Title
Thalidomide inhibits UVB-induced mouse keratinocyte apoptosis by both TNF-α-dependent and TNF-α-independent pathways
Author
Lu, K.Q.
Brenneman, S.
Burns Jr., R.
Vink, A.
Gaines, E.
Haake, A.
Gaspari, A.
Publication year
2003
Abstract
Background: Thalidomide is an anti-inflammatory pharmacologic agent that has been utilized as a therapy for a number of dermatologic diseases. Its anti-inflammatory properties have been attributed to its ability to antagonize tumor necrosis factor-alfa (TNF-α) production by monocytes. However, its mechanism of action in the skin is not known. Purpose: To test our hypothesis that thalidomide may antagonize TNF-α production in the skin, we used a mouse model for acute ultraviolet-B (UVB) exposure, a known stimulus for inducing this cytokine. Results: A single bolus dose of thalidomide (either 100 or 400 mg/kg) given immediately before UVB exposure (40-120 mJ/cm2) inhibited, in a dose-dependent manner, sunburn cell formation (i.e. keratinocyte (KC) apoptosis as defined by histologic appearance and confirmed by terminal transferase mediated biotinylated dUTP nick end labelling staining) in mouse skin biopsy specimens. However, this agent did not affect the formation of cyclobutane pyrimidine dimers, a measure of UVB-induced DNA damage, which is an early event associated with apoptosis. RNase protection assays confirmed that high (400 mg/kg), but not low (100mg/kg), doses of thalidomide inhibited the UVB-induced increase in steady-state TNF-α mRNA. Additionally, our in vitro data using neonatal mouse KCs showed that thalidomide prevented UVB-induced cell death (JAM assay). The antiapoptotic effects of thalidomide can be reversed by the addition of exogenous recombinant mouse TNF-α and hence reconstituting UVB-induced programmed cell death. The inhibition of sunburn cell formation by low-dose thalidomide in the absence of TNF-α inhibition suggests that other, unidentified mechanisms of apoptosis inhibition are active. Conclusions: These data suggest that the anti-inflammatory effects of thalidomide can affect UVB injury, and may, in part, explain its action in photosensitivity diseases such as cutaneous lupus erythematosus.
Subject
Toxicology Biology
Toxicology and Applied Pharmacology
α-N-phthalimido-glutarimide
Mouse model
Photoprotection
Sunburn cell
Ultraviolet light
antiinflammatory agent
apoptosis inhibitor
cell DNA
cyclobutane derivative
cytokine
dimer
drug vehicle
messenger RNA
pyrimidine derivative
recombinant tumor necrosis factor alpha
thalidomide
tumor necrosis factor alpha
animal cell
animal experiment
animal model
animal tissue
antiinflammatory activity
apoptosis
article
biosynthesis
bolus injection
cell assay
cell death
controlled study
cytokine production
DNA damage
dose response
drug blood level
drug mechanism
drug megadose
female
histopathology
hypothesis
immunostimulation
in vitro study
keratinocyte
low drug dose
monocyte
mouse
newborn
nick end labeling
nonhuman
photosensitivity disorder
priority journal
radiation dose
radiation exposure
radiation injury
ribonuclease protection assay
skin
skin biopsy
skin lupus erythematosus
steady state
sunburn
ultraviolet B radiation
Animals
Anti-Inflammatory Agents, Non-Steroidal
Apoptosis
Disease Models, Animal
Dose-Response Relationship, Drug
Erythema
Female
Injections, Intravenous
Keratinocytes
Mice
Mice, Inbred BALB C
RNA, Messenger
Thalidomide
Tumor Necrosis Factor-alpha
Ultraviolet Rays
To reference this document use:
http://resolver.tudelft.nl/uuid:57cf3562-b4e6-4378-9a17-08cec0a5063f
DOI
https://doi.org/10.1046/j.1600-0781.2003.00055.x
TNO identifier
237417
ISSN
0905-4383
Source
Photodermatology Photoimmunology and Photomedicine, 19 (6), 272-280
Document type
article