Inhibition of the CXCR3-mediated pathway suppresses ultraviolet B-induced pigmentation and erythema in skin.
BACKGROUND
Skin pigmentation by ultraviolet (UV) B radiation is caused in part by inflammation mediated by chemokines and cytokines secreted by keratinocytes in the irradiated area. However, such inflammatory processes have not been well documented.


OBJECTIVE
To elucidate the inflammation processes caused by UVB irradiation using skin-lightening agents that suppress melanin synthesis after UVB irradiation.


METHODS
Utilizing a three-dimensional (3D) skin model, agents that suppressed formation of sunburn cells (SBC) after UVB irradiation were screened. Molecules whose expression was upregulated by UVB irradiation and attenuated by pretreatment with the agent were then screened by gene microarray to explore the mechanism of UVB irradiation. Messenger RNA expression of the molecules identified to be responsible for melanin biosynthesis was knocked down with a Tet-off shRNA lentivirus construct to confirm the involvement of the molecule in the pigmentation pathway following UVB irradiation.


RESULTS
Paeonia suffruticosa Andrews (PSA) pretreatment suppressed SBC formation in the 3D skin model, and erythema formation and pigmentation in volunteers exposed to UVB irradiation. Comprehensive gene analysis after UVB irradiation showed upregulation of CXCR3 and its ligands, CXCL9/monokine induced by interferon (IFN)-γ (MIG), CXCL10/10-kDa IFN-γ-induced protein (IP-10) and CXCL11/inducible T-cell α-chemoattractant (I-TAC). Upregulation of these genes was partially suppressed by PSA pretreatment. Melanin biosynthesis increased upon stimulation of CXCR3 ligands (MIG, IP-10 or I-TAC) and decreased following CXCR3 downregulation by shRNA knockdown.


CONCLUSIONS
UVB irradiation activates CXCR3-mediated signalling that leads to melanin synthesis. PSA pretreatment shows a lightening effect partly by attenuating CXCR3-mediated signalling at the transcriptional level.
Kurata
R
R
Central Research Laboratories, Mandom Corp., 5-12 Juniken-cho, Chuo-ku, Osaka 540-8530, Japan.
Fujita
F
F
Oonishi
K
K
Kuriyama
K-I
KI
Kawamata
S
S
D002478:Cells, Cultured / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000378:metabolism; D003872:Dermatitis / Q000378:metabolism* / Q000503:physiopathology; D004890:Erythema / Q000235:genetics / Q000517:prevention & control*; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D008543:Melanins / Q000096:biosynthesis / Q000235:genetics; D046228:Microarray Analysis; D029596:Paeonia; D028321:Plant Preparations / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D054387:Receptors, CXCR / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000098:blood supply / Q000473:pathology; D012880:Skin Pigmentation / Q000235:genetics / Q000528:radiation effects*; D013471:Sunburn; D014466:Ultraviolet Rays / Q000009:adverse effects*; D015854:Up-Regulation
C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D008543:Melanins; D028321:Plant Preparations; D012333:RNA, Messenger; D054387:Receptors, CXCR; D054367:Receptors, CXCR3; D007371:Interferon-gamma