A GPR40 Agonist GW9508 Suppresses CCL5, CCL17, and CXCL10 Induction in Keratinocytes and Attenuates Cutaneous Immune Inflammation Tomoko Fujita, Toshiyuki.

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A GPR40 Agonist GW9508 Suppresses CCL5, CCL17, and CXCL10 Induction in Keratinocytes and Attenuates Cutaneous Immune Inflammation Tomoko Fujita, Toshiyuki Matsuoka, Tetsuya Honda, Kenji Kabashima, Takako Hirata, Shuh Narumiya Journal of Investigative Dermatology Volume 131, Issue 8, Pages 1660-1667 (August 2011) DOI: 10.1038/jid.2011.123 Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Inhibition by GW9508 of tumor necrosis factor (TNF)-α+IFN-γ-induced production of CCL17 and CCL5 in HaCaT cells. CCL17 (a) and CCL5 (b) production by TNF-α and/or IFN-γ. Inhibitory effect of GW9508 on TNF-α+IFN-γ-induced CCL17 (c) and CCL5 (d) production. Effect of pertussis toxin (PTX) (e and f) and forskolin (g) on TNF-α+IFN-γ-induced CCL17 and CCL5 production. TI, TNF-α+IFN-γ; veh, vehicle. Quantitative real-time RT-PCR data are shown as arbitrary units (a.u.) where the value for unstimulated sample is set at 1. Results show a representative of three independent experiments. Data show mean±SEM (n=3). *P<0.05, **P<0.01, ***P<0.001 versus TI+veh in (c–f). Journal of Investigative Dermatology 2011 131, 1660-1667DOI: (10.1038/jid.2011.123) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 GPR40 expression in HaCaT cells and GPR40 knockdown experiments. (a) GPR40 and GPR120 mRNA. Data of two different batches of HaCaT cells are shown. (-), Control without template. (b) Reduction of GPR40 mRNA by small interfering RNA (siRNA) treatment. (c) Reversal of GW9508-mediated inhibition of CCL17 (left) and CCL5 (right) mRNA expression by GPR40 depletion. Control, control siRNA. Bars=50μm. Results show a representative of three independent experiments. Data show mean±SEM (n=3). *P<0.05, **P<0.01, ***P<0.001 versus control RNA interference (b) or TI+veh (c). Journal of Investigative Dermatology 2011 131, 1660-1667DOI: (10.1038/jid.2011.123) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Effects of GW9508 on CCL5 and CXCL10 production in NHEK. Reverse transcription PCR analysis of GPR40 and GPR120 mRNA (a) and inhibition by GW9508 of CCL5 (b) and CXCL10 (c) production in normal human epidermal keratinocyte (NHEK). In (a), data of two different batches of NHEK are shown. (-), Control without template. QRT-PCR data are shown as arbitrary units (a.u.) where the value for unstimulated sample is set at 1 (b and c, left). Veh, vehicle. Results show a representative of three independent experiments. Data show mean±SEM (n=3). *P<0.05 versus IFN-γ+veh. Journal of Investigative Dermatology 2011 131, 1660-1667DOI: (10.1038/jid.2011.123) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 GPR40 and GPR120 expression in mouse epidermis. (a) Reverse transcription PCR (RT-PCR) of GPR40 mRNA expression in the ear (upper row) and GPR120 mRNA expression in the epidermis (lower row) of BALB/c and C57BL/6 mice. Mouse lung cDNA was used as a positive control for PCR of GPR120 (Hirasawa et al., 2005). (-), Control without template. (b,c) In situ hybridization for GPR40 mRNA in unstimulated ears of BALB/c mice (b) and C57BL/6 mice (c). Left, hybridization with antisense probe; right, hybridization with sense probe. Positive signals are indicated with arrows. Bars=100μm. A representative of three independent experiments is shown. Journal of Investigative Dermatology 2011 131, 1660-1667DOI: (10.1038/jid.2011.123) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Inhibition by GW9508 of immune inflammation with repeated DNFB treatment, a model of atopic dermatitis. (a) Time course of ear swelling of control- (broken line) and GW9508-treated (solid line) mice. (b) Hematoxylin–eosin staining. (c) QRT-PCR analysis of CCL5 mRNA expression. Data are shown as arbitrary units (a.u.) where the value for unstimulated group is set at 1. (d) Immunohistochemistry for CCL5 in inflamed ears. (e) Eosinophil count per field. (f) Toluidine blue staining. None, non-immunized and unstimulated group; veh, vehicle-treated group; GW9508, GW9508-treated group. *P<0.05, **P<0.01 and ***P<0.001 versus vehicle. Data show mean±SEM of four to five mice. Bars=100μm. A representative of three independent experiments is shown. Journal of Investigative Dermatology 2011 131, 1660-1667DOI: (10.1038/jid.2011.123) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Inhibition of contact hypersensitivity by topical application of GW9508. (a) Effect of GW9508. No sens., group without sensitization and treated with 0.3% DNFB; veh, vehicle-treated group; GW9508, GW9508-treated group. (b) Hematoxylin–eosin staining. (c) QRT-PCR analysis of CXCL10 mRNA. Data are shown as arbitrary units (a.u.) where the value for the group without sensitization is set at 1. (d) Immunostaining for CXCL10. Bars=100μm. Results are representative of three independent experiments. Data show mean±SEM of five mice. *P<0.05 compared with vehicle. Journal of Investigative Dermatology 2011 131, 1660-1667DOI: (10.1038/jid.2011.123) Copyright © 2011 The Society for Investigative Dermatology, Inc Terms and Conditions