TIMP3 is a CLOCK‐dependent diurnal gene that inhibits the expression of UVB‐induced inflammatory cytokines in human keratinocytes

Abstract

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-α, 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-α proteins and in the transcription of CXCL1 and IL-8 via CCAAT-enhancer binding protein (C/EBP)-α. UVB-induced TNF-α 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.

White light emitting diode induces autophagy in hippocampal neuron cells through GSK-3-mediated GR and RORα pathways

“…Genes such as clock , bmal1 , cry1 and cry2 , displayed time-phase shift and suppressed oscillation amplitudes, while others ( per1 , per2 and per3 ) demonstrated reduced frequency of oscillation. These results agree with previous reports that UVB exposure significantly altered the circadian rhythm of clock gene in human keratinocytes [35] and blue light irradiation disrupted the circadian rhythm of per1 , per2 , per3, cry1 and cry2 genes in Puffer Fish-derived Fugu eye cells [36]. In this study, we observed a striking light response in rorα gene that completely lost its circadian rhythm and kept increasing over the period of examination.…”

PER, a Circadian Clock Component, Mediates the Suppression of MMP-1 Expression in HaCaT Keratinocytes by cAMP

“…Bmal1 -deficient mutant mice have shown upregulated ROS levels and reduced lifespans and various symptoms of premature aging, suggesting that it might play a role in aging by regulating genes involved in anti-oxidant process [ 38 ]. In human keratinocytes, CLOCK regulates the expression of Aquaporin (AQO)-3 and tissue inhibitor of metalloproteinase (TIMP)-3 that control hydration and photoaging, respectively [ 39 , 40 ]. Knockdown of PER has shown diverse defects in cell differentiation, wound healing, autophagy in aging, and tumor development [ 15 , 41 , 42 , 43 , 44 ].…”

From Early Immunomodulatory Triggers to Immunosuppressive Outcome: Therapeutic Implications of the Complex Interplay Between the Wavebands of Sunlight and the Skin

“…Wound healing is also controlled by the circadian cycle; skin injuries suffered during the day heal faster than those suffered during the night due to a circadian control of actin polymerization regulated by CRY and PER2 proteins ( 12 ). Keratinocytes downregulate TIMP3, a metalloproteinase inhibitor linked to CLOCK upon UVR exposure, which in turn leads to an upregulation of MMP1, TNF-α, CXCL1, and IL-8 promoted by C/EBP (a CCAAT-enhancer binding protein) ( 13 ). This indicates that UVR affects tissue remodeling and inflammatory signaling pathways by modifying the transcriptional profile of keratinocytes.…”