Journal
JOURNAL OF DERMATOLOGICAL SCIENCE
Volume 77, Issue 1, Pages 46-53Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.jdermsci.2014.12.001
Keywords
Caspase; CCR6; Human beta-defensin; Interleukin-37; Keratinocyte
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan [23591655, 26461703]
- Atopy (Allergy) Research Center
- Juntendo University Graduate School of Medicine, Tokyo, Japan
- Japan International Cooperation Agency (JICA)
- Grants-in-Aid for Scientific Research [23591655, 26461703] Funding Source: KAKEN
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Background: Interleukin (IL)-37, a new member of the IL-1 family, is characterized as a fundamental inhibitor of innate immunity: it dampens the production of proinflammatory cytokines, protects against inflammatory and autoimmune diseases, and plays a potent immunosuppressive role in the pathogenesis of psoriasis. IL-37 is highly expressed in psoriatic skin, in which human beta-defensins (hBDs) have been detected. Although hBDs enhance the production of cytokines, including IL-1 cytokines, whether they stimulate the production of 1L-37 remains unclear. Objectives: To assess the ability of hBDs to stimulate IL-37 expression/production by human keratinocytes and to determine the mechanism involved. Methods: Real-time PCR and Western blotting were used to evaluate IL-37 expression. Caspase activities were assessed using colorimetric assay kits. A CCR6 antibody, siRNA, and caspase, Smad3, MAPK and NF-kappa B inhibitors were used to investigate the signaling mechanism of hBDs. Results: Among the four hBDs used, only hBD-3 up-regulated the mRNA and protein expression of IL-37. The combination of TNF-alpha, EGF and poly (I:C) with hBD-3 synergistically enhanced the mRNA but not the protein expression of IL-37. Furthermore, hBD-3 increased the release of IL-37 into the culture supernatants. Evaluation of the signaling mechanism of hBD-3 suggested that caspases 1 and 4, Smad3, CCR6, MAPKs and NF-kappa B were required for hBD-3-mediated IL-37 expression. Conclusions: The finding that hBD-3 stimulates IL-37 expression, a novel target for the pathogenesis and therapy of cutaneous inflammatory diseases, provides evidence that hBDs contribute to the suppression of inflammatory and innate immune responses through the regulation of IL-37 expression. (C) 2014 Published by Elsevier Ireland Ltd on behalf of Japanese Society for Investigative Dermatology.
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