TNF-α Downregulates Filaggrin and Loricrin through c-Jun N-terminal Kinase: Role for TNF-α Antagonists to Improve Skin Barrier
Open accessAbstract
Filaggrin (FLG), loricrin (LOR), and involucrin are important epidermal barrier proteins. As psoriasis is characterized by overexpression of tumor necrosis factor-α (TNF-α) and impaired skin barrier, we investigated the expression of skin barrier proteins in psoriasis patients and whether their expression was modulated by TNF-α. The expression of FLG and LOR was found to be decreased in lesional and non-lesional skin of psoriasis patients. A correlation was found between the expression of TNF-α and epidermal barrier proteins in psoriasis. TNF-α was found to modulate the expression of FLG and LOR via a c-Jun N-terminal kinase-dependent pathway. Importantly, we report that clinical treatment of psoriasis patients with a TNF-α antagonist results in significant enhancement of epidermal barrier protein expression. Our current study suggests that TNF inhibits barrier protein expression, and TNF-α antagonists may contribute to clinical improvement in patients with psoriasis by improving barrier protein expression.
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Inhibition of FLG expression by keratinocyte-derived cytokines including TNF-α, TSLP, IL-1β, IL-33, and IL-25 has been documented.
“Inhibition of FLG expression by keratinocyte-derived cytokines including TNF-α (37), thymic stromal lymphopoietin (TSLP) (38), IL-1β (39), IL-33 (40), and IL-25 (41) has been documented.”
From Particulate matter causes skin barrier dysfunction. (2021) · cites this paper as [37]
TNF-α downregulates FLG expression through the MAPK/c-JNK pathway.
“This finding is consistent with our previous observation that TNF-α downregulates FLG expression through the MAPK/c-JNK pathway (37).”
From Particulate matter causes skin barrier dysfunction. (2021) · cites this paper as [37]
PM2.5-induced TNF-α is associated with PM2.5-mediated inhibition of epidermal barrier proteins.
“This finding implies that PM2.5-induced TNF-α is associated with PM2.5-mediated inhibition of epidermal barrier proteins because we previously reported that TNF-α inhibits FLG and LOR but not IVL (37).”
From Particulate matter causes skin barrier dysfunction. (2021) · cites this paper as [37]
TNF-α inhibits FLG and LOR but not IVL.
“This finding implies that PM2.5-induced TNF-α is associated with PM2.5-mediated inhibition of epidermal barrier proteins because we previously reported that TNF-α inhibits FLG and LOR but not IVL (37).”
From Particulate matter causes skin barrier dysfunction. (2021) · cites this paper as [37]
Doses of NF-κB, ERK1/2, p38, and c-JNK inhibitors used were previously proved nontoxic to keratinocytes.
“The doses of inhibitors used in this study were previously proved to be nontoxic to the keratinocytes (37).”
From Particulate matter causes skin barrier dysfunction. (2021) · cites this paper as [37]
The Materials and Methods section (KC cell culture; page unavailable) lists the inhibitor doses used in keratinocytes but does not say they were previously proved nontoxic. Searches for toxicity, cell viability, and prior safety testing found no passage addressing that claim. (LLM, conf=0.73)
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References 27 · Cited by 239
- Authors
- Kim, B. E., Howell, M. D., Guttman, E., Gilleaudeau, P. M., Cardinale, I. R., Boguniewicz, M., Krueger, J. G., & Leung, D. Y. M.
- Affiliations
- National Jewish Health (US)
- Weill Cornell Medicine (US)
- Rockefeller University (US)
- Corresponding author
- Leung, Donald Y.M.
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2011-06
- Volume
- 131
- Issue
- 6
- Pages
- 1272-1279
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC8609659
- OpenAlex
- W2058826106
- Cited by
- 239
- References
- 27
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 40 · 2023: 12 · 2022: 19 · 2021: 21 · 2020: 9 · 2019: 11 · 2018: 11 · 2017: 10 · 2016: 9 · 2015: 13 · 2014: 20 · 2013: 16 · 2012: 11
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-06-01)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (RO1 AR41256)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
- Keywords
- TNF-α, filaggrin, loricrin, involucrin, c-Jun N-terminal kinase, psoriasis, skin barrier, TNF-alpha inhibitors, gene expression regulation
- MeSH terms
- Filaggrin Proteins, Adult, Humans, Intermediate Filament Proteins, Membrane Proteins, Psoriasis, Skin, Tumor Necrosis Factor-alpha, Down-Regulation, JNK Mitogen-Activated Protein Kinases
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