Tryptophan photo-product FICZ upregulates AHR/MEK/ERK-mediated MMP1 expression: Implications in anti-fibrotic phototherapy

J Dermatol Sci. 2018 Jul;91(1):97-103. doi: 10.1016/j.jdermsci.2018.04.010. Epub 2018 Apr 21.

Abstract

Background: Scleroderma is caused by aberrant transforming growth factor-ß signaling. The degradation of extracellular matrix proteins is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Ultraviolet (UV) radiation has been a therapy for scleroderma. 6-Formylindolo[3,2-b]carbazole (FICZ), an endogenous aryl hydrocarbon receptor (AHR) ligand, is a tryptophan metabolite generated by UV exposure. Nonetheless, whether FICZ regulates MMPs and TIMPs has not been investigated.

Objective: To elucidate the regulatory roles of FICZ in the expression of MMPs and TIMPs in normal human dermal fibroblasts (NHDFs).

Methods: Quantitative real-time polymerase chain reaction was performed to determine the expression of MMPs or TIMPs in the NHDFs treated with FICZ or UVB. The MMPs levels were measured by enzyme-linked immunosorbent assay. The actions of FICZ on MMPs were analyzed using AHR-knockdown NHDFs or selective inhibitors of mitogen-activated protein kinases (MAPKs). Microtubule-associated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) phosphorylation was examined by western blotting.

Results: UVB increased the mRNA and protein levels of MMP1 and MMP3 in NHDFs, while FICZ upregulated those of MMP1, but not MMP3. The effects of FICZ on TIMPs were negligible. FICZ increased MMP1 expression in an AHR-dependent manner. The FICZ-induced MMP1 upregulation was ameliorated with MEK/ERK inhibitors, whereas the effects of UVB were canceled with c-Jun N-terminal kinase (JNK) and p38-MAPK as well as MEK/ERK inhibitors. FICZ-induced ERK phosphorylation is dependent on AHR.

Conclusion: FICZ contributes to the UV-mediated anti-fibrotic effects via the AHR/MEK/ERK signal pathway in NHDFs. FICZ is a potential therapeutic agent for scleroderma.

Keywords: 6-Formylindolo[3,2-b]carbazole (FICZ); Aryl hydrocarbon receptor; Extracellular signal-regulated kinase (ERK); Matrix metalloproteinase-1 (MMP1); Scleroderma.

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carbazoles / metabolism*
  • Cells, Cultured
  • Dermis / cytology
  • Dermis / metabolism
  • Dermis / radiation effects
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblasts
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / radiation effects*
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism*
  • Matrix Metalloproteinase 3 / metabolism
  • Phosphorylation
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism
  • Scleroderma, Systemic / pathology
  • Scleroderma, Systemic / therapy*
  • Tissue Inhibitor of Metalloproteinases / metabolism
  • Tryptophan / metabolism
  • Ultraviolet Therapy / methods*
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 6-formylindolo(3,2-b)carbazole
  • AHR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Carbazoles
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Aryl Hydrocarbon
  • Tissue Inhibitor of Metalloproteinases
  • Tryptophan
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MMP3 protein, human
  • Matrix Metalloproteinase 3
  • MMP1 protein, human
  • Matrix Metalloproteinase 1