Adiponectin Deficiency Suppresses Lymphoma Growth in Mice by Modulating NK Cells, CD8 T Cells, and Myeloid-Derived Suppressor Cells

Han, Sora; Jeong, Ae Lee; Lee, Sunyi; Park, Jeong Su; Kim, Kwang Dong; Choi, Inpyo; Yoon, Suk Ran; Lee, Myung Sok; Lim, Jong‐Seok; Han, Seoung Hyun; Yoon, Do Young; Yang, Young

doi:10.4049/jimmunol.1202487

Cited by 22 publications

(25 citation statements)

References 43 publications

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“…These findings indicate a reversal in the functional phenotype of the TAMs in apn −/− mice or at least a reduction in their capacity to promote tumor growth. In addition, the altered frequencies of NK cells, CD4 and CD8 T cells we observed are in agreement with other reports which demonstrated the importance of immune effector cells in a murine lymphoma model in apn −/− mice . In apn −/− mice inoculated with MN/MCA1 cells, we observed a smaller tumor mass with lower number of TAMs compared to WT mice.…”

Section: Discussionsupporting

confidence: 93%

“…Recently, the ability of APN to modify tumor related immune cell function has generated interest. It has been reported that altered functions of CD8 + T cells, NK cells and myeloid derived suppressive cells (MDSCs) in APN deficient mice contributed to the suppression of lymphoma growth . These findings imply that APN can modulate not only on tumor cell function but also the immune system during tumor development.…”

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confidence: 99%

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Modulatory effects of adiponectin on the polarization of tumor-associated macrophages

Jiao

Tsang

et al. 2015

Int. J. Cancer

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The plasticity of macrophages with selective functional phenotypes partially arises in respective to their microenvironment. Tumor-associated macrophages (TAMs) may promote disease progression with tumor specific manner. Here we report that in pediatric malignant soft-tissue tumors, the presence of TAMs and expression of adiponectin (APN) are heterogeneous. Both APN and TAMs had high expression in rhabdomyosarcoma, especially in the malignant subtype, alveolar rhabdomyosarcoma. To investigate the mode of action of APN on TAM activation, a murine MN/MCA1 sarcoma model was used. The Results revealed that exogenous APN had no effect on MN/MCA1 proliferation but tumor size was markedly reduced in apn 2/2 mice versus WT controls. The accumulation of TAMs in apn 2/2 mice was also reduced which correlated to downregulated serum levels of MCP-1. Likewise, TAMs in apn 2/2 mice exhibited a M1-like phenotype, characterized by increase in MHC II high population and M1 phenotypic markers, such as iNOS gene and serum TNF-a accompanied by a decrease in M2 markers, namely YM1 gene and serum IL-10. In addition, APN deficiency increased the number of CD4 1 T cells, CD8 1 T cells and NK cells in tumors and reduced tumor metastasis. The altered phenotype of TAMs in apn 2/2 mice was associated with a marked decrease in phospho-p38 and treatment with a p38 MAPK inhibitor significantly reduced tumor size and increased MHC II expression on TAMs in WT mice, implying p38 MAPK signaling pathway may contribute to APN-mediated TAM polarization. Collectively, our findings suggest that APN may have a potential role in regulating soft tissue sarcoma growth.

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

Modulatory effects of adiponectin on the polarization of tumor-associated macrophages

Jiao

Tsang

et al. 2015

Int. J. Cancer

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“…In recent years, a new granulocytic population have been described as CD11b ϩ Gr-1 ϩ F4/80 Ϫ Ly-6c int Ly-6G hi with anti-inflammatory role in inflammation induced by tumor, also known as granulocytic myeloid-derived suppressor cells (g-MDSC or MDSC) (8,48,66). Adipo Ϫ/Ϫ mice bearing EL4 tumors have a significantly decreased recruitment of granulocytic MDSC (21). Importantly, BAL IL-6 was higher in Adipo Ϫ/Ϫ vs. WT mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice

Kasahara¹,

Kim

Mathews³

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24-72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin-deficient (Adipo(-/-)) mice. The IL-17/granulocyte colony-stimulating factor (G-CSF) axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo(-/-) mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 (Adipo(-/-)/IL-6(-/-)) and exposed them to ozone or air. In ozone-exposed mice, bronchoalveolar lavage (BAL) neutrophils, IL-6, and G-CSF, and pulmonary Il17a mRNA expression were greater in Adipo(-/-) vs. wild-type mice, but reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice. IL-17A(+) F4/80(+) cells and IL-17A(+) γδ T cells were also reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice exposed to ozone. Only BAL neutrophils were reduced in IL-6(-/-) vs. wild-type mice. In wild-type mice, IL-6 was expressed in Gr-1(+)F4/80(-)CD11c(-) cells, whereas in Adipo(-/-) mice F4/80(+)CD11c(+) cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 (Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo(-/-) vs. wild-type mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo(-/-) vs. wild-type mice but reduced in Adipo(-/-)/IL-6(-/-) vs. Adipo(-/-) mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo(-/-) mice after ozone exposure and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A, and G-CSF.

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“…Although an experimental study found that adiponectin deficiency inhibits lymphoma growth in mice by regulating NK cells, CD8+ T cells and myeloid-derived suppressor cells [97], controversial data exists in the literature in relation to plasma adiponectin as potential biomarker of hematopoietic cancer from "lymphoid" origin. An increase [84,89,90], no change [20,74,84,86,91], and even a decrease in circulating adiponectin levels have been reported [75,78,85,87,88].…”

Section: Adiponectin and Hematopoietic Cancer From "Lymphoid" Originmentioning

confidence: 99%

Adiponectin as a biomarker linking obesity and adiposopathy to hematologic malignancies

Christodoulatos

2015

Hormone Molecular Biology and Clinical Investigation

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Higher body mass index and adiposopathy have been associated with increased risk of hematologic malignancies such as leukemia, multiple myeloma, myeloproliferative disorders, Hodgkin's and non-Hodgkin's lymphoma, and myelodysplastic syndromes. Adiponectin is a multimeric protein of the white adipose tissue presenting anti-inflammatory, insulin-sensitizing, anti-atherogenic, cardioprotective, and anti-neoplastic properties. Its anti-neoplastic actions are manifested via two mechanisms: (i) direct action on tumor cells by enhancing receptor-mediated signaling pathways and (ii) indirect action by regulating inflammatory responses, influencing cancer angiogenesis, and modulating insulin sensitivity at the target tissue site. In the bone marrow milieu, adiponectin and its main receptors are expressed by the majority of bone marrow stromal cell populations influencing hematopoietic stem cells function. Adiponectin may represent a molecular mediator relating adiposopathy with leukemogenesis and myelomagenesis. Several epidemiological studies conducted to date relate hypoadiponectinemia to the risk of myeloid-derived hematopoietic cancer and multiple myeloma. Adiponectin may be a promising biomarker with potential diagnostic and prognostic utility in determining the likelihood of myeloma and leukemia progression in certain cohorts of monoclonal gammopathy of undetermined significance patients and in myeloid hematologic malignancies, respectively. This review summarizes experimental and epidemiologic data regarding the role of adiponectin in hematologic malignancies in the context of adiposopathy. Enhancement of endogenous adiponectin, adiponectin replacement, or manipulation of adiponectin receptor sensitivity may be an attractive goal for prevention and an effective therapeutic strategy against hematopoietic cancer, specifically in overweight/obese individuals. Further studies are required to elucidate the role of the bone marrow microenvironment adiponectin in complex interactions involved in preleukemic and leukemic states.

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Adiponectin Deficiency Suppresses Lymphoma Growth in Mice by Modulating NK Cells, CD8 T Cells, and Myeloid-Derived Suppressor Cells

Cited by 22 publications

References 43 publications

Modulatory effects of adiponectin on the polarization of tumor-associated macrophages

Modulatory effects of adiponectin on the polarization of tumor-associated macrophages

Pivotal role of IL-6 in the hyperinflammatory responses to subacute ozone in adiponectin-deficient mice

Adiponectin as a biomarker linking obesity and adiposopathy to hematologic malignancies

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