Inhibition of interferon-γ signaling by a mercurio-substituted dihydropsoralen in murine keratinocytes

Christine A. Martey, Anna M. Vetrano, Marilyn S. Whittemore, Thomas M. Mariano, Diane E. Heck, Debra L. Laskin, Ned D. Heindel, Jeffrey D. Laskin

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Psoralens and ultraviolet light A (PUVA) are used in the treatment of a variety of epidermal proliferative and inflammatory disorders. These compounds are known to intercalate and photo crosslink DNA. Specific receptor proteins for psoralens have also been identified. We describe a novel activity of a thiol reactive derivative, iodomercurio-4′,5′-dihydrotrimethylpsoralen (iodomercurio-H2TMP) in keratinocytes. Without UVA, this psoralen was found to be an effective inhibitor of interferon-γ (IFN-γ)- signaling as measured by induction of nitric oxide biosynthesis (IC50 = 0.8 μM). This activity was increased (IC50 = 0.1 μM) when the cells were depleted of intracellular glutathione (GSH) with buthionine sulfoximine. In keratinocytes, IFN-γ stimulates expression of inducible nitric oxide synthase (NOS2). Although iodomercurio-H2TMP did not alter NOS2 enzymatic activity, it blocked IFN-γ-induced expression of NOS2 mRNA and protein, an effect that was enhanced in GSH-depleted cells. Iodomercurio-H2TMP was found to readily inhibit IFN-γ signaling in transient transfection assays using NOS2 promoter/luciferase reporter constructs. NOS2 gene expression is known to require a variety of transcription factors including STAT-1, NF-κB and AP-1. Using mobility shift assays the psoralen, at concentrations that inhibit nitric oxide biosynthesis, had no effect on the DNA binding activity of STAT-1 or NF-κB. However, iodomercurio-H2TMP was found to suppress AP-1. These data indicate that iodomercurio-H2TMP acts at sulfhydryl-sensitive sites to inhibit NOS2. Moreover, this is dependent on early events in the IFN-γ signal transduction pathway. Inhibition of AP-1 suggests that the psoralen functions by interfering with an important transcription factor that regulates expression of NOS2 in keratinocytes.

Original languageEnglish (US)
Pages (from-to)1726-1734
Number of pages9
JournalBiochemical Pharmacology
Issue number12
StatePublished - Dec 5 2005

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology


  • Interferon-γ
  • Nitric oxide
  • PUVA
  • Psoriasis
  • Skin


Dive into the research topics of 'Inhibition of interferon-γ signaling by a mercurio-substituted dihydropsoralen in murine keratinocytes'. Together they form a unique fingerprint.

Cite this