Phosphatidylserine-Specific Receptor Contributes to TGF-.BETA. Production in Macrophages through a MAP Kinase, ERK

Otsuka, Masaki; Goto, Kentaro; Tsuchiya, Satoshi; Aramaki, Yukihiko

doi:10.1248/bpb.28.1707

Cited by 34 publications

(28 citation statements)

References 36 publications

(25 reference statements)

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“…antibody We previously reported that the ERK signaling pathway via PS-specific receptors was involved in the production of TGFb1 following the treatment with PS-liposomes [14,19]. How- ever, it remains unclear how PS-liposomes activate ERK in macrophages.…”

Section: Activation Of Akt By Ps-liposomes or Anti-ps-receptormentioning

confidence: 96%

“…Additionally, we reported that TGF-b1 is one of the factors produced by PS-liposomes that suppresses the production of NO in macrophages, and extracellular signal-regulated kinase (ERK), a MAP kinase, signaling pathway via PS-specific receptors is intimately involved in the production of TGF-b1 [14,19]. However, the precise mechanism of TGF-b1 production by PS-liposomes is still unresolved.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of phosphatidylinositol‐3‐kinase and ERK pathways in the production of TGF‐β1 by macrophages treated with liposomes composed of phosphatidylserine

2007

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We explored the involvement of phosphatidylinositol 3-kinase (PI3K) and ERK pathways in the production of TGFb1 by macrophages treated with liposomes composed of phosphatidylserine (PS-liposomes). PS-liposomes activated Akt, downstream of the PI3K signal cascade, and ERK which led to the expression of TGF-b1. PI3K inhibitors, LY294002 and wortmannin, inhibited the activation of Akt and ERK following the treatment with PS-liposomes. These inhibitors also suppressed the production of TGF-b1. Furthermore, PS-liposomes activated macrophages to induce TGF-b1 expression through PS-specific receptors. These findings suggested that a PI3K-ERK signaling pathway via the PS-receptor is intimately involved in the production of TGF-b1 which regulates macrophage functions.

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Section: Activation Of Akt By Ps-liposomes or Anti-ps-receptormentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Involvement of phosphatidylinositol‐3‐kinase and ERK pathways in the production of TGF‐β1 by macrophages treated with liposomes composed of phosphatidylserine

2007

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“…Earlier reports showed that LPSinduced IL-12 production in normal macrophages is regulated by the activation of p38MAPK signaling [29], and activation of ERK1/2 in macrophages is associated with the production of IL-10 and TGF-β and negatively regulates IL-12 production [30][31][32]. CuNGmediated ROS generation leads to the activation of p38MAPK that upregulated the initial IL-12 production and to the activation of ERK1/2 pathway along with GSH upregulation separately, found responsible for IFN-γ production by TAMs.…”

Section: Novel Approach For Modulation Of Tam Behavior By Cungmentioning

confidence: 99%

Potential Anticancer Drugs Targeting Immune Pathways

Das¹,

Biswas²,

Choudhuri³

2016

Anti-Cancer Drugs - Nature, Synthesis and Cell

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Studies on the tumor microenvironment reveal that infiltration or induction of tumorassociated immune regulatory populations at the local tumor site is strongly associated with severe immunosuppression as well as worse prognosis of patients. Despite major advances in cancer immunotherapy, most of the therapeutic agents often fail to break negative immunosuppressive network to trigger anticancer immunity, leading to tumor progression and metastasis. Therefore, emergence of potent immunostimulatory agents is of great clinical importance. Emerging evidence suggests that metal chelates of Schiff bases hold the promise to overcome tumor-associated immunosuppression by inhibiting or subverting suppressive immune population toward pro-immunogenic type and thus can be used clinically for immunotherapy of different types of cancers.

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Section: Phosphatidylserine Inhibits DC Activationmentioning

confidence: 99%

“…These criteria singled out phopshatidylserine (PS) as a likely candidate. PS is exposed on apoptotic and disrupted cells and was shown to exert immunosuppressive function on APC such as macrophages and DC [29][30][31].To test whether PS can negatively influence cytokine induction by DC in response to TLR agonists similar to F&T cells, we co-cultured DC with liposomes consisting of either PS or phosphatidylcholine (PC). While PC liposomes did not affect TLR agonist-stimulated cytokine induction, PS liposomes reduced the induction of IL-6 and IL-12 p40 by DC in response to CpG and LPS (Fig.…”

mentioning

confidence: 99%

Freeze‐and‐thaw‐disrupted tumour cells impair the responsiveness of DC to TLR stimulation

et al. 2008

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Cancer immunotherapy aims at inducing immune responses against tumour-associated antigens that mediate the eradication of tumour cells. For successful vaccination against antigens expressed by the tumour, the immune system has to be provided with sufficient amounts of these antigens in connection with strong immunostimulatory signals such as toll-like receptor (TLR) ligands. Tumour cells represent a convenient source of relevant tumour-associated antigens but can have suppressive properties. In this study, we explored how different forms of tumour cell material influence the activation of dendritic cells (DC), which play a crucial role in the induction of anti-tumour immune responses. We show that freeze-and-thaw-disrupted tumour cells inhibit DC activation in response to TLR stimulation, a phenomenon that is only partially seen with non-disrupted control cells. This suppression of DC stimulation is independent of tumour cell-and speciesspecific factors. We tested the hypothesis that phosphatidylserine on cells with disrupted membrane integrity mediates inhibition of TLR-induced DC activation. Our experimental evidence indicates that phosphatidylserine is not involved in the inhibition of TLR-mediated DC activation by freeze-and-thaw-disrupted cells. The inhibitory activity associated with disrupted tumour cells could explain why such preparations are less effective tumour vaccines than apoptotic tumour cells. IntroductionTumour cells represent an easily available source of tumourassociated antigens (TAA) for various immunotherapeutic approaches [1,2]. The use of tumour cells instead of recombinant proteins theoretically allows the immune response to be directed against several TAA expressed by a particular tumour without the need to identify them prior to therapy. In addition, the targeting of several TAA simultaneously should decrease the risk of immune evasion by tumour cells via down-regulation of TAA expression. However, tumour cells use a multitude of other strategies to evade the immune system [3], which could pose a problem when using them as the source of antigen. For example, it was shown that immunoregulatory factors such as tumour growth factor b (TGF-b) and interleukin 10 (IL-10) are expressed or induced by some tumours and are associated with disease progression [4,5]. The latter has been attributed to their ability to suppress the immunostimulatory activity of antigen presenting Ã These authors contributed equally to this study. 2740cells (APC), such as DC [6][7][8]. To avoid outgrowth and to abrogate the active immunoregulatory influence of live tumour cells, many immunotherapeutic strategies use apoptotic or necrotic tumour cell material as the source of TAA [9][10][11][12]. However, factors induced or exposed in apoptotic or necrotic cells may also affect the activation of APC and phagocytes that encounter such material [13,14]. Whether an apoptotic cell exerts immunogenic rather than immunosuppressive influence has been attributed to various factors such as release of heat shock proteins or ...

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Phosphatidylserine-Specific Receptor Contributes to TGF-.BETA. Production in Macrophages through a MAP Kinase, ERK

Cited by 34 publications

References 36 publications

Involvement of phosphatidylinositol‐3‐kinase and ERK pathways in the production of TGF‐β1 by macrophages treated with liposomes composed of phosphatidylserine

Involvement of phosphatidylinositol‐3‐kinase and ERK pathways in the production of TGF‐β1 by macrophages treated with liposomes composed of phosphatidylserine

Potential Anticancer Drugs Targeting Immune Pathways

Freeze‐and‐thaw‐disrupted tumour cells impair the responsiveness of DC to TLR stimulation

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