Expression of activation‐induced, T cell–derived, and chemokine‐related cytokine/lymphotactin and its functional role in rheumatoid arthritis

Blaschke, Sabine; Middel, Peter; Dorner, Brigitte G.; Blaschke, Volker; Hummel, Klaus M.; Kroczek, Richard A.; Reich, Kristian; Benoehr, Peter; Koziolek, Michael; Müller, Gerhard A.

doi:10.1002/art.11171

Cited by 51 publications

(46 citation statements)

References 63 publications

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“…As recently shown, XCR1-positive thymic dendritic cells were attracted into medulla by XCL1-positive medullary thymic epithelial cells in vivo (20). The XCL1-XCR1 axis contributes to the progression of various diseases, including rheumatoid arthritis (21), Crohn disease (22), and many others (23). The role of XCL1-XCR1 in cell proliferation, migration, and invasion has been reported in a carcinoma of epithelial origin and an oral squamous carcinoma (24).…”

Section: Introductionmentioning

confidence: 83%

The Lymphotactin Receptor Is Expressed in Epithelial Ovarian Carcinoma and Contributes to Cell Migration and Proliferation

Kim

Rooper

Xie

et al. 2012

Molecular Cancer Research

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Chemokine receptor-ligand interactions are important to support functioning of both normal and pathologic cells. The expression and function of chemokine receptors in epithelial ovarian carcinoma (EOC) is largely unknown. Here, we report that the lymphotactin receptor (XCR1) was expressed in primary and metastatic human epithelial ovarian carcinoma (EOC) specimens and cell lines. In contrast, expression of XCR1 was not detected in the normal ovary or in human normal ovarian surface epithelial cells. Our data indicate that XCL1 and XCL2 are either present in the malignant ascites or expressed by the ovarian carcinoma cells. The addition of lymphotactin (XCL1 and XCL2) stimulated migration and proliferation of XCR1-positive cells. Reduction of XCR1 expression in ovarian carcinoma cell line SKOV-3 resulted in abrogated diaphragm and peritoneal wall tumor formation and in reduced frequency of colonic, splenetic, and liver nodules in an in vivo xenograft mouse model. Taken together, our data suggest that XCR1 is expressed early during the course of tumorigenic transformation and contributes towards increased cell migration and proliferation, which can facilitate the prometastatic behavior of EOC cells.

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Section: Introductionmentioning

confidence: 83%

The Lymphotactin Receptor Is Expressed in Epithelial Ovarian Carcinoma and Contributes to Cell Migration and Proliferation

Kim

Rooper

Xie

et al. 2012

Molecular Cancer Research

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“…We were able to demonstrate that, 24 hours after intrapulmonary delivery of XCL1-targeting siRNA, lung cell suspensions showed an increase in Alexa 488 relative fluorescence when compared with cells obtained from organs of untreated mice ( Figure 1A). XCL1 is mainly produced by activated CD8 T cells (20)(21)(22)(23)(24), including during chronic pulmonary tuberculosis (12). Thus, in the same experiment, we stained for CD8 and CD4 T cells to determine if the XCL1-targeting siRNA colocalized with target cells producing XCL1.…”

Section: Intrapulmonary Delivery Of Aerosolized Sirna Is Confined To mentioning

confidence: 99%

Intrapulmonary Delivery of XCL1-Targeting Small Interfering RNA in Mice Chronically Infected withMycobacterium tuberculosis

Rosas-Taraco

Higgins

Sánchez-Campillo

et al. 2009

Am J Respir Cell Mol Biol

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Mice infected for 60 days with Mycobacterium tuberculosis were treated with aerosolized XCL1-targeting small interfering RNA (siRNA) to induce local and transient suppression of XCL1/lymphotactin (an important chemokine in tuberculoid granuloma formation). The local pulmonary siRNA therapy resulted in a 50% decrease in the total amount of xcl1 gene transcripts at 3 days, and 40 to 50% protein suppression 3 and 5 days after treatment. Reduced XCL1 expression in the lungs was associated with decreased numbers of T lymphocytes, reduction in the IFN-g response, disorganized granulomatous lesions, and higher fibrosis when compared with control mice treated with either PBS or nontargeting siRNA. This indicates that a transient but strong modulation of the production of XCL1 in the lungs has a significant effect on the influx of IFN-g-secreting T cells, as well as local pathology, but without significantly altering containment of the infection.Keywords: tuberculosis; small interfering RNA; lymphotactin; XCL1; aerosol deliveryUp to now, in vivo studies addressing the role of specific components of the immune response during chronic infection with Mycobacterium tuberculosis were limited to the use of genetargeted knockout mice or systemic antibody and drug delivery. Although these methods provided important information in regards to tuberculosis infection, they do not allow for targeted examination of the lung-unique environment. Furthermore, gene knockout mice have the deficiency from the onset, thus not allowing more temporal manipulation of the immune response. For that reason, here, we tried an innovative approach in which newly developed immunotherapeutic molecules were applied directly to the lungs. Specifically, we transiently changed the lung immune environment by delivery of small interfering RNA (siRNA) transcripts.siRNA is a technology being used to evaluate the function of a variety of genes by transient silencing of mRNA expression. This new technology has been used as a therapeutic procedure to treat a variety of genetic, viral, and cancer-related diseases (1). It has demonstrated therapeutic benefits after both local and systemic administration into subcutaneous tissue, muscle, eye, and the central nervous system (2, 3). The major challenge of using siRNA as an immunotherapy is to deliver it into tissues and then into the cytoplasm of cells. Exceptions to this are the mucosal tissues and the lung. In these tissues, it has been demonstrated that siRNA uptake is extremely efficient and occurs even in the absence of transfection reagents (4-7). We took advantage of this, and developed a procedure to transiently block expression of proteins by using a noninvasive procedure for intrapulmonary delivery of aerosolized siRNA. Using this approach we studied changes in the immunopathology in mice chronically infected with M. tuberculosis.Tuberculosis is a global problem caused by infection with the M. tuberculosis bacilli. At the present time, one third of the world population has been exposed to this bacillus, and ...

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“…Lymphotactin/XCL1 is expressed in CD8ϩ T cells and is significantly increased in CD4ϩ,CD28Ϫ T cells from RA versus normal peripheral blood (78). Blaschke et al demonstratd that in RA ST, lymphotactin/XCL1 was mainly localized in CD4ϩ sublining cells (78). Incubation of lymphotacin/ XCL1 with RA ST fibroblasts resulted in downregulation of matrix metalloproteinase 2 (MMP-2) production.…”

Section: Chemokinesmentioning

confidence: 99%

Chemokines and their receptors in rheumatoid arthritis: Future targets?

Koch¹

2005

Arthritis & Rheumatism

224

208

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Expression of activation‐induced, T cell–derived, and chemokine‐related cytokine/lymphotactin and its functional role in rheumatoid arthritis

Cited by 51 publications

References 63 publications

The Lymphotactin Receptor Is Expressed in Epithelial Ovarian Carcinoma and Contributes to Cell Migration and Proliferation

The Lymphotactin Receptor Is Expressed in Epithelial Ovarian Carcinoma and Contributes to Cell Migration and Proliferation

Intrapulmonary Delivery of XCL1-Targeting Small Interfering RNA in Mice Chronically Infected withMycobacterium tuberculosis

Chemokines and their receptors in rheumatoid arthritis: Future targets?

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