Abstract
Inflammation as a major defense mechanism against pathogens is modulated by diverse microbial products. A variety of plant and microbial products interacting with Toll-like receptors initiate a wide spectrum of responses from phagocytosis to cytokine production, which modulates inflammation. Jasmonates are fatty acid-derived cyclopentanones produced by plants and lower eukaryotes that play an important role in the defense against insects. In this study, we are set up to define the molecular targets of J2 action. While the lipopolysaccharide (LPS) stimulation of macrophage cell line RAW264.7 induced TNF-α, IL-6, iNOS, and COX-2 that were associated with an increase in miR-155 and miR-146a, the J2 suppressed the induction of these inflammatory cytokines and enzymes as well as miR-155 in a dose-dependent manner. To assess the associations of miR-155 with inflammatory markers, we overexpressed miR-155 and found attenuation of COX-2 suppression with J2 treatment. Furthermore, J2 inhibited NF-κB, p65, and IκB but had no or only minimal effects on the mitogen-activated protein kinase pathway. In conclusion, the present study demonstrates that J2 suppresses LPS stimulation of RAW264.7 cells by targeting NF-κB pathways.
Similar content being viewed by others
References
Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85:85–95
Kaisho T, Akira S (2006) Toll-like receptor function and signaling. J Allergy Clin Immunol 117:979–987, quiz 988
Takeda K, Akira S (2004) TLR signaling pathways. Semin Immunol 16:3–9
Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, Patriotis C, Jenkins NA, Copeland NG, Kollias G, Tsichlis PN (2000) TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103:1071–1083
Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:387–398
Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk HD, Gaestel M (1999) MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol 1:94–97
Lazarov S, Balutsov M, Ianev E (2000) The role of bacterial endotoxins, receptors and cytokines in the pathogenesis of septic (endotoxin) shock. Vutr Boles 32:33–40
Wu MJ, Wang L, Ding HY, Weng CY, Yen JH (2004) Glossogyne tenuifolia acts to inhibit inflammatory mediator production in a macrophage cell line by downregulating LPS-induced NF-kappa B. J Biomed Sci 11:186–199. doi:10.1159/000076031
D’Aiuto F, Parkar M, Andreou G, Suvan J, Brett PM, Ready D, Tonetti MS (2004) Periodontitis and systemic inflammation: control of the local infection is associated with a reduction in serum inflammatory markers. J Dent Res 83:156–160
Zhao Y, Srivastava D (2007) A developmental view of microRNA function. Trends Biochem Sci 32:189–197
Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, van Dongen S, Grocock RJ, Das PP, Miska EA, Vetrie D, Okkenhaug K, Enright AJ, Dougan G, Turner M, Bradley A (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608–611
Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, Fabbri M, Alder H, Liu CG, Calin GA, Croce CM (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179:5082–5089
Perry MM, Moschos SA, Williams AE, Shepherd NJ, Larner-Svensson HM, Lindsay MA (2008) Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells. J Immunol 180:5689–5698
Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103:12481–12486
Sembdner G, Atzorn R, Schneider G (1994) Plant hormone conjugation. Plant Mol Biol 26:1459–1481
Fingrut O, Flescher E (2002) Plant stress hormones suppress the proliferation and induce apoptosis in human cancer cells. Leukemia 16:608–616
Ishii Y, Kiyota H, Sakai S, Honma Y (2004) Induction of differentiation of human myeloid leukemia cells by jasmonates, plant hormones. Leukemia 18:1413–1419
Fingrut O, Reischer D, Rotem R, Goldin N, Altboum I, Zan-Bar I, Flescher E (2005) Jasmonates induce nonapoptotic death in high-resistance mutant p53-expressing B-lymphoma cells. Br J Pharmacol 146:800–808
Flescher E (2005) Jasmonates—a new family of anti-cancer agents. Anticancer Drugs 16:911–916
Rotem R, Heyfets A, Fingrut O, Blickstein D, Shaklai M, Flescher E (2005) Jasmonates: novel anticancer agents acting directly and selectively on human cancer cell mitochondria. Cancer Res 65:1984–1993
Dang HT, Lee HJ, Yoo ES, Hong J, Bao B, Choi JS, Jung JH (2008) New jasmonate analogues as potential anti-inflammatory agents. Bioorg Med Chem 16:10228–10235
Sweet MJ, Hume DA (1996) Endotoxin signal transduction in macrophages. J Leukoc Biol 60:8–26
Guha M, O’Connell MA, Pawlinski R, Hollis A, McGovern P, Yan SF, Stern D, Mackman N (2001) Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression. Blood 98:1429–1439
Ilangumaran S, Ramanathan S, Rottapel R (2004) Regulation of the immune system by SOCS family adaptor proteins. Semin Immunol 16:351–365
Krishnan AV, Moreno J, Nonn L, Malloy P, Swami S, Peng L, Peehl DM, Feldman D (2007) Novel pathways that contribute to the anti-proliferative and chemopreventive activities of calcitriol in prostate cancer. J Steroid Biochem Mol Biol 103:694–702
O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D (2007) MicroRNA-155 is induced during the macrophage inflammatory response. Proc Natl Acad Sci USA 104:1604–1609
Viatour P, Merville MP, Bours V, Chariot A (2005) Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci 30:43–52
Rajnik M, Salkowski CA, Thomas KE, Li YY, Rollwagen FM, Vogel SN (2002) Induction of early inflammatory gene expression in a murine model of nonresuscitated, fixed-volume hemorrhage. Shock 17:322–328
Yang F, Oz HS, Barve S, de Villiers WJ, McClain CJ, Varilek GW (2001) The green tea polyphenol (−)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal epithelial cell line IEC-6. Mol Pharmacol 60:528–533
Lo AH, Liang YC, Lin-Shiau SY, Ho CT, Lin JK (2002) Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. Carcinogenesis 23:983–991
Hoffmann A, Levchenko A, Scott ML, Baltimore D (2002) The IkappaB-NF-kappaB signaling module: temporal control and selective gene activation. Science 298:1241–1245
Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96
Acknowledgments
This work was supported by the research grant of the Jeju National University in 2008.
Disclosure of potential conflict of interests
The authors declare no conflict of interests related to this study.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Hye-Ja Lee and Kyungah Maeng were equally contributed to this work.
Rights and permissions
About this article
Cite this article
Lee, HJ., Maeng, K., Dang, HT. et al. Anti-inflammatory effect of methyl dehydrojasmonate (J2) is mediated by the NF-κB pathway. J Mol Med 89, 83–90 (2011). https://doi.org/10.1007/s00109-010-0688-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-010-0688-0