Anti-Inflammatory Compounds of Plant Origin. Part II. Modulation of Pro

Joo B. Calixto1 Anti-Inflammatory Compounds of Plant Origin. Maria M. Campos1 Part II. Modulation of Pro-Inflammatory Cytokines, Michel F. Otuki1 Adair R.S. Santos2 Chemokines and Adhesion Molecules Review Abstract EGCG: ±)-epigallocatechin gallate ELAM-1: endothelial-leukocyte adhesion molecule-1 It has been widely shown that many plant-derived compounds ERK: extracellular signal-regulated kinase present significant anti-inflammatory effects. For this reason, GRO: growth-related oncogene they represent potential molecules for the development of new HUVEC: human umbilical vein endothelial cells drugs, especially designed for the treatment and/or control of ICAM-1: intercellular adhesion molecule-1 chronic inflammatory states such as rheumatism, asthma, in- IFN: interferon flammatory bowel diseases, atherosclerosis, etc. This review fo- IL: interleukin cuses on the naturally-occurring compounds with anti-inflam- iNOS: inducible nitric oxide synthase matory properties and attempts to correlate their actions with IRA: the natural interleukin receptor activation the modulation of cytokines and associated intracellular signal- JAK: janus kinase ling pathways; it continues the review published in the Novem- JNK: c-Jun NH2-terminal kinase ber, 2003 issue of Planta Medica. LPS: lipopolysaccharide MAPK: mitogen-activated protein kinases Key words MCP: monocyte chemotactic protein Medicinal plants ´ plant constituents ´ inflammation ´ cytokines ´ MHC: major histocompatibility complex 93 chemokines ´ adhesion molecules MIP: macrophage inflammatory protein MMP: matrix metalloproteinases MPO: myeloperoxidase Abbreviations NF-kB nuclear factor kappa B AP-1: activator protein-1 NO: nitric oxide CCR1: chemokine receptor 1 PAF: platelet aggregation factor CINC-1: cytokine-induced neutrophil chemoattractant 1 PGEE: prostaglandin COX: cyclooxygenase PK: protein kinase Affiliation 1 Department of Pharmacology, CCB, Universidade Federal de Santa Catarina UFSC), Florianópolis, SC, Brazil 2 Department of Physiologic Sciences, CCB, Universidade Federal de Santa Catarina UFSC), Florianópolis, SC, Brazil Correspondence Joo B. Calixto ´ Department of Pharmacology ´ UFSC ´ Rua Ferreira Lima 82´ 88015-420, Florianópolis, SC ´ Brazil ´ Phone: +55-48-3319491 ´ Fax: +55-48-2224164 ´ E-mail: [email protected] or [email protected] Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. Note Part 1: Planta Med 2003;69:973± 983 Funding Michel F. Otuki is a PhD student in Pharmacology and he thanks CNPq for scholarship support. Maria M. Campos holds a post-doctoral fellowship from CoordenacË o de AperfeicË oamento de Pessoal de Nível Superior CAPES). The studies from our group were supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico CNPq), Financiadora de Estudos e Projetos FINEP) and by Programa de Apoio aos Grupos de Excelncia PRONEX), Brazil Received August 18, 2003 ´ Accepted October 18, 2003 Bibliography Planta Med 2004; 70: 93±103 ´ Georg Thieme Verlag Stuttgart ´ New York ´ ISSN 0032-0943 ´ DOI 10.1055/s-2004-815483 PMA/TPA: phorbol myristate acetate TNFa: tumour necrosis factor RANTES: regulated upon activation normal T-cell expressed VCAM-1: vascular cell adhesion molecule-1 and secreted TGF-b: transforming growth factor-b Introduction practice during the last few years. Despite the effectiveness de- scribed for these drugs, their use is associated with some side ef- The inflammatory process may be defined as a sequence of fects [15], [16], [17] and, most important, with high cost. In this events that occurs in response to noxious stimuli, trauma or in- context, the identification of small molecule plant-derived com- fection. These responses are orchestrated by a highly modulated pounds able to selectively interfere with the production and/or interaction between mediators of inflammation and inflamma- function of cytokines would constitute an important alternative Review tory cells [1]. Cytokines represent a group of multifunctional for the treatment of many inflammatory diseases. substances that are involved in many steps of the inflammatory response. Until now, more than 100 members of the cytokine In the second part of this review we will focus on the recent con- family and their specific receptors have been identified [2], [3], tributions to the identification of naturally-occurring com- [4]. Generally, cytokines can be classified as pro- or anti-inflam- pounds derived from plants as potential modulators of the cyto- matory, depending on the way they influence inflammation. In a kine network and related cell migration process. more simplified view, pro-inflammatory cytokines e.g., IL-1b, TNFa, IL-6 and IL-18) seem to be involved in the initiation and amplification of the inflammatory process, whereas the anti-in- Phenolic Compounds flammatory cytokines e. g., IL-10, TGF-b and IRA) negatively modulate these events [5], [6]. A substantial body of evidence obtained from both in vivo and in vitro studies supports the concept that various plant-derived Cytokines are produced by both resident and migrating cells, compounds with anti-inflammatory properties exert their ef- such as mast cells, macrophages and neutrophils and, after re- fects through the modulation of the cytokine system for recent lease; they can act either locally or systemically. Due to their re- review see [18]). For instance, flavonoids, a class of compounds dundant and pleiotropic actions, cytokines form a network in widely distributed throughout the plant kingdom, possess inter- which one cytokine can induce its own production or even the esting anti-inflammatory actions [19], [20], [21]. Very recently, secondary generation of other cytokines. In addition, it has been Xagorari et al. [22] have reported that luteolin 1) IC50 <1mM), widely shown that most cytokine actions involve the activation quercetin 2) IC50 1 mM), luteolin 7-glucoside approximate IC50 94 of transcription factors e.g., NF-kB and AP-1) and protein kina- 50 mM) and the isoflavonoid genistein IC50 5 mM) 3) inhibited ses e.g., MAPK and PKC) that, in turn, regulate the expression of LPS-stimulated TNFa and interleukin-6 release in RAW 264.7 many target genes indispensable to the maintenance of the in- macrophages, whereas eriodictyol and hesperetin only inhibited flammatory state [3], [7]. For instance, cytokines may be respon- TNFa release approximate IC50 value of 50 mM). Luteolin also in- sible for the induction of several enzymes e. g., iNOS and COX-2), hibited the production of TNFa in vivo and was capable of de- receptors PAF receptor, IL-2receptor) and adhesion molecules creasing both PMA and oxazolone-induced allergic ear oedema E-selectin, a- and b-integrins, ICAM-1, VCAM-1) [3], [8], [9]. [23]. Luteolin significantly reduced LPS-stimulated ICAM-1 expression in the liver of LPS Salmonella enteriditis)-treated mice A distinct group of cytokines, denoted chemokines including [24]. In a recent study, Das et al. [25] demonstrated that chronic IL-8, eotaxin, GRO, CINC-1 and RANTES) have the ability to che- administration of luteolin significantly attenuated ovalbumin- moattract and activate leukocytes at the site of inflammation induced airway bronchoconstriction and bronchial hyperreactiv- [10], [11]. Chemokine effects are mediated via interaction with ity. Moreover, the same treatment with luteolin was capable of G protein-coupled receptors. Binding of chemokines to their reducing the levels of both IL-4 and IL-5, whereas it induced an specific receptors allows rolling leukocytes to become firmly ad- increase in IFNg in the broncheoalveolar lavage fluid of sensitised herent and able to transmigrate to the target tissue, a process lar- mice [25]. These authors have suggested that luteolin could be Dieses Dokument wurde zum persönlichen Gebrauch heruntergeladen. Vervielfältigung nur mit Zustimmung des Verlages. gely dependent on the activation of adhesion molecules, mainly used as a lead molecule to identify effective therapies for the integrins [10], [12]. treatment of asthma. Recent evidence has indicated that cytokines and chemokines), Manna et al. [26] demonstrated that silymarin, a mixture of as well as their receptors, are involved in the pathophysiology of bioactive flavonoids isolated from Silybum marianum L. Astera- many inflammatory diseases, including sepsis, rheumatoid ar- ceae) was able to prevent, in a concentration-dependent manner, thritis, atherosclerosis and asthma. These pathological states TNFa-induced NF-kB activation in human histiocytic lymphoma seem to be linked to an imbalance of the cytokine network and U-937 cells. Johnson et al. [27] also reported the effects of sily- to the excessive recruitment of leukocytes to the inflammatory marin on the thymic lymphocyte population in mice. Intraperito- sites [3], [13], [15]. Because of this, the cytokine system constitu- neal administration of silymarin 10 to 250 mg/kg, once a day, for tes a very interesting and promising target for the development five days) resulted in the augmentation of CD4+ and CD8+ thy- of clinically relevant anti-inflammatory drugs. In fact, some mic lymphocyte populations, by a mechanism involving an in- specific cytokine modulators have been introduced into clinical crease in c-myc expression. In addition, silymarin significantly Calixto JB et al. Anti-Inflammatory Compounds of¼ Planta Med 2004; 70: 93 ±103 decreased the expression of IL-2and IL-4, without affecting MHC II expression in mouse lymphocytes [27]. It has

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