The endogenous protease inhibitor TIMP-1 mediates protection and recovery from cutaneous photodamage.
UVB exposure is well known to induce skin photodamage and photoaging that correlates with qualitative and quantitative deterioration of the dermal extracellular matrix (ECM) because of the upregulation of matrix metalloproteinases (MMPs). Although inhibitory effects of tissue inhibitor of metalloproteinases (TIMPs) on most MMPs have been reported, the protective role of TIMP-1 against photodamage is poorly understood. To address this, TIMP-1 function was augmented or abolished in a human skin xenograft photodamage model after the confirmation of significantly diminished TIMP-1 expression both in photoaged and intrinsically aged skins. During a chronic UVB exposure regimen, pre-treatment with a lentiviral vector overexpressing TIMP-1 or concomitant administration of an anti-TIMP-1-neutralizing antibody (NAB) led to photoprotection or more severe photodamage, respectively. Overexpression of TIMP-1 resulted in significant inhibition of UVB-induced ECM degradation, as well as suppression of decreased skin elasticity and roughness, whereas the NAB-mediated inhibition of TIMP-1 had opposite effects. Furthermore, UVB-induced production of the pro-inflammatory cytokine, tumor necrosis factor α, was inhibited by TIMP-1 treatment of human keratinocytes. Taken together, these data shed light on the important role of TIMP-1 in protection and recovery from cutaneous photodamage because of its suppression of ECM degradation and inflammation.
Kao Biological Science Laboratories, Haga, Tochigi, Japan.
Urara
U
Yokose
Akira
A
Hachiya
Penkanok
P
Sriwiriyanont
Tsutomu
T
Fujimura
Marty O
MO
Visscher
William J
WJ
Kitzmiller
Alexander
A
Bello
Ryoji
R
Tsuboi
Takashi
T
Kitahara
Gary P
GP
Kobinger
Yoshinori
Y
Takema
D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000473:pathology / Q000502:physiology; D004547:Elastic Tissue / Q000378:metabolism; D004817:Epidermis / Q000473:pathology / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D008875:Middle Aged; D015595:Skin Aging / Q000473:pathology* / Q000502:physiology*; D016038:Skin Transplantation; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
D057134:Antibodies, Neutralizing; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; C088390:TIMP3 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen