A Novel Mechanism of γ-Irradiation-Induced IL-6 Production Mediated by P2Y11 Receptor in Epidermal Keratinocytes

Ohsaki, Airi; Miyano, Yuki; Tanaka, R.; Tanuma, Sei Ichi; Kojima, Shuji; Tsukimoto, Mitsutoshi

doi:10.1248/bpb.b18-00075

Cited by 7 publications

(4 citation statements)

References 53 publications

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“…IL-6 is secreted by T cells and was identified as an essential cytokine for B cell terminal differentiation [ 4 ]. At present, it is known that the production of somatic cells, such as fibroblasts [ 5 ], epidermal cells [ 6 ], and muscles [ 7 ], involves macrophage activity [ 8 , 9 ]. IL-6 belongs to the cytokine superfamily that uses glycoprotein 130 (gp130) as a signal-transducing receptor.…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

Nara

Watanabe

2021

IJMS

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Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver.

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Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

Nara

Watanabe

2021

IJMS

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“…11) Further, we have also reported the involvement of P2Y11 receptor in IL-6 production by interferon-γ, silica nanoparticles, or γ-irradiation in HaCaT cells. [12][13][14] P2Y11 receptors are also involved in the induction of IL-6 production in response to UVA irradiation in HaCaT cells, 15) and activation of P2Y11 receptors induces IL-8 production in human monocyte-derived dendritic cells. 16) However, little work has been done on the mechanism of γ-irradiation-induced IL-8 production or the mediators of ATP release in HaCaT cells.…”

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confidence: 99%

TRPV4 Channel-Regulated ATP Release Contributes to γ-Irradiation-Induced Production of IL-6 and IL-8 in Epidermal Keratinocytes

Ohsaki

Tanuma

Tsukimoto

2018

Biological & Pharmaceutical Bulletin

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External stimuli, such as radiation, induce inflammatory cytokine and chemokine production in skin, but the mechanisms involved are not completely understood. We previously showed that the P2Y11 nucleotide receptor, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) all participate in interleukin (IL)-6 production induced by γ-irradiation. Here, we focused on the transient receptor potential vanilloid 4 (TRPV4) channel, which is expressed in skin keratinocytes and has been reported to play a role in inflammation. We found that irradiation of human epidermal keratinocytes HaCaT cells with 5 Gy of γ-rays (Cs: 0.75 Gy/min) induced IL-6 and IL-8 production. HaCaT cells treated with TRPV4 channel agonist GSK1016790A also showed increased IL-6 and IL-8 production. In both cases, IL-6/IL-8 production was not increased at 24 h after stimulation, but was increased at 48 h. ATP was released from cells exposed to γ-irradiation or TRPV4 channel agonist, and the release was suppressed by TRPV4 channel inhibitors. The γ-irradiation-induced increase in IL-6 and IL-8 production was suppressed by apyrase (ecto-nucleotidase), NF157 (selective P2Y11 receptor antagonist) and SB203580 (p38 MAPK inhibitor). GSK1016790A-induced inhibitor of kappa B-alpha (IκBα) decomposition, which causes NF-κB activation was suppressed by NF157 and SB203580, and γ-irradiation-induced IκBα decomposition was suppressed by TRPV4 channel inhibitors. Our results suggest that γ-irradiation of keratinocytes induces ATP release via activation of the TRPV4 channel, and then ATP activates P2Y11 receptor and p38 MAPK-NF-κB signaling, resulting in IL-6/IL-8 production.

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“…IL-6 production related to P2Y 11 activation has also been suggested to occur in the human keratinocyte cell line (HaCaT). However, in this cell culture system, P2Y 11 was not the driving force but instead it enhanced IFNγ-induced IL-6 production [ 55 , 56 ]. Moreover, P2Y 11 involvement in the IFNγ-induced IL-6 response was implied by use of NF157, which is however non-selective [ 23 , 57 ].…”

Section: The Expanding P2y 11 Secretomementioning

confidence: 99%

P2Y11/IL-1 receptor crosstalk controls macrophage inflammation: a novel target for anti-inflammatory strategies?

Klaver

Thurnher

2023

Purinergic Signalling

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Although first cloning of the human ATP receptor P2Y11 was successful 25 years ago, the exact downstream signaling pathways of P2Y11 receptor, which can couple to Gq and Gs proteins, have remained unclear. Especially the lack of rodent models as well as the limited availability of antibodies and pharmacological tools have hampered examination of P2Y11 expression and function. Many meaningful observations related to P2Y11 have been made in primary immune cells, indicating that P2Y11 receptors are important regulators of inflammation and cell migration, also by controlling mitochondrial activity. Our recent studies have shown that P2Y11 is upregulated during macrophage development and activates signaling through IL-1 receptor, which is well known for its ability to direct inflammatory and migratory processes. This review summarizes the results of the first transcriptomic and secretomic analyses of both, ectopic and native P2Y11 receptors, and discusses how P2Y11 crosstalk with the IL-1 receptor may govern anti-inflammatory and pro-angiogenic processes in human M2 macrophages.

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A Novel Mechanism of γ-Irradiation-Induced IL-6 Production Mediated by P2Y11 Receptor in Epidermal Keratinocytes

Cited by 7 publications

References 53 publications

Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

Anti-Inflammatory Effect of Muscle-Derived Interleukin-6 and Its Involvement in Lipid Metabolism

TRPV4 Channel-Regulated ATP Release Contributes to γ-Irradiation-Induced Production of IL-6 and IL-8 in Epidermal Keratinocytes

P2Y11/IL-1 receptor crosstalk controls macrophage inflammation: a novel target for anti-inflammatory strategies?

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