Synergistic Inhibition of Tumor Necrosis Factor-Alpha-Stimulated Pro-Inflammatory Cytokine Expression in HaCaT Cells by a Combination of Rapamycin and Mycophenolic Acid
- Authors
- Kim, Min Young; Lim, Yun Young; Kim, Hyeong Mi; Park, Young Min; Kang, Hoon; Kim, Beom Joon
- Issue Date
- Feb-2015
- Publisher
- KOREAN DERMATOLOGICAL ASSOC
- Keywords
- Anti-inflammation; Mycophenolic acid; Sirolimus; Tumor necrosis factor-alpha
- Citation
- ANNALS OF DERMATOLOGY, v.27, no.1, pp 32 - 39
- Pages
- 8
- Journal Title
- ANNALS OF DERMATOLOGY
- Volume
- 27
- Number
- 1
- Start Page
- 32
- End Page
- 39
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/9933
- DOI
- 10.5021/ad.2015.27.1.32
- ISSN
- 1013-9087
2005-3894
- Abstract
- Background: Keratinocytes release various pro-inflammatory cytokines, chemokines, and adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) in response to cytokines such as tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma Rapamycin and mycophenolic acid (MPA) have potent immunosuppressive activity because they inhibit lymphocyte proliferation. Objective: We investigated the effects of rapamycin and MPA on the expression of inflammation-related factors such as ICAM-1 and inducible nitric oxide synthase (iNOS), pro-inflammatory cytokines and chemokines, and related signaling pathways in TNF-alpha-stimulated HaCaT cells. Methods: The viability of HaCaT cells treated with rapamycin and MPA was confirmed using MTT assay. The expression of various cytokines such as interleukin (IL)-1 beta, IL-6, and IL-8; inflammation-related factors such as ICAM-1 and iNOS; and the activation of mitogen activated protein kinase (MAPK) signaling pathways mediated by extracellular signal-related kinases (ERK), p38, and c-Jun N-terminal kinases (JNK) in TNF-alpha-stimulated HaCaT cells were confirmed using reverse transcription-polymerase chain reaction and western blotting. Results: Combined treatment of TNF-alpha-induced HaCaT cells with rapamycin and MPA decreased ICAM-1 and iNOS expression and ERK and p38 activation more than treatment with either drug alone. The most significant decrease was observed with a combination of rapamycin (80 nM) and MPA (20 nM). These results show that co-treatment with these agents has a synergistic anti-inflammatory effect by blocking the activation of the ERK/p38 MAPK signaling pathway and thus suppressing the TNF-alpha-induced expression of ICAM-1 and iNOS. Conclusion: The combination of rapamycin and MPA could potentially be used as a therapeutic approach in inflammatory skin diseases.
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