Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation

Tian, Zhigang; Sun, Rui; Wei, Haiming; Gao, Bin

doi:10.1016/s0006-291x(02)02462-2

Cited by 231 publications

(166 citation statements)

References 30 publications

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“…[19][20][21] A deficiency of leptin is responsible for severe impairments of both innate and acquired immunity, including the differentiation and activation of NK cells. 22 During the early phase of metastasis, cancer cells are recognized and destroyed by the host's immune system, especially by NK cells. 23,24 Therefore, we have focused on NK cell function in obesity-promoted metastasis.…”

Section: Discussionmentioning

confidence: 99%

Severe pulmonary metastasis in obese and diabetic mice

Mori

Sakurai

Choo

et al. 2006

Intl Journal of Cancer

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Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. ' 2006 Wiley-Liss, Inc.Key words: obesity; metastasis; NK cell; leptin Obesity has become one of the most critical problems in human health, because it can lead to more serious disorders such as cardiovascular disease, pulmonary disorders and metabolic syndrome. 1 Attention has recently been focused on the influence of obesity on carcinogenesis and the progression of cancer. A cohort study in the United States revealed that an increased body-mass index is significantly associated with higher rates of death because of cancer. 2 In addition, obesity increases the risk of cancer developing in the prostate, colorectum, breast, endometrium and elsewhere. [3][4][5][6][7] Similarly, the risk of renal cell cancer is increased in patients with diabetes mellitus, a disease closely associated with obesity. 8 These observations are well correlated with the finding that the carcinogen-induced multiplicity of premalignant colonic lesions is increased in db/db obese and diabetic mice. 9 Metastasis is the major cause of mortality in cancer patients. Maehle et al. reported that breast cancer patients with obesity had a higher risk of lymph node metastases. 10 Although evidence has accumulated of an association of cancer with obesity, the influence of obesity and diabetes on cancer metastasis remains to be investigated. In addition, the mechanisms by which obesity promotes the development and progression of cancer are still unknown. Material and methods MiceMale C57BL/6, C57BL/KsJ-db/db (db/db) and C57BL/6J-ob/ob (ob/ob) mice, 5-6 weeks old, were maintained in a specific pathogen-free barrier facility under laminar airflow conditions with a 12-hr light/dark cycle, a controlled humidity of 55% 6 5% and a temperature of 22°C 6 1°C. This study was conducted in accordance with the standards outlined in the Guidelines for the Care and Use of Laboratory Animals of the University of Toyama. Cell cultureB16-BL6 ...

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Section: Discussionmentioning

confidence: 99%

Severe pulmonary metastasis in obese and diabetic mice

Mori

Sakurai

Choo

et al. 2006

Intl Journal of Cancer

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“…18,45,49,50 In NK cells, leptin is involved in all processes of cell development, differentiation, proliferation, activation and cytotoxicity, and this effect is mediated by STAT3 activation. 51 Based on the complex activation network of the STAT proteins, further analyses of their regulation by leptin signaling in immune cells will merit a better understanding of leptin-mediated immune modulation. 18 The MAPK, the insulin receptor substrate 1 and the phosphatidylinositol 3-kinase pathways are also important to mediate leptin's action on immune T cells.…”

Section: Leptin and Autoimmunity M Vadacca Et Al 204mentioning

confidence: 99%

Leptin in immuno-rheumatological diseases

et al. 2011

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Leptin is one of the most important hormones secreted by adipocytes, with a variety of physiological roles related to the control of metabolism and energy homeostasis. Since its discovery in 1994, leptin has attracted increasing interest in the scientific community for its pleiotropic actions. One of these functions is the relationship between nutritional status and immune competence. It structurally resembles proinflammatory cytokines, such as IL-6 and IL-12. The cytokine-like structural characteristic of leptin is implicative of its function in regulating immune responses. The role of leptin in regulating immune responses has been assessed in vitro as well as in clinical studies. It has been shown that disease conditions of reduced leptin production are associated with increased infection susceptibility. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with the increased secretion of leptin and the production of proinflammatory pathogenic cytokines. In this paper, we review the most recent advances of the role of leptin in immune-rheumatological diseases, and we discuss whether strategies aimed at modifying leptin levels could represent innovative and therapeutic tools for autoimmune disorders. Keywords: adipokines; autoimmune diseases; leptin; rheumatic diseases INTRODUCTIONThe existence of a factor secreted by white adipose tissue (WAT), which acts to control feeding, weight and WAT mass, was first proposed by Kennedy 1 and is supported by monogenic mutations resulting in obesity. [2][3][4] WAT is composed of adipocytes filled mainly with triacylglycerol and embedded in loose connective tissue containing adipocyte precursors, fibroblasts, immune and other cells. Obesity, the condition that originally motivated the research on WAT, is characterized by low-grade systemic inflammation. It is thought that excess WAT can contribute to the maintenance of obesity through inflammation-inducing lipotoxicity by secreting factors that stimulate the synthesis of inflammatory agents in other organs and by secreting inflammatory agents itself. 5 The current view of WAT states that it is an active contributor to body homeostasis by sending out and responding to signals that modulate appetite, energy expenditure, insulin sensitivity, the endocrine and reproductive systems, bone metabolism, inflammation and immunity. 6 Several findings have converged to indicate that adipocytes share certain properties with immune cells, such as complement activation 7 and proinflammatory cytokine production. 8 Fat cell precursors also share features with macrophages. Numerous genes that code for transcription factors, cytokines, inflammatory signaling molecules, and fatty acid transporters are essential for adipocyte biology and are also expressed and functional in macrophages. 9 Adipose tissue secrets a variety of factors: the term 'adipokine' is generally given to any protein that can be synthesized and secreted by adipocytes. Among these factors, only leptin and adiponectin (and possibly resistin, adipsi...

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“…Cytotoxicity was assessed by a 51 Cr release assay as described previously (28). YAC-1 cells (Cell Bank of Chinese Science Academy), which are lymphoma cells generally used to test the natural cytotoxicity of NK cells, were used as target cells.…”

Section: Cr Release Assaymentioning

confidence: 99%

Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice

Zhou

Wei

Sun

et al. 2007

The Journal of Immunology

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116

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The role of TLRs on intestinal epithelial cells (IECs) is controversial, and the mechanisms by which TLRs influence mucosal homeostasis are obscure. In this study, we report that genomic dsRNA from rotavirus, and its synthetic analog polyinosinic-polycytidylic acid (poly(I:C)), induce severe mucosal injury in the small intestine. Upon engaging TLR3 on IECs, dsRNA triggers IECs to secrete IL-15, which functions to increase the percentage of CD3+NK1.1+ intestinal intraepithelial lymphocytes (IELs) and enhances the cytotoxicity of IELs. Moreover, The CD3+NK1.1+ IELs are proved as CD8αα+ IELs. These results provide direct evidence that abnormal TLR3 signaling contributes to breaking down mucosal homeostasis and the first evidence of pathogenic effects mediated by CD8αα+ IELs. The data also suggest that genomic dsRNA may be involved in the pathogenesis of acute rotavirus gastroenteritis.

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Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation

Cited by 231 publications

References 30 publications

Severe pulmonary metastasis in obese and diabetic mice

Severe pulmonary metastasis in obese and diabetic mice

Leptin in immuno-rheumatological diseases

Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice

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