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Thalidomide inhibits UVB‐induced mouse keratinocyte apoptosis by both TNF‐α‐dependent and TNF‐α‐independent pathways
Author(s) -
Lu Kurt Q.,
Brenneman Stephen,
Burns Robert,
Vink Ard,
Gaines Erika,
Haake Anne,
Gaspari Anthony
Publication year - 2003
Publication title -
photodermatology, photoimmunology and photomedicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.736
H-Index - 60
eISSN - 1600-0781
pISSN - 0905-4383
DOI - 10.1046/j.1600-0781.2003.00055.x
Subject(s) - thalidomide , apoptosis , tumor necrosis factor alpha , keratinocyte , cytokine , pharmacology , programmed cell death , medicine , chemistry , immunology , in vitro , biochemistry , multiple myeloma
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/cm 2 ) 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 (100 mg/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.