcription factors Batf3 and Irf8, and interleukin-12 production.

Zhang S, Guo Y, Zhang C, et al.
Primary laryngeal cancer-derived miR-193b induces interleukin-10-expression monocytes.
Cancer Invest. 2015; 33(2):29-33 [PubMed] Related Publications
The pathogenesis of laryngeal cancer (LC) is unclear. Published data indicate that micro RNAs (miRNA) play an important role in the pathogenesis of cancer. This study aims to elucidate the role of miR-193b in the tumor tolerance of LC. High levels of miR-193b were detected in LC cells as well as in the culture supernatant. Interleukin (IL)-10-expressing Mos were detected in the LC tissue-derived single cells. Treating naïve Mos with a miR-193b induced expression of IL-10 in the Mos. Culturing the IL-10(+) Mos with effector CD8(+) T cells resulted in the suppression of CD8(+) T-cell activities.

Mrizak D, Martin N, Barjon C, et al.
Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells.
J Natl Cancer Inst. 2015; 107(1):363 [PubMed] Related Publications
BACKGROUND: Regulatory T cells (Treg) and tumor-exosomes are thought to play a role in preventing the rejection of malignant cells in patients bearing nasopharyngeal carcinoma (NPC).
METHODS: Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients' plasma (Patient-Exo), and CCL20 were tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model (n = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA, and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). The Student's t test was used for group comparisons. All statistical tests were two-sided.
RESULTS: CCL20 allowed the intratumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30 ± 0.34 fold increase, P < .001), which was statistically significantly inhibited (P < .001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4(+)CD25(-) T cells and mediated their conversion into inhibitory CD4(+)CD25(high) cells. Moreover, NPC-Exo enhanced (P = .0048) the expansion of human Treg, inducing the generation of Tim3(Low) Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45 ± 1.75 (P < .001). These results were consistent with a stronger suppression of responder cells' proliferation and the secretion of immunosuppressive cytokines (IL10, TGFB1).
CONCLUSION: Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC.

Hsia TC, Chang WS, Liang SJ, et al.
Interleukin-10 (IL-10) promoter genotypes are associated with lung cancer risk in Taiwan males and smokers.
Anticancer Res. 2014; 34(12):7039-44 [PubMed] Related Publications
Interleukin-10 (IL-10) is an immunosuppressive cytokine involved in carcinogenesis via immune escape. The present study aimed at evaluating the contribution of IL-10 promoter A-1082G (rs1800896), T-819C (rs3021097), A-592C (rs1800872) genetic polymorphisms to the risk of lung cancer in Taiwan. Associations of three IL-10 polymorphic genotypes with lung cancer risk were investigated among 358 lung cancer patients and 716 age- and gender-matched healthy controls. In addition, the genetic-lifestyle interaction was also examined. The results showed that the percentages of TT, TC and CC for IL-10 T-819C genotypes were differentially represented as 59.2%, 35.8% and 5.0% in the lung-cancer patient group and 52.0%, 37.0% and 11.0% in the non-cancer control group, respectively (p for trend=0.0025). The CC genotype carriers were of lower risk for lung cancer (OR=0.4, 95% CI=0.23-0.69, p=0.0005). Further stratification of the population by gender and smoking behavior showed that the IL-10 T-819C genotype conducted a protective effect on lung cancer susceptibility, which was obvious among males and smokers (p=0.0003 and 0.0004, respectively). The CC and TC genotypes of IL-10 T-819C compared to the TT genotype may have a protective effect on lung cancer risk in Taiwan, particularly among males and smokers.

Shi Q, Wang XS, Li G, et al.
Racial/ethnic disparities in inflammatory gene single-nucleotide polymorphisms as predictors of a high risk for symptom burden in patients with multiple myeloma 1 year after diagnosis.
Cancer. 2015; 121(7):1138-46 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
BACKGROUND: This study was conducted to determine whether any regulatory single-nucleotide polymorphism (SNP) in an inflammatory gene was associated with a high symptom burden in patients 1 year after the diagnosis of multiple myeloma (MM).
METHODS: MM patients rated symptoms with the MD Anderson Symptom Inventory multiple myeloma module (MDASI-MM) and provided buccal-swab DNA samples. SNPs for 4 cytokine genes (interleukin 6 [IL6] -174G>C, IL1β -511C>T, tumor necrosis factor α [TNFα] -308G>A, and IL10 -1082G>A) were tested. Logistic regression models were used to identify SNPs that might predict moderate/severe symptoms (rated ≥ 4 on the MDASI-MM 0-10 scale). For the evaluation of the relationship between SNPs and overall symptom burden, a 2-step cluster analysis was used to divide patients into subgroups with high or low symptom levels.
RESULTS: Forty-one percent of the 344 patients enrolled had a high overall symptom burden. The most prevalent moderate/severe symptoms were fatigue (47%), pain (42%), numbness (38%), and bone aches (32%). For non-Hispanic whites, the IL1β -511 CC genotype was associated with a high overall symptom burden (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.25-4.72; P = .004), whereas the IL6 -174 GG genotype predicted less moderate/severe fatigue (OR, 0.53; 95% CI, 0.29-0.88; P = .013). For other patients, the IL6 -174 GG genotype predicted moderate/severe pain (OR, 3.36; 95% CI, 1.23-13.64; P = .010).
CONCLUSIONS: These results support growing evidence showing that inflammation is associated with cancer-related symptoms, and they suggest that racial/ethnic factors contribute to this association.

Fujita Y, Okamoto M, Goda H, et al.
Prognostic significance of interleukin-8 and CD163-positive cell-infiltration in tumor tissues in patients with oral squamous cell carcinoma.
PLoS One. 2014; 9(12):e110378 [PubMed] Article available free on PMC after 01/04/2016 Related Publications
PURPOSE: We investigated whether serum interleukin (IL)-8 reflects the tumor microenvironment and has prognostic value in patients with oral squamous cell carcinoma (OSCC).
EXPERIMENTAL DESIGN: Fifty OSCC patients who received radical resection of their tumor(s) were enrolled. Preoperative sera were measured for IL-8 by ELISA. Expression of IL-8 and the infiltration of immune cells in tumor tissues were analyzed by an immunohistochemical staining of surgical specimens.
RESULTS: We found that disease-free survival (DFS) was significantly longer in the Stage I/II OSCC patients with low serum IL-8 levels compared to those with high levels (p = 0.001). The tumor expression of IL-8, i.e., IL-8(T) and the density of CD163-positive cells in the tumor invasive front, i.e., CD163(IF) were correlated with the serum IL-8 level (p = 0.033 and p = 0.038, respectively), and they were associated with poor clinical outcome (p = 0.007 and p = 0.002, respectively, in DFS) in all patients. A multivariate analysis revealed that N status, IL-8(T) and CD163(IF) significantly affected the DFS of the patients. Further analysis suggested that combination of N status with serum IL-8, IL-8(T) or CD163(IF) may be a new criterion for discriminating between OSCC patients at high and low risk for tumor relapse. Interestingly, the in vitro experiments demonstrated that IL-8 enhanced generation of CD163-positive M2 macrophages from peripheral blood monocytes, and that the cells produced IL-10.
CONCLUSIONS: These findings indicate that IL-8 may be involved in poor clinical outcomes via generation of CD163-positive M2 macrophages, and that these factors in addition to N status may have prognostic value in patients with resectable OSCSS.

Ruffell B, Chang-Strachan D, Chan V, et al.
Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells.
Cancer Cell. 2014; 26(5):623-37 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Blockade of colony-stimulating factor-1 (CSF-1) limits macrophage infiltration and improves response of mammary carcinomas to chemotherapy. Herein we identify interleukin (IL)-10 expression by macrophages as the critical mediator of this phenotype. Infiltrating macrophages were the primary source of IL-10 within tumors, and therapeutic blockade of IL-10 receptor (IL-10R) was equivalent to CSF-1 neutralization in enhancing primary tumor response to paclitaxel and carboplatin. Improved response to chemotherapy was CD8(+) T cell-dependent, but IL-10 did not directly suppress CD8(+) T cells or alter macrophage polarization. Instead, IL-10R blockade increased intratumoral dendritic cell expression of IL-12, which was necessary for improved outcomes. In human breast cancer, expression of IL12A and cytotoxic effector molecules were predictive of pathological complete response rates to paclitaxel.

Wang X, Wang T, Xu M, et al.
B7-H4 overexpression impairs the immune response of T cells in human cervical carcinomas.
Hum Immunol. 2014; 75(12):1203-9 [PubMed] Related Publications
OBJECTIVE: To investigate B7-H4 expression and its correlation with the number of infiltrating T lymphocytes and cytokine production by those lymphocytes in human cervical cancer and to determine the effect of recombinant B7-H4 on the active peripheral blood T cells of the patients in vitro.
METHODS: B7-H4 expression was detected in 67 cases of cervical cancer using immunohistochemical staining. Tumor-infiltrating CD8(+)T, CD4(+)T, and FOXP3(+) (Forkhead Box P3) T lymphocytes and their levels of IFN-γ and TGF-β₁ production were determined by immunofluorescent double-staining. After the peripheral blood T lymphocytes of patients were co-cultured with B7-H4, proliferation, apoptosis, and cell subtypes were analyzed using flow cytometry. Cytokines in the supernatant were detected by ELISA.
RESULTS: B7-H4 was expressed in 46% (31/67) of the cases of cervical cancer. The number of infiltrating CD8(+)T lymphocytes and their IFN-γ production in positive B7-H4 expression cervical cancers was significantly lower than in negative B7-H4 cases (P<0.01, P<0.05), but there was no significant difference between cases positive and negative for B7-H4 with respect to infiltrating FOXP3(+)T and CD4(+)T cells or TGF-β1 production. After co-culture with B7-H4 for 48 h, the patients' activated T lymphocytes were arrested at G1/G2 phase. The Ki67 positive rates of CD4(+)T and CD8(+)T cells were 2.13 ± 0.13% and 1.03 ± 1.33%, and they were lower than in the blank group. The proportion of CD4(+)T and CD8(+)T cells decreased, but CD4(+)T/CD8(+)T and the proportion of CD4(+)CD25(+)Foxp3(+)T cells increased. In addition, concentrations of IL-10 and TGF-β1 in the supernatant of co-cultured T cells increased significantly (P<0.05, P<0.05), but that of IFN-γ decreased. B7-H4 had no significant effect on apoptosis of the T cells.
CONCLUSION: B7-H4 is overexpressed in human cervical cancers, and it is associated with lower numbers of tumor-infiltrating CD8(+)T lymphocytes and therefore less IFN-γ production. In vitro, B7-H4 inhibits the proliferation of CD4(+)T and CD8(+)T but promotes the proliferation of Tregs and the secretion of IL-10 and TGF-β1. B7-H4 plays an important role in depressing the anti-tumor immunity of CD8(+)T cell in microenvironments of cervical cancer.

Lopes RL, Borges TJ, Araújo JF, et al.
Extracellular mycobacterial DnaK polarizes macrophages to the M2-like phenotype.
PLoS One. 2014; 9(11):e113441 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Macrophages are myeloid cells that play an essential role in inflammation and host defense, regulating immune responses and maintaining tissue homeostasis. Depending on the microenvironment, macrophages can polarize to two distinct phenotypes. The M1 phenotype is activated by IFN-γ and bacterial products, and displays an inflammatory profile, while M2 macrophages are activated by IL-4 and tend to be anti-inflammatory or immunosupressive. It was observed that DnaK from Mycobacterium tuberculosis has immunosuppressive properties, inducing a tolerogenic phenotype in dendritic cells and MDSCs, contributing to graft acceptance and tumor growth. However, its role in macrophage polarization remains to be elucidated. We asked whether DnaK was able to modulate macrophage phenotype. Murine macrophages, derived from bone marrow, or from the peritoneum, were incubated with DnaK and their phenotype compared to M1 or M2 polarized macrophages. Treatment with DnaK leads macrophages to present higher arginase I activity, IL-10 production and FIZZ1 and Ym1 expression. Furthermore, DnaK increased surface levels of CD206. Importantly, DnaK-treated macrophages were able to promote tumor growth in an allogeneic melanoma model. Our results suggest that DnaK polarizes macrophages to the M2-like phenotype and could constitute a virulence factor and is an important immunomodulator of macrophage responses.

Singhal P, Kumar A, Bharadwaj S, et al.
Association of IL-10 GTC haplotype with serum level and HPV infection in the development of cervical carcinoma.
Tumour Biol. 2015; 36(4):2287-98 [PubMed] Related Publications
AIM: Cervical cancer is the most common gynecological malignancy in the developing countries like India. In addition to human papillomavirus (HPV) infection, host genetic factors play an important role in viral persistence and neoplastic growth. IL-10, a multifunctional cytokine, plays an active role to promote tumor growth in the presence of HPV. The present study aims to find out the impact of IL-10 promoter polymorphisms at -1082A/G (rs1800896), -819C/T (rs1800872), and -592C/A (rs1800871) sites along with IL-10 production and HPV infection in the progression of cervical cancer.
METHODS: We have genotyped a total of 506 subjects, 256 cases (208 cervical cancer + 48 precancer), and 250 healthy controls by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method followed by sequencing. IL-10 serum concentration was measured by enzyme-linked immunosorbent assay.
RESULTS: The frequency of IL-10 -592 variant genotype (AA) was found significantly reduced in cases as compare to controls while -1082 variant genotype (GG) was found ~4-fold higher risk of cervical cancer (p = <0.0001, OR = 3.667, 95% CI = 2.329-5.773). On construction of haplotypes, GTC haplotype was emerged as a major risk haplotype while ACA haplotype was seemed as a marker for precancerous lesions. IL-10 serum concentration was observed higher in HPV-infected precancer and cancer cases. GTC haplotype was found to be coupled with higher serum concentration of IL-10 and HPV infection.
CONCLUSION: IL-10 polymorphisms play a role in cervical cancer development and that GTC haplotype, which is closely related to its serum concentration, maybe a useful biomarker for HPV-mediated cervical cancer.

Chao PZ, Hsieh MS, Cheng CW, et al.
Dendritic cells respond to nasopharygeal carcinoma cells through annexin A2-recognizing DC-SIGN.
Oncotarget. 2015; 6(1):159-70 [PubMed] Article available free on PMC after 10/11/2015 Related Publications
Dendritic cells (DCs) play an essential role in immunity and are used in cancer immunotherapy. However, these cells can be tuned by tumors with immunosuppressive responses. DC-specific intercellular adhesion molecule 3-Grabbing Nonintegrin (DC-SIGN), a C-type lectin expressed on DCs, recognizes certain carbohydrate structures which can be found on cancer cells. Nasopharyngeal carcinoma (NPC) is an epithelial cell-derived malignant tumor, in which immune response remains unclear. This research is to reveal the molecular link on NPC cells that induces the immunosuppressive responses in DCs. In this article, we report identification of annexin A2 (ANXA2) on NPC cells as a ligand for DC-SIGN on DCs. N-linked mannose-rich glycan on ANXA2 may mediate the interaction. ANXA2 was abundantly expressed in NPC, and knockdown of ANXA2 suppressed NPC xenograft in mice, suggesting a crucial role of ANXA2 in NPC growth. Interaction with NPC cells caused DC-SIGN activation in DCs. Consequently DC maturation and the proinflammatory interleukin (IL)-12 production were inhibited, and the immunosuppressive IL-10 production was promoted. Blockage of either DC-SIGN or ANXA2 eliminated the production of IL-10 from DCs. This report suggests that suppression of ANXA2 at its expression or glycosylation on NPC may improve DC-mediated immunotherapy for the tumor.

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