Cutting Edge: Transgenic Expression of Human MUC1 in IL-10−/− Mice Accelerates Inflammatory Bowel Disease and Progression to Colon Cancer

Beatty, Pamela; Plevy, Scott E.; Sepulveda, Antonia R.; Finn, Olivera J.

doi:10.4049/jimmunol.179.2.735

Cited by 62 publications

(77 citation statements)

References 29 publications

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“…In humans, polymorphisms in MUC19 have been associated with an increased susceptibility to CD [54], and aberrant expression of mucin genes has been demonstrated in both inflamed and uninvolved intestinal epithelial biopsies [55], particularly at the edges of ulcers. The interruption of mucin secretion by MUC1 deletion results in a worsening of colitis in IL-10-deficient mice [56], while MUC2-deficient mice develop spontaneous intestinal damage and more severe chemical colitis [57]. Mucin disruption may therefore have an early role to play in increasing susceptibility to mucosal damage and the impaired healing of established ulcers.…”

Section: Other Factors Influencing Bacterial Clearance Intestinal Barmentioning

confidence: 99%

Crohn’s disease as an immunodeficiency

Hayee

Rahman

Sewell

et al. 2010

Expert Review of Clinical Immunology

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The pathogenesis of Crohn's disease (CD) has widely been regarded as the consequence of a dysregulated T-cell-mediated response to intestinal microbes, and the majority of the worldwide research effort has focused on characterizing and treating the chronic inflammatory phase of the disease. However, recent molecular biological and clinical investigations indicate that CD is actually a primary immunodeficiency. At first counter-intuitive, the apparent paradox of a pathogenic innate immune defect can be linked mechanistically to the granulomatous chronic inflammation characteristic of the disease. Genome-wide association studies have corroborated the involvement of innate immune dysfunction in the pathogenesis of CD, but less than 20% of the heritable risk is accounted for. By contrast, in vitro and in vivo stimulation of the immune system has highlighted novel areas of interest that may lead to the development of targeted therapeutic and diagnostic tools. Keywordsbacteria; Crohn's disease; immunodeficiency; innate immunity; macrophage; neutrophil Established intestinal lesions in Crohn's disease (CD) contain a massive, mixed inflammatory cell infiltrate associated with a complex storm of cytokines in a selfperpetuating, chronic inflammatory response [1][2][3]. Most research to date has focused on the the immunological characteristics of established lesions and drawn inferences about their initiation. The predominance of a classically Th1-associated cytokine profile in these lesions led to the assumption that T lymphocytes were central to the initial pathogenesis. More recently, the role of regulatory (Treg) FoxP3 + and IL-23-induced responsive Th17-type T lymphocytes has gained popularity [2,4,5]. Treg cell populations are diminished in patients with CD [6] and, although the hypothesis of CD as an immunodeficiency does not necessarily exclude defects in T-cell function, to date, no convincing intrinsic (primary) defect has been identified to implicate these cells in the pathogenesis of human CD.The hypothesis that immunodeficiency underpins the development of CD seems, at first, to be in direct contrast with histological observations of established intestinal lesions and the † Author for correspondence: Tel.: +44 207 679 6170 Fax: +44 207 679 0967 b.hayee@nhs.net. Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Europe PMC Funders Group Association between immunodeficiency diseases & CDThere is a well-known and strong association between primary immunodeficiency disorders and non-infectious granulomatous intestinal inflammation. Chronic granulomatous disease (CGD), glycogen storage disease type 1b, leukocyte adhesion deficiency, Chediak-Higashi and Hermansky-Pudlak syndromes are all strongly associated with intestinal inflammation that is indistinguishable from CD [...

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Section: Other Factors Influencing Bacterial Clearance Intestinal Barmentioning

confidence: 99%

Crohn’s disease as an immunodeficiency

Hayee

Rahman

Sewell

et al. 2010

Expert Review of Clinical Immunology

View full text Add to dashboard Cite

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“…PCR conditions were as follows: 95°C for 10 minutes; 39 cycles of 94°C for 1 minute, 59°C for 1 minute and 72°C for 1 minute; followed by 10 minutes at 72°C (Beatty et al, 2007). The MUC1 primer sequences are: forward 5Ј-CTTGCCAGCCA TAGCACCAAG-3Ј and reverse 5Ј-CTCCACGTCGTGGACATTGATG-3Ј.…”

Section: Pcr Genotypingmentioning

confidence: 99%

A conditional mouse model for human MUC1-positive endometriosis shows the presence of anti-MUC1 antibodies and Foxp3+ regulatory T cells

Budiu

Diaconu

Chrissluis

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARYEndometriosis is defined by the presence of tissue implants resembling endometrial glands outside of the uterus, at ectopic sites, frequently on the ovarian surface. The ectopic lesions are often invasive, resistant to therapy, and may predispose to endometrioid and clear cell ovarian tumors. The complex mechanisms leading to chronic endometriosis are mediated partly by impaired immune surveillance in the host. Although innate immunity has been addressed previously, the response of adaptive immune effectors to specific antigens has not been characterized, mostly because very few endometriosis antigens have been defined to date. We postulated that the mucin 1 (MUC1) glycoprotein, which is normally present on eutopic human endometrial glands and overexpressed in endometrioid and clear cell ovarian tumors, is also present in ectopic lesions of ovarian endometriosis. Furthermore, changes in MUC1 expression in endometriosis could promote adaptive anti-MUC1 immunity that might play a role in the malignant progression. To test our hypothesis, we crossed MUC1 transgenic mice, which express human MUC1 under the endogenous promoter, with the loxP-Stop-loxP-Kras G12D/+ (Kras) mice, in which endometriosis can be induced through Cre-loxP recombination. The double transgenic MUC1Kras mice develop benign, MUC1-positive ovarian lesions, closely resembling human endometriosis. Subsequent to disease induction, the mice generate high titers of IgM and IgG antibodies that are specific for MUC1. Antibodies appear early in disease and the predominance of the IgG1 subclass suggests Th2-driven immunity. Immune phenotyping revealed an accumulation of Foxp3+ CD4 regulatory T cells (Tregs) in the draining lymph nodes at late-stage disease. Furthermore, our observations in human endometriosis showed a similar recruitment of FOXP3+ CD4 T cells. Overall, our results reveal a Th2/Treg-dominant natural immunity in endometriosis with potential implications for cancer progression.

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“…1 Furthermore, MUC1 has been shown to accelerate premalignant inflammatory lesion transformation to malignancy. 2 We have previously reported on antitumor properties of a splice variant of MUC1, which is secreted and known as MUC1/sec. [3][4][5] MUC1/sec is found in normal 6,7 and tumor tissue, 8 but, interestingly, malignancy in ovarian lesions has been correlated with loss of its expression.…”

Section: Introductionmentioning

confidence: 99%

Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec

Ilkovitch¹,

López

2009

Blood

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IntroductionMucin 1 (MUC1) is a tumor antigen that is overexpressed on the surface of various epithelial tumor cells. The transmembrane isoform of MUC1 can promote tumor progression by creating a barrier around tumor cells against immune cells, sequestering compounds that suppress immune responses, interacting with growth-promoting signaling molecules, and aiding in the metastatic process. 1 Furthermore, MUC1 has been shown to accelerate premalignant inflammatory lesion transformation to malignancy. 2 We have previously reported on antitumor properties of a splice variant of MUC1, which is secreted and known as MUC1/sec. [3][4][5] MUC1/sec is found in normal 6,7 and tumor tissue, 8 but, interestingly, malignancy in ovarian lesions has been correlated with loss of its expression. 9 DA-3 murine mammary tumor cells expressing MUC1/sec (DA-3/sec) are rejected from BALB/c mice, whereas expression of the transmembrane isoform of MUC1 (MUC1/TM; DA-3/TM) has little effect. [3][4][5] DA-3/sec cells, however, lead to tumor development in immunocompromised BALB/c nude mice, or BALB/c mice depleted of T lymphocytes. Furthermore, depletion of innate immune cells allows initial tumor growth, followed by tumor regression once the adaptive immune response develops. 3 We have determined that MUC1/sec modulates various factors involved in tumorigenesis, such as up-regulating signal transducer and activator of transcription 1 (Stat1), leading to the downregulation of tumor-derived urokinase plasminogen activator (uPA), a serine protease correlated with tumor progression in human cancers. 5 Other investigators have reported that tumor cell expression of MUC1/TM recruits immature dendritic cells (DCs). 10 In our previous studies, we analyzed whether there was a difference in recruitment of immune cells to DA-3/TM or DA-3/sec cells, and we reported that DA-3/TM cells recruit more GR-1 ϩ cells than DA-3/sec tumor cells. 3 We and others have also previously described that a myeloid population that accumulates in many tumor models, and are known as CD11b ϩ GR-1 ϩ myeloid-derived suppressor cells (MDSCs), [11][12][13][14][15][16] orchestrate immunosuppression by suppressing T cells. 13 In this study, we show that GR-1 ϩ cells that are recruited to high levels by DA-3/TM cells, but not DA-3/sec, are in fact MDSCs. Furthermore, we report for the first time that uPA, which is down-regulated by MUC1/sec, is capable of recruiting MDSCs. This is a new mechanism by which uPA may be augmenting and contributing to tumor development.MUC1 has also been shown to impair differentiation and function of DCs, 17 along with inducing a regulatory phenotype with immune-suppressive cytokine secretion. 10,17,18 We therefore investigated whether in addition to modulating recruitment of MDSCs, MUC1/sec can alter MDSC-suppressive mechanisms. We found that whereas DA-3/TM cells induce high levels of arginase in MDSCs, associated with suppression, 19 DA-3/sec cells block that induction. Furthermore, a unique peptide found in MUC1/sec and called immunoenhancing pe...

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Cutting Edge: Transgenic Expression of Human MUC1 in IL-10−/− Mice Accelerates Inflammatory Bowel Disease and Progression to Colon Cancer

Cited by 62 publications

References 29 publications

Crohn’s disease as an immunodeficiency

Crohn’s disease as an immunodeficiency

A conditional mouse model for human MUC1-positive endometriosis shows the presence of anti-MUC1 antibodies and Foxp3+ regulatory T cells

Urokinase-mediated recruitment of myeloid-derived suppressor cells and their suppressive mechanisms are blocked by MUC1/sec

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