title: Thalidomide inhibits UVB-induced mouse keratinocyte apoptosis by both TNF-alpha-dependent and TNF-alpha-independent pathways.
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-alpha) production by monocytes. However, its mechanism of action in the skin is not known.
  
  
  OBJECTIVE
  To test our hypothesis that thalidomide may antagonize TNF-alpha 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 (100 mg/kg), doses of thalidomide inhibited the UVB-induced increase in steady-state TNF-alpha 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-alpha and hence reconstituting UVB-induced programmed cell death. The inhibition of sunburn cell formation by low-dose thalidomide in the absence of TNF-alpha 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.
authors: Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors: Kurt Q
authors: KQ
authors: Lu
authors: Stephen
authors: S
authors: Brenneman
authors: Robert
authors: R
authors: Burns
authors: Ard
authors: A
authors: Vink
authors: Erika
authors: E
authors: Gaines
authors: Anne
authors: A
authors: Haake
authors: Anthony
authors: A
authors: Gaspari
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004890:Erythema / Q000276:immunology* / Q000473:pathology; D005260:Female; D007275:Injections, Intravenous; D015603:Keratinocytes / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger; D013792:Thalidomide / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D014466:Ultraviolet Rays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide