Planta Medica, Table of Contents Planta Med 2019; 85(04): 302-311DOI: 10.1055/a-0777-2420 Biological and Pharmacological Activity Original Papers Georg Thieme Verlag KG Stuttgart · New York Anti-Inflammatory Activity of Lobaric Acid via Suppressing NF-κB/MAPK Pathways or NLRP3 Inflammasome Activation Hee-Weon Lee 1 School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea , JinWook Kim 1 School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea , Joung-Han Yim 2 Polar BioCenter, Korea Polar Research Institute, KORDI, Incheon, Republic of Korea , Hong-Kum Lee 2 Polar BioCenter, Korea Polar Research Institute, KORDI, Incheon, Republic of Korea , Suhkneung Pyo 1 School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea › Author Affiliations Recommend Article Abstract Buy Article Abstract Lobaric acid (LA) is a constituent of the lichen Stereocaulon alpinum. LA has multiple biological activities, including antibacterial and antioxidant ones. The purpose of this study was to investigate the effect of LA and its mechanism on lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Macrophages were pretreated with different concentrations of LA (0.2 – 20 µM), followed by LPS stimulation. LA treatment of LPS stimulated macrophages decreased their nitric oxide production and the expression of cyclooxygenase-2 and prostaglandin E2. LA also significantly reduced the production of tumor necrosis factor-α and interleukin (IL)-6 by inhibiting the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). Additionally, LA inhibited the production of IL-1β and IL-18, as well as caspase-1 maturation, by inhibition of NLRP3 inflammasome activation in LPS/ATP-stimulated cells. These results strongly suggest that LA could inhibit inflammation by downregulating NF-κB/MAPK pathways and NLRP3 inflammasome activation in activated macrophages. These results reveal a new therapeutic approach to modulate inflammatory diseases linked to deregulated inflammasome activities. Key words Key wordsanti-inflammatory - lobaric acid - macrophage - NF-κB - cytokines - Stereocaulon aplinum Laurer. - Stereocaulaceae Full Text References References 1 Cragg GM, Newman DJ. Natural products: a continuing source of novel drug leads. Biochim Biophys Acta 2013; 1830: 3670-3695 2 Huneck S. The significance of lichens and their metabolites. Naturwissenschaften 1999; 86: 559-570 3 Müller K. Pharmaceutically relevant metabolites from lichens. Appl Microbiol and Biotechnol 2001; 56: 9-16 4 Bhattarai HD, Kim T, Oh H, Yim JH. A new pseudodepsidone from the Antarctic lichen Stereocaulon alpinum and its antioxidant, antibacterial activity. J Antibiot 2013; 66: 559 5 Paudel B, Bhattarai HD, Lee JS, Hong SG, Shin HW, Yim JH. Antibacterial potential of Antarctic lichens against human pathogenic Gram-positive bacteria. Phytother Res 2008; 22: 1269-1271 6 Kwon IS, Yim JH, Lee HK, Pyo S. Lobaric acid inhibits VCAM-1 expression in TNF-α-stimulated vascular smooth muscle cells via modulation of NF-κB and MAPK signaling pathways. Biomol Ther (Seoul) 2016; 24: 25-32 7 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821-832 8 Fujiwara N, Kobayashi K. Macrophages in inflammation. Curr Drug Targets Inflamm Allergy 2005; 4: 281-286 9 Baker RG, Hayden MS, Ghosh S. NF-κB, inflammation, and metabolic disease. Cell Metab 2011; 13: 11-22 10 Chawla A, Nguyen KD, Goh YS. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011; 11: 738-749 11 Rathinam VA, Vanaja SK, Fitzgerald KA. Regulation of inflammasome signaling. Nat Immunol 2012; 13: 333-342 12 Lamkanfi M, Dixit VM. The inflammasomes. PLoS Pathog 2009; 5: e1000510 13 Baron L, Gombault A, Fanny M, Villeret B, Savigny F, Guillou N, Panek C, Le Bert M, Lagente V, Rassendren F. The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine. Cell Death Dis 2015; 6: e1629 14 Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 2009; 10: 241-247 15 Haraldsdóttir S, Guolaugsdóttir E, Ingólfsdóttir K, Ogmundsdóttir HM. Anti-proliferative effects of lichen-derived lipoxygenase inhibitors on twelve human cancer cell lines of different tissue origin in vitro. Planta Med 2004; 70: 1098-1100 16 Ingolfsdottir K, Gissurarson S, Müller-Jakic B, Breu W, Wagner H. Inhibitory effects of the lichen metabolite lobaric acid on arachidonate metabolism in vitro . Phytomedicine 1996; 2: 243-246 17 Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ. Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 2001; 410: 471-475 18 Kang YJ, Wingerd BA, Arakawa T, Smith WL. Cyclooxygenase-2 gene transcription in a macrophage model of inflammation. J Immunol 2006; 177: 8111-8122 19 Liu F, Sun GQ, Gao HY, Li RS, Soromou LW, Chen N, Deng YH, Feng HH. Angelicin regulates LPS-induced inflammation via inhibiting MAPK/NF-κB pathways. J Surg Res 2013; 185: 300-309 20 Reddy DB, Reddanna P. Chebulagic acid (CA) attenuates LPS-induced inflammation by suppressing NF-κB and MAPK activation in RAW 264.7 macrophages. Biochem Biophys Res Commun 2009; 381: 112-117 21 Li Q, Verma IM. NF-κB regulation in the immune system. Nat Rev Immunol 2002; 2: 725-734 22 Pilon G, Dallaire P, Marette A. Inhibition of inducible nitric-oxide synthase by activators of AMP-activated protein kinase a new mechanism of action of insulin-sensitizing drugs. J Biol Chem 2004; 279: 20767-20774 23 Deshpande R, Khalili H, Pergolizzi RG, Michael SD, Chang MDY. Estradiol down-regulates LPS-induced cytokine production and NFkB activation in murine macrophages. Am J Reprod Immunol 1997; 38: 46-54 24 Clancy RM, Abramson SB. Nitric oxide: a novel mediator of inflammation. Proc Soc Exp Biol Med 1995; 210: 93-101 25 Baeuerle PA, Baichwal VR. NF-kB as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol 1997; 65: 111-138 26 Jung DH, Kim KH, Byeon HE, Park HJ, Park B, Rhee DK, Um SH, Pyo S. Involvement of ATF3 in the negative regulation of iNOS expression and NO production in activated macrophages. Immunol Res 2015; 62: 35-45 27 Gilchrist M, Thorsson V, Li B, Rust AG, Korb M, Kennedy K, Hai T, Bolouri H, Aderem A. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 2006; 441: 173-178 28 Hsu HY, Wen MH. Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression. J Biol Chem 2002; 277: 22131-22139 29 Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 2009; 183: 787-791 30 Liao PC, Chao LK, Chou JC, Dong WC, Lin CN, Lin CY, Chen A, Ka SM, Ho CL, Hua KF. Lipopolysaccharide/adenosine triphosphate-mediated signal transduction in the regulation of NLRP3 protein expression and caspase-1-mediated interleukin-1β secretion. Inflamm Res 2013; 62: 89-96 31 Thadhani VM, Naaz Q, Choudhary MI, Mesaik MA, Karunaratne V. Enzyme inhibitory and immunomodulatory activities of the depsidone lobaric acid extracted from the lichen Heterodermia sp . J Natl Sci Found 2014; 42: 193-196 32 Lee HW, Lee CG, Rhee DK, Um SH, Pyo S. Sinigrin inhibits production of inflammatory mediators by suppressing NF-κB/MAPK pathways or NLRP3 inflammasome activation in macrophages. Int Immunopharmacol 2017; 45: 163-173
