Biological and Pharmaceutical Bulletin

Featured article

Volume 41 (2018) Issue 6 Pages 925-936

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

Airi Ohsaki, Yuki Miyano, Rei Tanaka, Sei-ichi Tanuma, Shuji Kojima, Mitsutoshi Tsukimoto

Skin inflammation is caused by excessive production of cytokines and chemokines in response to an external stimulus, such as radiation, but the mechanisms involved are not completely understood. Here, we report a novel mechanism of γ-irradiation-induced interleukin-6 (IL-6) production mediated by P2Y11 receptors in epidermal cells. After irradiation of HaCaT cells derived from human epidermal keratinocytes with 5 Gy of γ-rays (¹³⁷Cs: 0.78 Gy/min), IL-6 production was unchanged at 24 h after γ-irradiation, but was increased at 48 h. IL-6 mRNA was increased at 30 h, and IL-6 production was increased at 33 h after irradiation. The production of IL-6 was sustained at least for 4 d after irradiation. P2Y11 receptor antagonist NF157 inhibited IL-6 production in irradiated cells. Treatment with ATP, a ligand of P2Y11 receptor caused IL-6 production within 24 h. ATP-induced IL-6 production was also suppressed by NF157. Extracellular ATP level was increased after irradiation. The p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling was involved in the production of IL-6 at the downstream of P2Y11 receptor activation. In addition, the cell cycle was arrested at the G2/M phase, and DNA repair foci were not disappeared at 48 h after γ-irradiation. The protein level of histone methylation enzyme G9a, which inhibits IL-6 production, was decreased after γ-irradiation. In conclusion, we suggest that γ-irradiation induces sustained IL-6 production in HaCaT cells from 33 h after irradiation, which is mediated through P2Y11 receptor-p38 MAPK-NF-κB signaling pathway and G9a degradation. This is a novel mechanism of cytokine production in γ-irradiated cells.

Editor’s picks

The article by Ohsaki et al. proposed a novel mechanism of cytokine production in γ-irradiated cells. γ-Ray irradiation induced sustained IL-6 production in HaCaT epidermal cells from 33 h after irradiation. Extracellular ATP-induced activation of P2Y11 receptor was involved in the production of IL-6. At the downstream of P2Y11 receptor activation, the p38 MAPK and NF-kB signaling was involved in IL-6 production. The protein level of G9a, which inhibits IL-6 production, was decreased after g-irradiation. These findings should be helpful to understand the pathogenesis of radiation-induced inflammation, as well as the potential side effects of therapeutic irradiation.

View the past featured articles

Volume 41 (2018) Issue 6

Yokukansan, a Herbal Medicine in Japan, Buffers Social Crowding Stress via Ameliorating Glucocorticoid Secretion Response to Vasopressin Haruna Tamano, Hiroki Morioka, Haruka Iwaki, Hiroki Suzuki, Yuichi Sato, Atsushi Takeda
In Vitro Anti-inflammatory Effects of the Phenylbutyric Acid Metabolite Phenylacetyl Glutamine Mai Hazekawa, Kazuhiko Ono, Takuya Nishinakagawa, Tomoyo Kawakubo-Yasukochi, Manabu Nakashima
Possibility of Exosome-Based Therapeutics and Challenges in Production of Exosomes Eligible for Therapeutic Application Takuma Yamashita, Yuki Takahashi, Yoshinobu Takakura
Two-Step Sustained-Release PLGA/Hyaluronic Acid Gel Formulation for Intra-articular Administration Takehiro Noda, Tomoyuki Okuda, Ryota Mizuno, Tetsuya Ozeki, Hirokazu Okamoto

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