Highlights
- •An endogenous photo-product FICZ upregulates MMP1 expression in dermal fibroblasts.
- •This function of FICZ is dependent on the AHR/MEK/ERK signal pathways.
- •FICZ partially contributes to the UV-mediated anti-fibrotic effects.
- •FICZ might have therapeutic potential for treating scleroderma.
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.
Abbreviations:
FICZ (formylindolo[3,2-b]carbazole), AHR (aryl hydrocarbon receptor), NHDF (normal human dermal fibroblast), MMP (matrix metalloproteinase), TIMP (tissue inhibitor of matrix metalloproteinase), MAPK (mitogen-activated protein kinase), ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), MEK (microtubule-associated protein kinase), siRNA (small interfering RNA)Keywords
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Article info
Publication history
Published online: April 20, 2018
Accepted:
April 17,
2018
Received in revised form:
March 26,
2018
Received:
February 27,
2018
Identification
Copyright
© 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
