Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure.
Low-level formaldehyde exposure is inevitable in industrialized countries. Although daily-life formaldehyde exposure level is practically impossible to induce cell death, most of mechanistic studies related to formaldehyde toxicity have been performed in cytotoxic concentrations enough to trigger cell death mechanism. Currently, toxicological mechanisms underlying the sub-cytotoxic exposure to formaldehyde are not clearly elucidated in skin cells. In this study, the genome-scale transcriptional analysis in normal human keratinocytes (NHKs) was performed to investigate cutaneous biological pathways associated with daily life formaldehyde exposure. We selected the 175 upregulated differentially expressed genes (DEGs) and 116 downregulated DEGs in NHKs treated with 200μM formaldehyde. In the Gene Ontology (GO) enrichment analysis of the 175 upregulated DEGs, the endoplasmic reticulum (ER) unfolded protein response (UPR) was identified as the most significant GO biological process in the formaldeyde-treated NHKs. Interestingly, the sub-cytotoxic formaldehyde affected NHKs to upregulate two enzymes important in the cellular transsulfuration pathway, cystathionine γ-lyase (CTH) and cystathionine-β-synthase (CBS). In the temporal expression analysis, the upregulation of the pro-inflammatory DEGs such as MMP1 and PTGS2 was detected earlier than that of CTH, CBS and other ER UPR genes. The metabolites of CTH and CBS, l-cystathionine and l-cysteine, attenuated the formaldehyde-induced upregulation of pro-inflammatory DEGs, MMP1, PTGS2, and CXCL8, suggesting that CTH and CBS play a role in the negative feedback regulation of formaldehyde-induced pro-inflammatory responses in NHKs. In this regard, the sub-cytotoxic formaldehyde-induced CBS and CTH may regulate inflammation fate decision to resolution by suppressing the early pro-inflammatory response.
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
Eunyoung
E
Lee
Basic Research and Innovation Division, AmorePacific Corporation R&D Center, Yongin, Gyeounggi-do 17074, Republic of Korea.
Hyoung-June
HJ
Kim
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Moonyoung
M
Lee
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
Sun Hee
SH
Jin
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
Soo Hyun
SH
Hong
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
Seyeon
S
Ahn
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
Sae On
SO
Kim
Basic Research and Innovation Division, AmorePacific Corporation R&D Center, Yongin, Gyeounggi-do 17074, Republic of Korea.
Dong Wook
DW
Shin
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
Seung-Taek
ST
Lee
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: minsoonoh@snu.ac.kr.
Minsoo
M
Noh
D003540:Cystathionine / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D005557:Formaldehyde / Q000633:toxicity*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D015603:Keratinocytes / Q000473:pathology*
D005557:Formaldehyde; D003540:Cystathionine; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase
Cystathionine γ-lyase (CTH); Cystathionine-β-synthase (CBS); Formaldehyde; Gene Ontology (GO) enrichment analysis; Human keratinocytes; Inflammation resolution