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2018 ; 32
(3
): 1510-1523
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TIMP3 is a CLOCK-dependent diurnal gene that inhibits the expression of
UVB-induced inflammatory cytokines in human keratinocytes
#MMPMID29180440
Park S
; Kim K
; Bae IH
; Lee SH
; Jung J
; Lee TR
; Cho EG
FASEB J
2018[Mar]; 32
(3
): 1510-1523
PMID29180440
show ga
As the outermost physical barrier of an organism, the skin is diurnally exposed
to UV radiation (UVR). Recent studies have revealed that the skin exhibits a
circadian rhythm in various functions, and this oscillation is disturbed and
reset via a strong environmental cue, the UVR. However, a molecular link between
circadian perturbation by UVR and UVR-induced cellular responses has not been
investigated. We identified tissue inhibitor of metalloproteinase ( TIMP)- 3 as a
novel circadian locomotor output cycles kaput (CLOCK)-dependent diurnal gene by
using a CLOCK-knockdown strategy in human keratinocytes. Among dozens of
identified transcripts down-regulated by CLOCK knockdown, TIMP3 displayed a
rhythmic expression in a CLOCK-dependent manner, in which the expression of
matrix metalloproteinase (MMP)-1 and inflammatory cytokines, such as TNF-?,
chemokine (C-X-C motif) ligand (CXCL)-1, and IL-8, were inversely regulated. Upon
UVB exposure, the expression of CLOCK and TIMP3 was down-regulated, which led to
an up-regulation of secretion of MMP1 and TNF-? proteins and in the transcription
of CXCL1 and IL-8 via CCAAT-enhancer binding protein (C/EBP)-?. UVB-induced TNF-?
secretion increased further or decreased by knockdown or overexpression of TIMP3,
respectively, as well as by CLOCK. As a novel CLOCK-dependent diurnal gene, TIMP3
inhibits the expression of inflammatory cytokines that are up-regulated by UV
irradiation in human keratinocytes. Thus, our work suggests a molecular link
between circadian perturbation by UVR and UVR-induced inflammation.-Park, S.,
Kim, K., Bae, I.-H., Lee, S. H., Jung, J., Lee, T. R., Cho, E.-G. TIMP3 is a
CLOCK-dependent diurnal gene that inhibits the expression of UVB-induced
inflammatory cytokines in human keratinocytes.
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