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Inhibition of the CXCR3‐mediated pathway suppresses ultraviolet B‐induced pigmentation and erythema in skin
Author(s) -
Kurata R.,
Fujita F.,
Oonishi K.,
Kuriyama KI.,
Kawamata S.
Publication year - 2010
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/j.1365-2133.2010.09850.x
Subject(s) - downregulation and upregulation , cxcl10 , gene knockdown , small hairpin rna , microphthalmia associated transcription factor , chemistry , chemokine , cxcr3 , melanin , tyrosinase , microbiology and biotechnology , cancer research , inflammation , biology , immunology , apoptosis , biochemistry , gene , chemokine receptor , enzyme
Summary 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. Objectives 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.