Novel immunomodulatory effects of adiponectin on dendritic cell functions

Tsang, Julia Yuen Shan; Li, Daxu; Ho, Derek Hoi Hang; Jiao, Peng; Xu, Aimin; Lamb, Jonathan R.; Chen, Yan; Tam, Paul Kwong Hang

doi:10.1016/j.intimp.2010.11.009

Cited by 80 publications

(69 citation statements)

References 31 publications

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“…Contrastingly, others have reported that APN can induce the expansion of regulatory T cells via its interaction with DCs (43). Our work indicates that at least 40 µg/mL APN is required to induce IL10 production (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 94%

Adiponectin Receptor Signaling on Dendritic Cells Blunts Antitumor Immunity

et al. 2014

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Immune escape is a fundamental trait of cancer. Dendritic cells (DC) that interact with T cells represent a crucial site for the development of tolerance to tumor antigens, but there remains incomplete knowledge about how DC-tolerizing signals evolve during tumorigenesis. In this study, we show that DCs isolated from patients with metastatic or locally advanced breast cancer express high levels of the adiponectin receptors AdipoR1 and AdipoR2, which are sufficient to blunt antitumor immunity. Mechanistic investigations of ligand–receptor interactions on DCs revealed novel signaling pathways for each receptor. AdipoR1 stimulated IL10 production by activating the AMPK and MAPKp38 pathways, whereas AdipoR2 modified inflammatory processes by activating the COX-2 and PPARγ pathways. Stimulation of these pathways was sufficient to block activation of NF-κB in DC, thereby attenuating their ability to stimulate antigen-specific T-cell responses. Together, our findings reveal novel insights into how DC-tolerizing signals evolve in cancer to promote immune escape. Furthermore, by defining a critical role for adiponectin signaling in this process, our work suggests new and broadly applicable strategies for immunometabolic therapy in patients with cancer.

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Section: Discussionmentioning

confidence: 94%

Adiponectin Receptor Signaling on Dendritic Cells Blunts Antitumor Immunity

et al. 2014

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“…Tsang et al (47) reported that CD4 + CD25 + Foxp3 + T cells increased in the cocultures of T cells and APN-stimulated DCs. In contrast, our results showed that APN treatment had no effect on, or even slightly decreased, Foxp3 + T cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Adiponectin Induces Dendritic Cell Activation via PLCγ/JNK/NF-κB Pathways, Leading to Th1 and Th17 Polarization

Jung

Kim

Hong

et al. 2012

The Journal of Immunology

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Adiponectin (APN) is a crucial regulator for many inflammatory processes, but its effect on Th cell-mediated responses has not been fully understood. Thus, we investigated the immune-modulatory effects of APN on dendritic cells (DCs) controlling Th cell polarization. APN induced maturation and activation of DCs, as demonstrated by the increased expression of MHC class II, costimulatory molecules in both mouse and human DCs, and it significantly enhanced production of proinflammatory cytokines. APN triggered degradation of IκB proteins, nuclear translocation of NF-κB p65 subunit, and phosphorylation of MAPKs in DCs. Pretreatment with a phospholipase C (PLC)γ inhibitor and a JNK inhibitor suppressed IL-12 production and NF-κB binding activity. Additionally, PLCγ inhibitor downregulated phosphorylation of JNK, indicating that PLCγ and JNK may be upstream molecules of NF-κB. Importantly, APN-treated DCs significantly induced both Th1 and Th17 responses in allogeneic CD4+ T cells. The addition of a neutralizing anti–IL-12 mAb to the cocultures abolished the secretion of IFN-γ, whereas the blockage of IL-23 and IL-1β suppressed APN-induced IL-17 production. Immunization of mice with OVA-pulsed, APN-treated DCs efficiently led to Ag-specific Th1 and Th17 cell responses. Taken together, these results demonstrated that APN effectively induced activation of DCs through PLCγ/JNK/NF-κB-signaling pathways, leading to enhanced Th1 and Th17 responses.

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“…Adiponectin receptors are upregulated on T cells following activation, and adiponectin stimulation of CD8 + T cells inhibits proliferation and IL-2 production, as well as production of the pro-inflammatory cytokines IFN-γ and TNFα (37). Additionally, adiponectin suppresses DC IL-12p40 production and co-stimulatory molecule expression, and in DC/T-cell co-cultures favor the generation of regulatory T cells (38). …”

Section: Hormonesmentioning

confidence: 99%

Soluble Mediators Regulating Immunity in Early Life

2014

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Soluble factors in blood plasma have a substantial impact on both the innate and adaptive immune responses. The complement system, antibodies, and anti-microbial proteins and peptides can directly interact with potential pathogens, protecting against systemic infection. Levels of these innate effector proteins are generally lower in neonatal circulation at term delivery than in adults, and lower still at preterm delivery. The extracellular environment also has a critical influence on immune cell maturation, activation, and effector functions, and many of the factors in plasma, including hormones, vitamins, and purines, have been shown to influence these processes for leukocytes of both the innate and adaptive immune systems. The ontogeny of plasma factors can be viewed in the context of a lower effectiveness of immune responses to infection and immunization in early life, which may be influenced by the striking neonatal deficiency of complement system proteins or enhanced neonatal production of the anti-inflammatory cytokine IL-10, among other ontogenic differences. Accordingly, we survey here a number of soluble mediators in plasma for which age-dependent differences in abundance may influence the ontogeny of immune function, particularly direct innate interaction and skewing of adaptive lymphocyte activity in response to infectious microorganisms and adjuvanted vaccines.

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Novel immunomodulatory effects of adiponectin on dendritic cell functions

Cited by 80 publications

References 31 publications

Adiponectin Receptor Signaling on Dendritic Cells Blunts Antitumor Immunity

Adiponectin Receptor Signaling on Dendritic Cells Blunts Antitumor Immunity

Adiponectin Induces Dendritic Cell Activation via PLCγ/JNK/NF-κB Pathways, Leading to Th1 and Th17 Polarization

Soluble Mediators Regulating Immunity in Early Life

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