IL21

Gene Summary

Gene:IL21; interleukin 21
Aliases: Za11, IL-21, CVID11
Location:4q27
Summary:This gene encodes a member of the common-gamma chain family of cytokines with immunoregulatory activity. The encoded protein plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells and cytotoxic T cells. Dysregulation of this gene plays a role in multiple immune-mediated diseases including lupus, psoriasis and chronic inflammatory diseases. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:interleukin-21
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
Show (16)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Genetic Predisposition
  • Chromosome 4
  • Receptors, Interleukin-21
  • Lymphocyte Activation
  • Angiogenesis
  • Transduction
  • Interferon-gamma
  • Ovarian Cancer
  • Case-Control Studies
  • Interleukins
  • Cancer Gene Expression Regulation
  • Chronic Lymphocytic Leukemia
  • Promoter Regions
  • Breast Cancer
  • Interleukin-23
  • Cell Differentiation
  • Apoptosis
  • Genotype
  • Natural Killer Cells
  • Spleen
  • Multiple Myeloma
  • Th17 Cells
  • Messenger RNA
  • Diffuse Large B-Cell Lymphoma
  • Odds Ratio
  • B-Lymphocytes
  • Cell Proliferation
  • Gene Expression Regulation
  • CD40
  • Up-Regulation
  • CD4-Positive T-Lymphocytes
  • Gene Expression
  • Genetic Therapy
  • Staging
  • Cytotoxicity, Immunologic
  • Interleukin-21 Receptor alpha Subunit
  • Gene Expression Profiling
  • Mice, Inbred BALB C
  • Disease Progression
  • Signal Transduction
  • Single Nucleotide Polymorphism
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: IL21 (cancer-related)

Jaime-Ramirez AC, McMichael EL, Kondadasula S, et al.
NK Cell-Mediated Antitumor Effects of a Folate-Conjugated Immunoglobulin Are Enhanced by Cytokines.
Cancer Immunol Res. 2016; 4(4):323-36 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Optimally effective antitumor therapies would not only activate immune effector cells but also engage them at the tumor. Folate conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor-expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR)-overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by natural killer (NK) cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased by about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P< 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNγ, MIP-1α, and RANTES in response to F-IgG-coated KB target cells in the presence of the NK cell-activating cytokine IL12, and these coculture supernatants induced significant T-cell chemotaxis (P< 0.001). F-IgG-coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P =0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.

Kwakkenbos MJ, van Helden PM, Beaumont T, Spits H
Stable long-term cultures of self-renewing B cells and their applications.
Immunol Rev. 2016; 270(1):65-77 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Monoclonal antibodies are essential therapeutics and diagnostics in a large number of diseases. Moreover, they are essential tools in all sectors of life sciences. Although the great majority of monoclonal antibodies currently in use are of mouse origin, the use of human B cells to generate monoclonal antibodies is increasing as new techniques to tap the human B cell repertoire are rapidly emerging. Cloned lines of immortalized human B cells are ideal sources of monoclonal antibodies. In this review, we summarize our studies to the regulation of the replicative life span, differentiation, and maturation of B cells that led to the development of a platform that uses immortalization of human B cells by in vitro genetic modification for antibody development. We describe a number of human antibodies that were isolated using this platform and the application of the technique in other species. We also discuss the use of immortalized B cells as antigen-presenting cells for the discovery of tumor neoantigens.

Wang LN, Cui YX, Ruge F, Jiang WG
Interleukin 21 and Its Receptor Play a Role in Proliferation, Migration and Invasion of Breast Cancer Cells.
Cancer Genomics Proteomics. 2015 Sep-Oct; 12(5):211-21 [PubMed] Related Publications
Interleukin 21 (IL21) is a cytokine produced predominantly by cluster of differentiation 4 (CD4+) T-cells and natural killer T-cells. There exists evidence that IL21 is implicated in various immunological processes through its specific receptor (IL21R). However, the participation of IL21 in the pathogenesis of solid tumors is not fully conclusive. In the present study, we demonstrated that there was differential expression of IL21R in breast cancer cells using reverse transcription-polymerase chain reaction (RT-PCR), western blotting and sequence analysis. The expression of IL21R was stronger in MDA-231 cells, weaker in MCF7 but negative in ZR-75.1 cells. The invasion and migratory capacity of IL21R+ MDA-231 cells was enhanced by IL21 in a dose-dependent manner. After IL21R was knocked-down by siRNA gene silencing, the response of MDA-231 to treatment with IL21 was attenuated. We found that siRNA silencing of IL21R also spontaneously suppressed cell proliferation. However, IL21 had no additional effect on the proliferation of MDA-231 cells. We also found that IL21R was involved in signaling pathways of matrix metalloproteinases (MMPs), that are crucial for spreading and migration of metastatic MDA231 cells. In conclusion, we unveiled the roles of IL21R in breast cancer cells, which enhances our knowledge on immunological regulation of cancer cells through the axis of IL21 and its receptor.

Yu YN, Yu TC, Zhao HJ, et al.
Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment.
Oncotarget. 2015; 6(31):32013-26 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated.
METHODS: 454 FLX pyrosequencing was used to evaluate the disturbance of intestinal microbiota during the adenoma-carcinoma sequence pathway of CRC. Intestinal microbiota and mucosa tumor-immune cytokines were detected in mice after introducing 1,2-dimethylhydrazine (DMH), F. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting.
RESULTS: The levels of opportunistic pathogens, such as Fusobacterium, Streptococcus and Enterococcus spp. gradually increased during the colorectal adenoma-carcinoma sequence in human fecal and mucosal samples. F. nucleatum treatment significantly altered lumen microbial structures, with increased Tenericutes and Verrucomicrobia (opportunistic pathogens) (P < 0.05 = in wild-type C57BL/6 and mice with DMH treatment). BBR intervention reversed the F. nucleatum-mediated increase in opportunistic pathogens, and the secretion of IL-21/22/31, CD40L and the expression of p-STAT3, p-STAT5 and p-ERK1/2 in mice, compared with mice fed with F. nucleatum alone.
CONCLUSIONS: F. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F. nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways.

Jain S, Chen J, Nicolae A, et al.
IL-21-driven neoplasms in SJL mice mimic some key features of human angioimmunoblastic T-cell lymphoma.
Am J Pathol. 2015; 185(11):3102-14 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
SJL/J mice exhibit a high incidence of mature B-cell lymphomas that require CD4(+) T cells for their development. We found that their spleens and lymph nodes contained increased numbers of germinal centers and T follicular helper (TFH) cells. Microarray analyses revealed high levels of transcripts encoding IL-21 associated with high levels of serum IL-21. We developed IL-21 receptor (IL21R)-deficient Swiss Jim Lambart (SJL) mice to determine the role of IL-21 in disease. These mice had reduced numbers of TFH cells, lower serum levels of IL-21, and few germinal center B cells, and they did not develop B-cell tumors, suggesting IL-21-dependent B-cell lymphomagenesis. We also noted a series of features common to SJL disease and human angioimmunoblastic T-cell lymphoma (AITL), a malignancy of TFH cells. Gene expression analyses of AITL showed that essentially all cases expressed elevated levels of transcripts for IL21, IL21R, and a series of genes associated with TFH cell development and function. These results identify a mouse model with features of AITL and suggest that patients with the disease might benefit from therapeutic interventions that interrupt IL-21 signaling.

De Cecco L, Capaia M, Zupo S, et al.
Interleukin 21 Controls mRNA and MicroRNA Expression in CD40-Activated Chronic Lymphocytic Leukemia Cells.
PLoS One. 2015; 10(8):e0134706 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Several factors support CLL cell survival in the microenvironment. Under different experimental conditions, IL21 can either induce apoptosis or promote CLL cell survival. To investigate mechanisms involved in the effects of IL21, we studied the ability of IL21 to modulate gene and miRNA expressions in CD40-activated CLL cells. IL21 was a major regulator of chemokine production in CLL cells and it modulated the expression of genes involved in cell movement, metabolism, survival and apoptosis. In particular, IL21 down-regulated the expression of the chemokine genes CCL4, CCL3, CCL3L1, CCL17, and CCL2, while it up-regulated the Th1-related CXCL9 and CXCL10. In addition, IL21 down-regulated the expression of genes encoding signaling molecules, such as CD40, DDR1 and PIK3CD. IL21 modulated a similar set of genes in CLL and normal B-cells (e.g. chemokine genes), whereas other genes, including MYC, TNF, E2F1, EGR2 and GAS-6, were regulated only in CLL cells. An integrated analysis of the miRNome and gene expression indicated that several miRNAs were under IL21 control and these could, in turn, influence the expression of potential target genes. We focused on hsa-miR-663b predicted to down-regulate several relevant genes. Transfection of hsa-miR-663b or its specific antagonist showed that this miRNA regulated CCL17, DDR1, PIK3CD and CD40 gene expression. Our data indicated that IL21 modulates the expression of genes mediating the crosstalk between CLL cells and their microenvironment and miRNAs may take part in this process.

Wang K, Karin M
Tumor-Elicited Inflammation and Colorectal Cancer.
Adv Cancer Res. 2015; 128:173-96 [PubMed] Related Publications
The link between chronic inflammation and cancer has long been suspected, due to the pioneering work of Rudolf Virchow over 150 years ago. Yet the causal relationship between inflammation and cancer was only deciphered in the past decade or so, using animal models of various cancers. Up to 20% of all human cancers result from chronic inflammation and persistent infections. Proinflammatory cytokines and tumor-infiltrating myeloid and immune cells play critical roles in almost every developmental stages of inflammation-induced cancers, from initiation, promotion, and progression to malignant metastasis. However, even in cancers with no preceding inflammation, inflammatory cells infiltrate tumor stroma and contribute to cancer development. Such "tumor-elicited inflammation" further emphasizes the importance of inflammation in different types of cancers, including that of the colon. In this review, we summarize our current knowledge of the function and induction mechanisms of inflammatory cytokines during colorectal cancer development, and hope to provide insight into the development of novel anticancer therapies by modulating tumor-elicited inflammation.

Paiva C, Godbersen JC, Berger A, et al.
Targeting neddylation induces DNA damage and checkpoint activation and sensitizes chronic lymphocytic leukemia B cells to alkylating agents.
Cell Death Dis. 2015; 6:e1807 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Microenvironment-mediated upregulation of the B-cell receptor (BCR) and nuclear factor-κB (NF-κB) signaling in CLL cells resident in the lymph node and bone marrow promotes apoptosis evasion and clonal expansion. We recently reported that MLN4924 (pevonedistat), an investigational agent that inhibits the NEDD8-activating enzyme (NAE), abrogates stromal-mediated NF-κB pathway activity and CLL cell survival. However, the NAE pathway also assists degradation of multiple other substrates. MLN4924 has been shown to induce DNA damage and cell cycle arrest, but the importance of this mechanism in primary neoplastic B cells has not been studied. Here we mimicked the lymph node microenvironment using CD40 ligand (CD40L)-expressing stroma and interleukin-21 (IL-21) to find that inducing proliferation of the primary CLL cells conferred enhanced sensitivity to NAE inhibition. Treatment of the CD40-stimulated CLL cells with MLN4924 resulted in deregulation of Cdt1, a DNA replication licensing factor, and cell cycle inhibitors p21 and p27. This led to DNA damage, checkpoint activation and G2 arrest. Alkylating agents bendamustine and chlorambucil enhanced MLN4924-mediated DNA damage and apoptosis. These events were more prominent in cells stimulated with IL-21 compared with CD40L alone, indicating that, following NAE inhibition, the culture conditions were able to direct CLL cell fate from an NF-κB inhibition to a Cdt1 induction program. Our data provide insight into the biological consequences of targeting NAE in CLL and serves as further rationale for studying the clinical activity of MLN4924 in CLL, particularly in combination with alkylating agents.

Deniger DC, Yu J, Huls MH, et al.
Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1) into Diverse Memory T-Cell Populations.
PLoS One. 2015; 10(6):e0128151 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3ζ and either CD28 (designated ROR1RCD28) or CD137 (designated ROR1RCD137) and were introduced into T cells. We selected for T cells expressing CAR through co-culture with γ-irradiated activating and propagating cells (AaPC), which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL)-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString) and multi-panel flow cytometry. Such T cells produced interferon-γ and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1-specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire.

Yao JY, Chao K, Li MR, et al.
Interleukin-21 gene polymorphisms and chronic hepatitis B infection in a Chinese population.
World J Gastroenterol. 2015; 21(14):4232-9 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
AIM: To investigate the relationship between interleukin-21 (IL21) gene polymorphisms and chronic hepatitis B virus (HBV) infection in a Chinese population.
METHODS: In this case-control study, 366 Chinese HBV-infected patients were recruited and divided into hepatocellular carcinoma (HCC; n = 94) and non-HCC (n = 272) groups at The First Affiliated Hospital of Sun Yat-Sen University, from April 2009 to December 2012. In the non-HCC group, the patients were classified into three clinical subsets, 76 patients had chronic hepatitis B, 101 were HBV carriers and 95 patients had HBV-related cirrhosis. Two hundred eight unrelated healthy controls were also included. Genomic DNA was extracted from peripheral blood. Single nucleotide polymorphisms (SNPs) rs13143866, rs2221903, and rs907715 were subsequently genotyped using the SNaPshot SNP technique.
RESULTS: There were no significant differences in allele and genotype frequencies of SNPs rs13143866, rs2221903, and rs907715 between chronic HBV-infected patients and control subjects. Furthermore, no significant differences were found in the frequencies of all alleles and genotypes between the HCC group and the non-HCC group. However, in the subgroup analysis, IL21 rs13143866 genotype AA frequency in the HBV carrier group was higher than in controls (OR = 6.280, 95%CI: 1.238-31.854; P = 0.019), and the effect of the recessive model (AA vs GG + GA, OR = 6.505, 95%CI: 1.289-32.828) was observed in the HBV carrier group. IL21 rs2221903 genotype TC frequency in the HBV carrier group was higher than in controls (OR = 1.809, 95%CI: 1.043-3.139; P = 0.035). In the haplotype analysis, the ATA haplotype (rs13143866, rs2221903, and rs907715) of IL21 was more frequent in the HCC group than in the non-HCC group (0.165 vs 0.104, P = 0.044; OR = 1.700, 95%CI: 1.010-2.863).
CONCLUSION: Genotypes rs13143866 AA and rs2221903 TC are risk factors for carrying HBV; ATA haplotype increases the risk of HBV-related HCC onset in a Chinese population.

Merkel O, Hamacher F, Griessl R, et al.
Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation.
J Pathol. 2015; 236(4):445-56 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).

Amé-Thomas P, Hoeller S, Artchounin C, et al.
CD10 delineates a subset of human IL-4 producing follicular helper T cells involved in the survival of follicular lymphoma B cells.
Blood. 2015; 125(15):2381-5 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
In follicular lymphoma (FL), follicular helper T cells (TFH) have been depicted as one of the main components of the malignant B-cell niche and a promising therapeutic target. Although defined by their capacity to sustain FL B-cell growth together with specific gene expression and cytokine secretion profiles, FL-TFH constitute a heterogeneous cell population. However, specific markers reflecting such functional heterogeneity are still lacking. In this study, we demonstrate that CD10 identifies a subset of fully functional germinal center TFH in normal secondary lymphoid organs. Importantly, this subset is amplified in the FL context, unlike in other B-cell lymphomas with a follicular growth pattern. Furthermore, whereas FL-TFH produce high levels of interleukin (IL)-21 and low levels of IL-17 irrespectively of their CD10 expression, CD10(pos) FL-TFH specifically exhibit an IL-4(hi)IFN-γ(lo)TNF-α(hi) cytokine profile associated with a high capacity to sustain directly and indirectly malignant B-cell survival. Altogether, our results highlight the important role of this novel functional subset in the FL cell niche.

Yang ZZ, Grote DM, Ziesmer SC, et al.
PD-1 expression defines two distinct T-cell sub-populations in follicular lymphoma that differentially impact patient survival.
Blood Cancer J. 2015; 5:e281 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
To determine the biological and clinical relevance of programmed death 1 (PD-1) in follicular lymphoma (FL), we characterized PD-1(+) T-cell subsets and assessed their biological function as well as potential clinical impact. We found that PD-1 is expressed on intratumoral CD4(+) T cells with both bright and dim intensity, representing two different sub-populations of cells. By immunohistochemistry, we found that CD4(+)PD-1(high) T cells predominantly reside in the lymph node follicles, while PD-1(low) T cells are mainly located in an interfollicular pattern. Intratumoral CD4(+)PD-1(high) T cells have a TFH cell phenotype, express CXCR5, secrete IL-21 and are BCL-6 positive with no TIM-3 expression. In contrast, CD4(+)PD-1(low) T cells have an exhausted phenotype, express TIM-3 and do not express BCL-6 and CXCR5. Functionally, CD4(+)PD-1(high) T cells actively supported B-cell growth, while CD4(+)PD-1(low) T cells displayed a reduced cytokine production and cell-signal transduction. Clinically, we observed that the numbers of CD4(+) or CD8(+)PD-1(low) T cells significantly correlate with a reduced overall survival in FL patients (P=0.007 and 0.04 respectively; n=32). In contrast, the number of CD4(+)PD-1(high) T cells was not associated with patient outcome. Taken together, these results indicated that PD-1 expression defines two sub-populations with distinct functions that differentially impact patient outcome in FL.

Végran F, Apetoh L, Ghiringhelli F
Th9 cells: a novel CD4 T-cell subset in the immune war against cancer.
Cancer Res. 2015; 75(3):475-9 [PubMed] Related Publications
CD4 T cells are key components of the immune system that shape the anticancer immune response in animal models and in humans. The biology of CD4 T cells is complex because naïve T cells can differentiate into various subpopulations with various functions. Recently, a new population called Th9 cells was described. These cells are characterized by their ability to produce IL9 and IL21. They were first described in the context of parasite infections and allergic processes. However, some reports described their presence in the tumor bed in mice and humans. Their high secretion of IL9 and IL21 in the tumor bed contributes to their anticancer functions. Indeed, these cytokines trigger the activation of dendritic cells, mast cells, natural killer cells, and CD8 T cells to mount an antitumor immune response, thus explaining the remarkable ability of Th9 cells to control tumor growth. This review summarizes the latest advances in the Th9 field in cancer and focuses on their potential role as new tool for cell therapy.

Davis MR, Zhu Z, Hansen DM, et al.
The role of IL-21 in immunity and cancer.
Cancer Lett. 2015; 358(2):107-14 [PubMed] Related Publications
Interleukin-21 (IL-21), produced predominantly by CD4+ T cells and natural killer T (NKT) cells, is a newly discovered member of the common γ-chain family of cytokines. It has been implicated in many immunological processes and has been linked to autoimmune diseases, allergies and other inflammatory diseases. In recent years, the role for IL-21 in the pathogenesis of cancer has also been extensively studied. In this review, we will discuss recent advances concerning the role of IL-21 in immunological processes and the pathogenesis of cancer.

Balabko L, Andreev K, Burmann N, et al.
Increased expression of the Th17-IL-6R/pSTAT3/BATF/RorγT-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung.
Sci Rep. 2014; 4:7396 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (RORγT), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.

De Simone V, Franzè E, Ronchetti G, et al.
Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth.
Oncogene. 2015; 34(27):3493-503 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing immune/inflammatory cells. The exact contribution of each immune cell subset and cytokine in the activation of the intracellular pathways sustaining CRC cell growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs) and lamina propria mononuclear cells (LPMCs) from the tumor area and the macroscopically unaffected, adjacent, colonic mucosa of patients who underwent resection for sporadic CRC and show that the culture supernatants of TILs, but not of LPMCs, potently enhance the growth of human CRC cell lines through the activation of the oncogenic transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization of immune cell complexity of TILs and LPMCs reveals no differences in the percentages of T cells, natural killer T cells, natural killer (NK) cells, macrophages and B cells. However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and TNF-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A, IL-21, IL-22, TNF-α and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation. Mice therapeutically given BP-1-102, an orally bioavailable compound targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon tumorigenesis and diminished expression of STAT3/NF-kB-activating cytokines in the neoplastic areas. These data suggest that strategies aimed at the cotargeting of STAT3/NF-kB activation and interaction between them might represent an attractive and novel approach to combat CRC.

Li J, Mai J
Polymorphism in interleukin 21 gene is associated with decreased susceptibility to diffuse large B cell lymphoma.
Tumour Biol. 2014; 35(11):11295-300 [PubMed] Related Publications
Interleukin 21 (IL-21) plays a key role in innate and adaptive immunity. Polymorphisms in IL-21 gene may be greatly involved in various diseases. The aim of the study was to investigate the association between IL-21 genetic polymorphisms and the susceptibility to diffuse large B cell lymphoma (DLBCL). IL-21 -2498G/A and +78A/G polymorphisms were examined in 221 DLBCL patients and 243 healthy controls. We found that distributions of -2498GA genotype and -2498AA genotype were clearly decreased in DLBCL cases compared to healthy donors (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.43-0.92, P = 0.021; OR = 0.36, 95 % CI = 0.15-0.48, P < 0.001; data were adjusted for age and sex). Stratification analyses revealed that patients with advanced Ann Arbor stages (III+IV) had further decreased percentage of -2498AA genotype than those with primary stages (OR = 0.31, 95% CI = 0.13-0.87, P = 0.023; data were adjusted for age and sex). In addition, we evaluated the possible effect of IL-21 polymorphisms on gene expression by examining serum level of IL-21 in patients and controls. Data revealed that subjects carrying -2498AA genotype had significantly higher serum level of IL-21 than those with GG genotype or GA genotype. These data suggest that IL-21 -2498G/A polymorphism is associated with decreased susceptibility to DLBCL and may increase serum level of IL-21.

Huang Q, Du J, Fan J, et al.
The effect of proinflammatory cytokines on IL-17RA expression in NSCLC.
Med Oncol. 2014; 31(9):144 [PubMed] Related Publications
Interleukin-17 receptor (IL-17RA) is essential for proinflammatory cytokine IL-17-mediated pathogenesis of various tumors. IL-17RA is upregulated by some proinflammatory cytokines such as IL-21 and IL-15 and downregulated by IL-2, while the effect of IL-1β, IL-6, IL-8, TNF-α on IL-17RA expression in non-small cell lung caner (NSCLC) remains unknown. Our findings revealed that IL-17RA mRNA was increased in NSCLC tissues compared with the corresponding peritumor tissues (P = 0.0039) and high expression of IL-17RA protein in human NSCLC tissues was significantly associated with histological subtype, primary tumor size and clinical stages (P = 0.033, 0.033 and 0.011, respectively). IL-17RA mRNA expression was positively related to IL-1β, IL-6, IL-8, TNF-α mRNA expression (P = 0.013, 0.0001, 0.002 and 0.010 respectively) in NSCLC tissues. Furthermore, IL-1β, IL-6, IL-8, TNF-α upregulated IL-17RA mRNA and protein in A549 and H460 cells (all P < 0.05). It is suggested that IL-1β, IL-6, IL-8, TNF-α promoted IL-17RA expression in NSCLC and they may involve in IL-17RA signaling in NSCLC.

Li Y, Li D, Yan Z, et al.
Potential relationship and clinical significance of miRNAs and Th17 cytokines in patients with multiple myeloma.
Leuk Res. 2014; 38(9):1130-5 [PubMed] Related Publications
We evaluated the potential relationship between miRNAs and Th17 cytokines in multiple myeloma (MM) patients. Twenty-seven newly diagnosed myeloma patients and eight normal donors were studied. We determined that the relative expression levels of miR-15a/16, miR-34a, miR-194 in MM patients were significantly lower than those in the healthy controls with exception for miR-181a/b, which showed significantly higher in MM patients (P<0.05). In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated (P<0.05). The expression patterns of them were differentially present in various groups according to the International Staging System (ISS) criteria. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease.

Deniger DC, Maiti SN, Mi T, et al.
Activating and propagating polyclonal gamma delta T cells with broad specificity for malignancies.
Clin Cancer Res. 2014; 20(22):5708-19 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: To activate and propagate populations of γδ T cells expressing polyclonal repertoire of γ and δ T-cell receptor (TCR) chains for adoptive immunotherapy of cancer, which has yet to be achieved.
EXPERIMENTAL DESIGN: Clinical-grade artificial antigen-presenting cells (aAPC) derived from K562 tumor cells were used as irradiated feeders to activate and expand human γδ T cells to clinical scale. These cells were tested for proliferation, TCR expression, memory phenotype, cytokine secretion, and tumor killing.
RESULTS: γδ T-cell proliferation was dependent upon CD137L expression on aAPC and addition of exogenous IL2 and IL21. Propagated γδ T cells were polyclonal as they expressed TRDV1, TRDV2-2, TRDV3, TRDV5, TRDV7, and TRDV8 with TRGV2, TRGV3F, TRGV7, TRGV8, TRGV9*A1, TRGV10*A1, and TRGV11 TCR chains. IFNγ production by Vδ1, Vδ2, and Vδ1(neg)Vδ2(neg) subsets was inhibited by pan-TCRγδ antibody when added to cocultures of polyclonal γδ T cells and tumor cell lines. Polyclonal γδ T cells killed acute and chronic leukemia, colon, pancreatic, and ovarian cancer cell lines, but not healthy autologous or allogeneic normal B cells. Blocking antibodies demonstrated that polyclonal γδ T cells mediated tumor cell lysis through combination of DNAM1, NKG2D, and TCRγδ. The adoptive transfer of activated and propagated γδ T cells expressing polyclonal versus defined Vδ TCR chains imparted a hierarchy (polyclonal>Vδ1>Vδ1(neg)Vδ2(neg)>Vδ2) of survival of mice with ovarian cancer xenografts.
CONCLUSIONS: Polyclonal γδ T cells can be activated and propagated with clinical-grade aAPCs and demonstrate broad antitumor activities, which will facilitate the implementation of γδ T-cell cancer immunotherapies in humans.

Ahearne MJ, Allchin RL, Fox CP, Wagner SD
Follicular helper T-cells: expanding roles in T-cell lymphoma and targets for treatment.
Br J Haematol. 2014; 166(3):326-35 [PubMed] Related Publications
Follicular helper T-cells (Tfh cells) are a subset of CD4(+) T-cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and show high expression of surface markers CXCR5, ICOS, PDCD1 (PD-1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T-cell non-Hodgkin lymphoma: angioimmunoblastic T-cell lymphoma (AITL) and ~20% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET2 and DNMT3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL-NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre-clinical development.

van der Fits L, Out-Luiting JJ, Tensen CP, et al.
Exploring the IL-21-STAT3 axis as therapeutic target for Sézary syndrome.
J Invest Dermatol. 2014; 134(10):2639-47 [PubMed] Related Publications
Sézary syndrome is an aggressive cutaneous T-cell lymphoma. The malignant cells (Sézary cells) are present in skin, lymph nodes, and blood, and express constitutively activated signal transducer and activator of transcription (STAT)3. STAT3 can be activated by IL-21 in vitro and the IL-21 gene itself is a STAT3 target gene, thereby creating an autocrine positive feedback loop that might serve as a therapeutic target. Sézary cells underwent apoptosis when incubated with Stattic, a selective STAT3 inhibitor. STAT3 activation in Sézary cells did not affect expression of the supposed anti-apoptotic STAT3 target genes BCL2, BCL-xL, and SURVIVIN, whereas expression of (proto)oncogenes miR-21, TWIST1, MYC, and PIM1 was significantly increased. CD3/CD28-mediated activation of Sézary cells induced IL-21 expression, accompanied by STAT3 activation and increased proliferation. Blocking IL-21 in CD3/CD28-activated cells had no effects, whereas Stattic abrogated IL-21 expression and cell proliferation. Thus, specific inhibition of STAT3 is highly efficient in the induction of apoptosis of Sézary cells, likely mediated via the regulation of (proto)oncogenes. In contrast, blocking IL-21 alone seems insufficient to affect STAT3 activation, cell proliferation, or apoptosis. These data provide further insights into the pathogenic role of STAT3 in Sézary syndrome and strengthen the notion that STAT3 represents a promising therapeutic target in this disease.

Duckworth A, Glenn M, Slupsky JR, et al.
Variable induction of PRDM1 and differentiation in chronic lymphocytic leukemia is associated with anergy.
Blood. 2014; 123(21):3277-85 [PubMed] Related Publications
Despite antigen engagement and intact B-cell-receptor (BCR) signaling, chronic lymphocytic leukemia (CLL) cells fail to undergo terminal differentiation. We hypothesized that such failure may be due to anergy, as CLL cells exhibit variable levels of nonresponsiveness to surface IgM stimulation that is reversible in vitro. Moreover, anergy is associated with reduced differentiation capacity in normal B cells. We investigated responses of CLL cells to two potent differentiation-promoting agents, IL-21 and cytosine guanine dinucleotide-enriched oligo-deoxynucleotides. The induction of PR domain-containing protein 1 (PRDM1; also known as Blimp-1), a critical regulator of plasmacytic differentiation, by these agents was closely correlated but varied between individual cases, despite functionally intact IL-21 receptor- and Toll-like receptor 9-mediated signal transducer and activator of transcription 3, and nuclear factor-κB pathways. PRDM1 induction was inversely correlated with the extent of anergy as measured by the ability to mobilize intracellular Ca(2+) following BCR crosslinking. PRDM1 responsiveness was associated with other markers of differentiation and proliferation but not with differences in apoptosis. The ability to induce PRDM1 did correlate with differential transcriptional and epigenetic regulation of the PRDM1 gene. These studies extend our understanding of CLL pathobiology, demonstrating that reduced differentiation capacity may be a consequence of anergy. Epigenetic drugs may offer possibilities to reactivate PRDM1 expression as part of novel differentiation therapy approaches.

Hagn M, Blackwell SE, Beyer T, et al.
B-CLL cells acquire APC- and CTL-like phenotypic characteristics after stimulation with CpG ODN and IL-21.
Int Immunol. 2014; 26(7):383-95 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
CpG oligodeoxynucleotides (CpG) and IL-21 are two promising agents for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Recently, we reported that the combination of CpG and IL-21 (CpG/IL-21) can induce granzyme B (GrB)-dependent apoptosis in B-CLL cells. Here, we demonstrate that treatment of B-CLL cells with CpG and IL-21 results in the development of antigen-presenting cell (APC)-like cells with cytotoxic features. These properties eventually give rise to B-CLL cell apoptosis, independently of their cytogenetic phenotype, whereas normal B-cell survival is not negatively affected by CpG/IL-21. APC- and CTL-typical molecules found to be up-regulated in CpG/IL-21-stimulated B-CLL cells include GrB, perforin, T-bet, monokine-induced by IFN-γ and IFN-γ-inducible protein 10 (IP-10), as well as molecules important for cell adhesion, antigen cross-presentation and costimulation. Also induced are molecules involved in GrB induction, trafficking and processing, whereas the GrB inhibitor Serpin B9 [formerly proteinase inhibitor-9 (PI-9)] is down-modulated by CpG/IL-21. In conclusion, CpG/IL-21-stimulated B-CLL cells acquire features that are reminiscent of killer dendritic cells, and which result in enhanced immunogenicity, cytotoxicity and apoptosis. Our results provide novel insights into the aberrant immune state of B-CLL cells and may establish a basis for the development of an innovative cellular vaccination approach in B-CLL.

Zhang Y, Wang J, Ren M, et al.
Gene therapy of ovarian cancer using IL-21-secreting human umbilical cord mesenchymal stem cells in nude mice.
J Ovarian Res. 2014; 7:8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: The human umbilical cord mesenchymal stem cells (hUCMSCs) have the ability to migrate into tumors and therefore have been considered as an alternative source of mesenchymal progenitors for the therapy of malignant diseases. The present study was aimed to investigate effect of hUCMSCs as vehicles for a constant source of transgenic interleukin-21 (IL-21) on ovarian cancer in vivo.
METHODS: The hUCMSCs were engineered to express IL-21 via lentiviral vector- designated 'hUCMSCs-LV-IL-21', and then were transplanted into SKOV3 ovarian cancer xenograft-bearing nude mice. The therapeutic efficacy and mechanisms of this procedure on ovarian cancer was evaluated.
RESULTS: The isolated hUCMSCs were induced to differentiate efficiently into osteoblast and adipocyte lineages in vitro. The expressed IL-21 in the supernatant from hUCMSCs-LV-IL-21 obviously stimulated splenocyte's proliferation. The hUCMSCs-LV-IL-21 significantly reduced SKOV3 ovarian cancer burden in mice indicated by tumor sizes compared with control mice. The expressed IL-21 not only regulated the levels of IFN-γ and TNF-α in the mouse serum but also increased the expression of NKG2D and MIC A molecules in the tumor tissues. The down regulation of β-catenin and cyclin-D1 in the tumor tissues may refer to the inhibition of SKOV3 ovarian cancer growth in mice. In addition, hUCMSCs did not form gross or histological teratomas up to 60 days posttransplantation in murine lung, liver, stomach and spleen.
CONCLUSION: These results clearly indicate a safety and usability of hUCMSCs-LV- IL-21 in ovarian cancer gene therapy, suggesting the strategy may be a promising new method for clinical treatment of ovarian cancer.

Su Z, Sun Y, Zhu H, et al.
Th17 cell expansion in gastric cancer may contribute to cancer development and metastasis.
Immunol Res. 2014; 58(1):118-24 [PubMed] Related Publications
Th0 cells differentiate into Th1 or Th2 depending on multiple transcription factors acting on specific time points to regulate gene expression. Th17 cells, a subset of IL-17-producing T cells distinct from Th1 or Th2 cells has been described as key players in inflammation and autoimmune diseases as well as cancer development. In the present study, 66 patients with gastric cancer were included; the expression level of Th1- and Th17-related IFN-γ, IL-17, T-bet, RORγt in gastric cancer tissues and peripheral blood mononuclear cell (PBMC) were detected, analyzed the relationship between Th17 or Th1 infiltration and metastasis and explored the possible mechanism. Our results showed that IL-17 and RORγt expression were significantly increased in gastric cancer tissues and PBMC, especially, in metastasis patients; plasma IL-17 also increased; furthermore, the mRNA and protein levels of IL-1β, IL-21 and TGF-β were up-regulated. All the data indicated that Th17 was infiltrated the cancer tissue; IL-1β, IL-21 and TGF-β were also involved in gastric cancer development by promoting Th17 cell generation. From the above data, we speculated that Th17 cell expansion in gastric cancer may contribute to cancer development and metastasis.

Xiao M, Hu S, Tang J, et al.
Interleukin (IL)-21 promoter polymorphism increases the risk of thyroid cancer in Chinese population.
Gene. 2014; 537(1):15-9 [PubMed] Related Publications
Polymorphisms in Interleukin (IL)-21 have been researched in several cancers, but the association between IL-21 polymorphisms and thyroid cancer remains unclarified. This case-control study explored the role of five tagSNPs (rs12508721C>T, rs907715G>A, rs13143866G>A, rs2221903A>G and rs4833837A>G) in IL-21 gene in thyroid cancer development. IL-21 genotypes were examined in 615 thyroid cancer patients and 600 controls in Chinese population, and the associations with the risk of thyroid cancer were estimated by logistic regression. Moreover, the potential role of rs12508721C>T in thyroid cancer was further explored by biochemical assays. Compared with the rs12508721CC genotype, CT genotype presented a significantly decreased risk of thyroid cancer (adjusted odds ratios [OR]=0.72; 95%CI=0.57-0.94), the TT carriers had a further decreased risk of thyroid cancer (OR=0.56; 95%CI=0.41-0.87). Furthermore, our quantitative real-time PCR and Enzyme-linked immunosorbent assay (ELISA) results demonstrated that the presence of rs12508721T allele led to more IL-21 expression. However, no significant difference was found in genotype frequencies for other four sites between cases and controls. These findings suggested that rs12508721 polymorphism in IL-21 might be a genetic modifier for the development of thyroid cancer.

Cheng M, Zhi K, Gao X, et al.
Activation of cellular immunity and marked inhibition of liver cancer in a mouse model following gene therapy and tumor expression of GM-SCF, IL-21, and Rae-1.
Mol Cancer. 2013; 12(1):166 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Cancer is both a systemic and a genetic disease. The pathogenesis of cancer might be related to dampened immunity. Host immunity recognizes nascent malignant cells - a process referred to as immune surveillance. Augmenting immune surveillance and suppressing immune escape are crucial in tumor immunotherapy.
METHODS: A recombinant plasmid capable of co-expressing granulocyte-macrophage colony- stimulating factor (GM-SCF), interleukin-21 (IL-21), and retinoic acid early transcription factor-1 (Rae-1) was constructed, and its effects determined in a mouse model of subcutaneous liver cancer. Serum specimens were assayed for IL-2 and INF-γ by ELISA. Liver cancer specimens were isolated for Rae-1 expression by RT-PCR and Western blot, and splenocytes were analyzed by flow cytometry.
RESULTS: The recombinant plasmid inhibited the growth of liver cancer and prolonged survival of tumor-loaded mice. Activation of host immunity might have contributed to this effect by promoting increased numbers and cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) following expression of GM-SCF, IL-21, and Rae-1. By contrast, the frequency of regulatory T cells was decreased, Consequently, activated CTL and NK cells enhanced their secretion of INF-γ, which promoted cytotoxicity of NK cells and CTL. Moreover, active CTL showed dramatic secretion of IL-2, which stimulates CTL. The recombinant expression plasmid also augmented Rae-1 expression by liver cancer cells. Rae-1 receptor expressing CTL and NK cells removed liver cancer.
CONCLUSIONS: The recombinant expression plasmid inhibited liver cancer by a mechanism that involved activation of cell-mediated immunity and Rae-1 in liver cancer.

Sun YX, Kong HL, Liu CF, et al.
The imbalanced profile and clinical significance of T helper associated cytokines in bone marrow microenvironment of the patients with acute myeloid leukemia.
Hum Immunol. 2014; 75(2):113-8 [PubMed] Related Publications
BACKGROUND: Immunological disorder has shown to be related to the pathogenesis of acute myeloid leukemia (AML). The microenvironment of AML is immunosuppressive, favoring the survival of malignant hematopoietic cells. However, the systematic research on AML abnormal immune microenvironment, especially the T helper (Th) cells imbalance, remains unsettled.
DESIGN AND METHODS: The levels of cytokines in bone marrow plasma including Th1-associated cytokine (IFN-γ), Th2-associated cytokine (IL-4), Th17-associated cytokines (IL-17, IL-6, TGF-β, and IL-21), regulatory T cell (Treg)-associated cytokines (IL-35 and IL-10) and Th22-associated cytokine (IL-22) were examined by enzyme-linked immunosorbent assay (ELISA) in AML patients and controls. The relative expression levels of IL-4, IL-10, and IL-21 mRNA were analyzed by real time polymerase chain reaction (PCR).
RESULTS: Significant differences on cytokine levels tested were observed among the AML newly-diagnosed (ND) patients, AML patients in complete remission (CR) and controls except IL-21 and IL-35. In AML-ND group IFN-γ level was positively correlated with IL-21 or IL-22 level. Additionally, significant associations were observed between IL-17, IL-21 and some clinical characteristics.
CONCLUSION: Our results showed that many cytokines were abnormal in AML bone marrow microenvironment. The dysregulation of Th subsets cytokines is thought to contribute to the pathogenesis of AML.

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