Anti-inflammatory Activity

  • María Rosario AlonsoEmail author
  • Claudia A. Anesini
  • Renzo F. Martino


It is known that inflammation involves a complex series of protective and reparative responses to tissue injury caused by either mechanical and autoimmune stimuli or infection. Inflammation can be either acute or chronic. In the acute phase, in the early stages of inflammation, neutrophils, macrophages, and dendritic cells contribute to cytokine production that spreads the inflammatory events. Although inflammation has a protective role, many diseases have the etiological origin in inflammatory processes such as atherosclerosis, arthritis, cancer, and ischemic heart disease. There are many pathways involving the synthesis and secretion of pro-inflammatory mediators. In this chapter we analyze different intracellular signaling routes related to inflammation. There are two principal types of anti-inflammatory drugs, namely, steroidal anti-inflammatory drugs, which reduce inflammation by binding to cortisol receptors and nonsteroidal anti-inflammatory drugs, which decrease damage by inhibition of cyclooxygenase enzymes. These anti-inflammatory drugs entail many risks, in particular, gastrointestinal ulceration, bleeding, and hepatotoxicity. Over the last decades, the potential of sesquiterpene lactones as anti-inflammatory agents has been pointed out by different authors.


Acute inflammation Chronic inflammation Pro-inflammatory mediators Intracellular signaling routes Anti-inflammatory activity Sesquiterpene lactones 



activator protein-1


antioxidant response element


complement component

Chemokine R

chemokine receptors


ciclooxigenase 2


complement receptor


cysteinyl leukotrienes

Cytokine R

cytokine receptors


damage-associated molecular patterns


extracellular signal-regulated kinase


heme oxygenase 1




IκB kinase




IL-1 receptor antagonist


IL-1 receptor accessory protein


IL-1 type 1 receptor


IL-1 type 2 receptor


inducible type-2 isoform of nitric oxide synthase NOS-2


Janus kinases


c-Jun N-terminal kinase






mitogen-activated protein kinases


monocyte chemoattractant protein 1


monosodium urate


nuclear factor kappa B


inflammasome complex Nod-like receptor family pyrin domain containing 3


Nucleotide-binding oligomerization-domain protein-like receptors


factor (erythroid-derived 2)-related factor 2


Nonsteroidal anti-inflammatory drugs


pathogen-associated molecular patterns




phospholipase A2


polymorphonuclear neutrophils

Purine R

purine receptors


RIG-I-like (retinoic acid inducible gene 1) receptor family


reactive nitrogen species


reactive oxygen species


signal transducers and activators of transcription


sesquiterpene lactones


tumor growth factor


helper T cells


Toll-like receptors


tumor necrosis factor alpha




tyrosine kinase 2


  1. Atreya R, Neurath MF (2008) Signaling molecules: the pathogenic role of the IL6/STAT-3 trans signaling pathway in intestinal inflammation and in colonic cancer. Curr Drug Targets 9:369–374CrossRefPubMedGoogle Scholar
  2. Baeuerle PA, Henkel T (1994) Function and activation of NF-kB in the immune system. Rev Immunol 12:141–179CrossRefGoogle Scholar
  3. Banks WA, Kastin AJ, Gutierrez EG (1994) Penetration of interleukin-6 across the murine blood-brain barrier. Neurosci Lett 179:53–56. PMID 7845624CrossRefPubMedGoogle Scholar
  4. Bazzoni F, Beutler B (1996) The tumor necrosis factor ligand and receptor families. N Engl J Med 334:1717–1725CrossRefPubMedGoogle Scholar
  5. Braddock M, Quinn A (2004) Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention. Nat Rev Drug Discov 3:1–10CrossRefGoogle Scholar
  6. Butturini E, Cavalieri E, de Prati AC et al (2011) Two naturally occurring terpenes, dehydrocostuslactone and costunolide, decrease intracellular GSH content and inhibit STAT3 activation. PLoS One 6:e20174. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Butturini E, Paola RD, Suzuki H (2014) Costunolide and dehydrocostuslactone, two natural sesquiterpene lactones, ameliorate the inflammatory process associated to experimental pleurisy in mice. Eur J Pharmacol 730:107–115CrossRefPubMedGoogle Scholar
  8. Choy EHS, Panayi GS (2001) Cytokine 9 pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 344:907–916. CrossRefPubMedGoogle Scholar
  9. Dai Y, Guzman ML, Chen S et al (2010) The NF (Nuclear factor)-κB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. Br J Haematol 151:70–83CrossRefPubMedPubMedCentralGoogle Scholar
  10. Danese S, Mantovani A (2010) Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin-Yang interplay between inflammation and cancer. Oncogene 29:3313–3323CrossRefPubMedGoogle Scholar
  11. Davicino R, Alonso MR, Anesini C et al (2015) Preventive anti-inflammatory activity of an aqueous extract of larrea divaricata cav. and digestive and hematological toxicity. Int J Pharm Sci Res 6:3215–3223Google Scholar
  12. De Bosscher K, Haegeman G (2009) Minireview: latest perspectives on antiinflammatory actions of glucocorticoids. Mol Endocrinol 23:281–291CrossRefPubMedPubMedCentralGoogle Scholar
  13. de Prati AC, Ciampa AR, Cavalieri E et al (2005) STAT1 as a new molecular target of anti-inflammatory treatment. Curr Med Chem 12:1819–1828CrossRefPubMedGoogle Scholar
  14. Decker T, Kovarik P (2000) Serine phosphorylation of STATs. Oncogene 19:2628–2637CrossRefPubMedGoogle Scholar
  15. Dinarello CA (1996) Biological basis for Interleukin-1 in disease. Blood 87:2095–2147PubMedGoogle Scholar
  16. Dinarello CA (2004) Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation. Curr Opin Pharmacol 4:378–385CrossRefPubMedGoogle Scholar
  17. Dong L, Qiao H, Zhang X et al (2013) Parthenolide is neuroprotective in rat experimental stroke model: downregulating NF-κB, phospho-p38MAPK, and caspase-1 and ameliorating BBB permeability. Mediat Inflamm 2013:370804. CrossRefGoogle Scholar
  18. Ferrero-Miliani L, Nielsen OH, Andersen PS et al (2007) Chronic inflammation: importance of nod2 and nalp3 in interleukin-1beta generation. Clin Exp Immunol 147:227–235PubMedPubMedCentralGoogle Scholar
  19. Funk CD, FitzGerald GA (2007) COX-2 inhibitors and cardiovascular risk. J Cardiovasc Pharmacol 50:470–479CrossRefPubMedGoogle Scholar
  20. Gilmore TD (2006) Introduction to NF-kB: players, pathways, perspectives. Oncogene 25:6680–6684CrossRefPubMedGoogle Scholar
  21. Gitlin JD, Colten HR (1987) Molecular biology of acute phase plasma proteins. In: Pick F (ed) Lymphokines, vol 14. Academic Press, San Diego, pp 123–153CrossRefGoogle Scholar
  22. Haddad JJ (2002) Antioxidant and prooxidant mechanisms in the regulation of redox(y)-sensitive transcription factors. Cell Signal 14:879–897CrossRefPubMedGoogle Scholar
  23. Heinrich PC, Behrmann I, Müller-Newen G et al (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hohmann MS, Longhi-Balbinot DT, Guazelli CF et al (2016) Sesquiterpene lactones: structural diversity and perspectives as anti-inflammatory molecules. In: Atta-ur-Rahman (ed) Studies in natural products chemistry, vol 49. Elsevier, Amsterdam, pp 243–264Google Scholar
  25. Jeong WS, Keum YS, Chen C et al (2005) Differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chemopreventive compounds in HepG2 human hepatoma cells. Biochem Mol Biol 38:167–176Google Scholar
  26. Juliana C, Fernandes-Alnemri T, Wu J et al (2010) Anti-inflammatory compounds parthenolide and bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem 285:9792–9802CrossRefPubMedPubMedCentralGoogle Scholar
  27. Jung HW, Mahesh R, Park JH et al (2010) Effect of Sesbania grandiflora on lung antioxidant defense system in cigarette smoke exposed rats. Int Immunopharmacol 10:155–162CrossRefPubMedGoogle Scholar
  28. Kamimura D, Ishihara K, Hirano T (2003) IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 149:1–38PubMedGoogle Scholar
  29. Kang T, Han N, Kim H et al (2011) Blockade of IL-6 secretion pathway by the sesquiterpenoid atractylenolide III. J Nat Prod 74:223–227CrossRefPubMedGoogle Scholar
  30. Kim SJ, Park YS, Paik HD et al (2011) Effect of anthocyanins on expression of matrix metalloproteinase-2 in naproxen-induced gastric ulcers. Br J Nutr 106:1792–1801CrossRefPubMedGoogle Scholar
  31. Kingsbury S, Conaghan P, McDermott MF (2011) The role of the NLRP3 inflammasome in gout. J Inflamm Res 4:39–49PubMedPubMedCentralGoogle Scholar
  32. Landis RC, Haskard DO (2001) Pathogenesis of crystal-induced inflammation. Curr Rheumatol Rep 1:36–41CrossRefGoogle Scholar
  33. Lee J, Tae N, Lee JJ et al (2010) Effect of MF on NO production and iNOS expression levels in LPS-stimulated RAW264.7 cells. Eur J Pharmacol 636:173–180CrossRefPubMedGoogle Scholar
  34. Li X, Cui X, Li Y et al (2006) Parthenolide has limited effects on nuclear factor-kappa beta increases and worsens survival in lipopolysaccharide-challenged C57BL/6J mice. Cytokine 33:299–308CrossRefPubMedGoogle Scholar
  35. Li X, Zhang Y, Xia M et al (2014) Activation of Nlrp3 inflammasomes enhances macrophage lipid-deposition and migration: implication of a novel role of inflammasome in atherogenesis. PLoS One 9:e87552. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Li X, Peng Z, Su C (2015) Potential anti-cancer activities and mechanisms of costunolide and dehydrocostuslactone. Int J Mol Sci 16:10888–10906CrossRefGoogle Scholar
  37. Li-Weber M, Palfi K, Giaisi M et al (2005) Dual role of the anti-inflammatory sesquiterpene lactone: regulation of life and death by parthenolide. Cell Death Differ 12:408–409CrossRefPubMedGoogle Scholar
  38. Lyss G, Knorre A, Schmidt TJ et al (1998) The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65. J Biol Chem 273:33508–33516CrossRefPubMedGoogle Scholar
  39. Mariotto S, Esposito E, Di Paola R et al (2008) Protective effect of Arbutus unedo aqueous extract in carrageenan-induced lung inflammation in mice. Pharmacol Res 57:110–124CrossRefPubMedGoogle Scholar
  40. Mathema VB, Koh Y, Thakuri B et al (2012) Parthenolide, a sesquiterpene lactone, expresses multiple anti-cancer and anti-inflammatory activities. Inflammation 35:560–565CrossRefPubMedGoogle Scholar
  41. Matsuda H, Toguchida I, Ninomiya K et al (2003) Effects of sesquiterpenes and amino acid-sesquiterpene conjugates from the roots of Saussurea lappa on inducible nitric oxide synthase and heat shock protein in lipopolysaccharide-activated macrophages. Bioorg Med Chem 11:709–715CrossRefPubMedGoogle Scholar
  42. Mease P (2002) Tumor necrosis factor (TNF) 36. In psoriatic arthritis: pathophysiology and treatment with TNF inhibitors. Ann Rheum Dis 61:298–304CrossRefPubMedPubMedCentralGoogle Scholar
  43. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:28–435CrossRefGoogle Scholar
  44. Mittal M, Siddiqui MR, Tran K et al (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20:1126–1167CrossRefPubMedPubMedCentralGoogle Scholar
  45. Nakamura Y, Yoshida C, Murakami A et al (2004) Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes. FEBS Lett 572:245–250CrossRefPubMedGoogle Scholar
  46. Nicolete R, Arakawa NS, Rius C et al (2009) Budlein a from Viguiera robusta inhibits leukocyte-endothelial cell interactions, adhesion molecule expression and inflammatory mediators release. Phytomedicine 16:904–915CrossRefPubMedGoogle Scholar
  47. Nuki G (2008) Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 10:218–227CrossRefPubMedGoogle Scholar
  48. Pae HO, Jeong GS, Kim HS et al (2007) Costunolide inhibits production of tumor necrosis factor-alpha and interleukin-6 by inducing heme oxygenase-1 in RAW264.7 macrophages. Inflamm Res 56:520–526CrossRefPubMedGoogle Scholar
  49. Park EH, Han YM, Jeong M et al (2015) Omega-3 polyunsaturated fatty acids as an angelus custos to rescue patients from NSAID-induced gastroduodenal damage. J Gastroenterol 50:614–625. CrossRefPubMedGoogle Scholar
  50. Peschon JJ, Torrance DS, Stocking KL et al (1998) TNF receptor-deficient mice reveals divergent roles for p55 and p75 in several models of inflammation. J Immunol 160:943–952PubMedGoogle Scholar
  51. Qin JJ, Wang LY, Zhu JX et al (2011) Neojaponicone A, a bioactive sesquiterpene lactone dimer with an unprecedented carbon skeleton from Inula japonica. Chem Commun 47:1222–1224CrossRefGoogle Scholar
  52. Rayan NA, Baby N, Pitchai D et al (2011) Costunolide inhibits proinflammatory cytokines and iNOS in activated murine BV2 microglia. Front Biosci 3:1079–1091Google Scholar
  53. Robbins SL, Kumar V, Abbas A et al (2010) Patologia bases patológicas das doenças, 8th edn. Elsevier, Rio de JaneiroGoogle Scholar
  54. Rodriguez E, Towers GHN, Mitchell JC (1976) Biological activities of sesquiterpene lactones. Phytochemistry 15:1573–1580CrossRefGoogle Scholar
  55. Romano M, Sironi M, Toniatti C et al (1997) Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6:315–325CrossRefPubMedGoogle Scholar
  56. Ross R, Reske-Kunz AB (2001) The role of nitric oxide in contact hypersensitivity. Int Immunopharmacol 1:1469–1478CrossRefPubMedGoogle Scholar
  57. Rummel C, Gerstberger R, Roth J et al (2011) Parthenolide attenuates LPS-induced fever, circulating cytokines and markers of brain inflammation in rats. Cytokine 56:739–748CrossRefPubMedGoogle Scholar
  58. Scarpignato C, Hunt RH (2010) Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am 39:433–464CrossRefPubMedGoogle Scholar
  59. Scarponi C, Butturini E, Sestito R et al (2014) Inhibition of inflammatory and proliferative responses of human keratinocytes exposed to the sesquiterpene lactones dehydrocostuslactone and costunolide. PLoS One 16:e107904CrossRefGoogle Scholar
  60. Schäcke H, Döcke WD, Asadullah K (2002) Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 96:23–43CrossRefPubMedGoogle Scholar
  61. Schjerning Olsen AM, Fosbol EL, Lindhardsen J et al (2011) Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation 123:2226–2235CrossRefPubMedGoogle Scholar
  62. Siedle B, Garcia-Piñeres AJ, Murillo R et al (2004) Quantitative structure-activity relationship of sesquiterpene lactones as inhibitors of the transcription factor NF-KB. Med Chem 47:6042–6054CrossRefGoogle Scholar
  63. Smyth EM, Grosser T, Wang M et al (2009) Prostanoids in health and disease. J Lipid Res 50:S423–S428CrossRefPubMedPubMedCentralGoogle Scholar
  64. Sumner H, Salan U, Knight DW et al (1992) Inhibition of 5-lipoxygenase and cyclo-oxygenase in leukocytes by feverfew. Involvement of sesquiterpene lactones and other components. Biochem Pharmacol 43:2313–2320CrossRefPubMedGoogle Scholar
  65. Tamura R, Chen Y, Shinozaki M et al (2012) Eudesmane-type sesquiterpene lactones inhibit multiple steps in the NF-κB signaling pathway induced by inflammatory cytokines. Bioorg Med Chem Lett 22:207–211CrossRefPubMedGoogle Scholar
  66. Teixeira C, Landucci E, Antunes E et al (2003) Inflammatory effects of snake venom myotoxic phospholipases A2. Toxicon 42:947–962CrossRefPubMedGoogle Scholar
  67. Umemura K, Itoh T, Hamada N et al (2008) Preconditioning by sesquiterpene lactone enhances H2O2-induced Nrf2/ARE activation. Biochem Biophys Res Commun 368:948–954CrossRefPubMedGoogle Scholar
  68. Valerio DA, Cunha TM, Arakawa NS et al (2007) Anti-inflammatory and analgesic effects of the sesquiterpene lactone budlein A in mice: inhibition of cytokine production-dependent mechanism. Eur J Pharmacol 562:155–163CrossRefPubMedGoogle Scholar
  69. Vargas Salazar M (2009) El factor de necrosis tumoral-alfa (fnt-α) en la patogenesis de la artritis reumatoide y el riesgo de tuberculosis con infliximab. Revista Médica de Costa Rica y Centroamérica LXVII 590:345–351Google Scholar
  70. Verri WA, Cunha TM, Parada CA et al (2006) Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development? Pharmacol Ther 112:116–138CrossRefPubMedGoogle Scholar
  71. Wang JX, Hou LF, Yang Y et al (2009) SM905, an artemisinin derivative, inhibited NO and pro-inflammatory cytokine production by suppressing MAPK and NF-κB pathways in RAW 264.7 macrophages. Acta Pharmacol Sin 30:1428–1435CrossRefPubMedPubMedCentralGoogle Scholar
  72. Wang Y, Huang Z, Wang L et al (2011) Artemisinin inhibits monocyte adhesion to HUVECs through the NF-κB and MAPK pathways in vitro. Int J Mol Med 27:233–241PubMedGoogle Scholar
  73. Wong HR, Menendez IY (1999) Sesquiterpene lactones inhibit inducible nitric oxide synthase gene expression in cultured rat aortic smooth muscle cells. Biochem Bio Res Commun 262:375–380CrossRefGoogle Scholar
  74. Xie C, Li X, Wu J et al (2015) Anti-inflammatory activity of magnesium isoglycyrrhizinate through inhibition of phospholipase A2/arachidonic acid pathway. Inflammation 38:1639–1648CrossRefPubMedGoogle Scholar
  75. Zhang JM, An J (2007) Cytokines, inflammation and pain. Int Anesthesiol Clin 45:27–37CrossRefPubMedPubMedCentralGoogle Scholar
  76. Zhao HQ, Li WM, Lu ZQ et al (2014) The growing spectrum of anti-inflammatory interleukins and their potential roles in the development of sepsis. J Interf Cytokine Res 35:242–251CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • María Rosario Alonso
    • 1
    • 2
    Email author
  • Claudia A. Anesini
    • 2
    • 3
  • Renzo F. Martino
    • 4
  1. 1.Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Cátedra de FarmacologíaBuenos AiresArgentina
  2. 2.CONICET – Universidad de Buenos Aires, Instituto de Química y Metabolismo del Fármaco (IQUIMEFA)Buenos AiresArgentina
  3. 3.Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Farmacología, Cátedra de FarmacognosiaBuenos AiresArgentina
  4. 4.Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología y Biotecnología, Cátedra de InmunologíaBuenos AiresArgentina

Personalised recommendations