Tetraspanin CD9 Negatively Regulates Lipopolysaccharide-Induced Macrophage Activation and Lung Inflammation

Suzuki, Mayumi; Tachibana, Isao; Takeda, Yoshito; He, Ping; Minami, Seigo; Iwasaki, Takeo; Kida, Hiroshi; Goya, Sho; Kijima, Takashi; Yoshida, Mitsuhiro; Kumagai, Toru; Osaki, Tadashi; Kawase, Ichiro

doi:10.4049/jimmunol.0802797

Cited by 86 publications

(86 citation statements)

References 30 publications

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“…Whole cell lysates were separated in a 10% to 20% gradient gel (Wako) by SDS-PAGE under nonreducing conditions, transferred to Immobilon-P membrane (Millipore) as described previously (35). Proteins were immunoblotted with proper primary antibodies (diluted 1:500-1,000) followed by appropriate horseradish peroxidase-conjugated secondary antibodies (diluted 1:1,000, donkey anti-rabbit or sheep antimouse IgG; Amersham) for 1 hour at room temperature.…”

Section: Immunoblottingmentioning

confidence: 99%

Cell Surface Tetraspanin CD9 Mediates Chemoresistance in Small Cell Lung Cancer

et al. 2010

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Small cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearance of widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial therapy. A theory of cell adhesion-mediated drug resistance is thought to be a principal mechanism in which extracellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found that the tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from three of seven relapsed patients, whereas chemonaïve primary tumors from 16 patients were CD9 negative with only one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisplatin or etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to either of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via β1 integrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of the chemoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreover, selective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering RNA triggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell adhesion-mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC. Cancer Res; 70(20); 8025-35. ©2010 AACR.

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Section: Immunoblottingmentioning

confidence: 99%

Cell Surface Tetraspanin CD9 Mediates Chemoresistance in Small Cell Lung Cancer

et al. 2010

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“…For example, tetraspanins CD9 and CD151 regulate tumor progression, either negatively (CD9) or positively (CD151), in multiple tumor types (7,8). Specifically regarding lung diseases, CD9 plays protective roles in lung inflammation and emphysema, which we have studied using genetic models in mice (9,10).…”

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confidence: 99%

Tetraspanin CD151 Protects against Pulmonary Fibrosis by Maintaining Epithelial Integrity

Tsujino

Takeda

Arai

et al. 2012

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. Objectives: To investigate the role of tetraspanin CD151 in pulmonary fibrosis. Methods: CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wildtype mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. Measurements and Main Results: A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased a-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. Conclusions: CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.Keywords: alveolar epithelial cell; adhesion strength; epithelial-tomesenchymal transition; Smad2; CD9 Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology; the condition has a poor prognosis, and there are no effective treatments. IPF is characterized by progressive deposition of collagen and other extracellular matrix (ECM) molecules (1). Previously, IPF was viewed as a "smoldering" inflammatory response that ultimately led to chronic lung injury with subsequent fibrosis. However, inflammation is now not regarded as crucial to the etiology, largely because current antiinflammatory therapies for IPF have provided little benefit for patients (2). Instead, it has become clear that abnormal behavior of alveolar epithelial cells (AECs) is a primary source of the development of pulmonary fibrosis (3, 4). The disease process is initiated through repetitive injury of AECs, causing AEC activation, which in turn leads to recruitment of immune cells and fibroblasts within the lung microenvironment. Aberrant activated AECs, in cooperation with migrated immune cells and fibroblasts, secrete and activate latent transforming growth factor (TGF)-b 1 , as well as other profibrotic factors, which promote the differentiation of fibroblasts and AECs to myofibroblasts, resulting in overproduction of ECM in the lung.The tet...

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“…Since the classically activated M1 macrophages are known to be induced by LPS [78], it can be hypothesized that CD9 controls the polarization of M1 macrophages. This is supported by the finding that CD9-deficient mice show enhanced macrophage infiltration and TNF␣ production in the lung after LPS administration in vivo [80]. The presence of CD81 into the CD14/TLR4 receptor complex has also been reported [81], but the significance remains largely unknown.…”

Section: Macrophagesmentioning

confidence: 76%