Pharmacological Modulation of Th17

Recent Patents on Inflammation & Allergy Drug Discovery 2009, 3, 000-000

1

Pharmacological Modulation of Th17 1 2 Juan B. De Sanctis , Jenny V. Garmendia1, Dolores Moreno2, Nancy Larocca , Michael Mijares4 2,3, 3 3 4 Camilo Di Giulio , Margarita Salazar-Bookaman , Gabriella Wojewodka and Danuta Radzioch 1

Institute of Immunology, Faculty of Medicine. 2 Cátedra de Patología general y Fisiopatología. Experimental Medicine Institute, 3Faculty of Pharmacy. Universidad Central de Venezuela. 4 McGill University Health Centre, McGill University, Faculty of Medicine, Department of Human Genetics and Department of Medicine Received: March 24, 2009; Accepted: April 1, 2009; Revised: April 9, 2009

Abstract: Recently, a third subset of Th17 cells has been described. . This T helper subset induces the release of chemokines and growth factors and causes neutrophil accumulation in several mammalian organs. Pharmacological intervention blocking Th17 generation as well as IL-17 signaling might prove useful in a variety of diseases including asthma, chronic obstructive pulmonary disease, Crohn’s disease, cystic fibrosis, multiple sclerosis, psoriatic disease and rheumatoid arthritis. Here, we describe the patents that address a potential pharmacological use of promoting or targeting IL-17.

Keywords: IL-17, IL-17 receptors, Th-17, Th-1, Th-2, autoimmune diseases, allergic diseases, retinoids, retinoid orphan receptors, inflammation. INTRODUCTION Interleukin 17 (IL-17A) is a 155 amino (35 Kd) proinflammatory cytokine, initially identified in mouse cytotoxic T cells [1-6]. It belongs to a family that includes IL17B, IL-17C, IL-17D, IL-17E and IL-17F which share 16 50% amino acid identity but differ in tissue expression patterns [1-6]. Several cells produce IL-17, CD4+, CD8+ and T cells, NKT cell, and to less extent NK and other cells [1-9]. The differentiation program of Th17 cells is based on the activation of STAT3by TGF- and IL-6, and the orphan retinoid nuclear receptors (ROR)t and ROR in CD4 cells where CD161+ is a marker for precursor Th17 cells in humans [1-11]. The development of Th17 is inhibited under Th1 or Th2 polarizing conditions (T-bet or GATA-3) [1-13]. The cytokines IL-12, IFN-, IL-4, IL-25 (induces IL-4 transcription and secretion), and IL-27 (induce IL-10 transcription and secretion), as well as other STAT1 and STAT 5 activators, play negative regulatory roles in the development of Th17 cells. Th-17 cells can also be generated by modulation of T regulatory cells (Foxp3 positive) or Tr1 cells (STAT3+ derived upon IL-27 stimulation) by IL-1, IL-2, IL-21 and IL-23 [1-13]. Thus indicating that the modulation of IL-17 production and Th-17 generation is largely dependent on the microenvironment[1-13]. IL-17A and IL-17F appear to be important in host defense against extracellular bacteria and fungi, and activation of mesenchymal cells [1-2]. An overproduction of IL-17A and IL-17F, has been associated with a number of autoimmune diseases [1-3, 14, 15]. It has been widely suggested that the regulation of IL-17 transcription and secretion is crucial for the induction and maintenance of the *Address correspondence to this author at the Universidad Central de Venezuela, Faculty of Medicine Institute of Immunology, Apartado Postal 50109, Caracas, Venezuela; Tel: +58-212-693-4767; Ext: 134; Fax: +58212-6932815; Email: [email protected], [email protected]

1872-213X/09 $100.00+.00

inflammatory response. Nevertheless, its overproduction can be responsible for the pathogenic effects recorded in exaggerated immune responses either to infectious agents or in autoimmune disorders [1-17]. In humans, the IL-17F gene polymorphism +161 resulting in His-to-Arg substitution has been shown to be protective in asthma. The mutated protein is unable to activate bronchial epithelial cells in vitro that consequently induce eosinophil and Th2 migration and activation [18]. The effects of IL-17 are dependent of a unique family of dimeric receptors RAE [3, 7, 11]. IL-17 binds mainly to a receptor complex consisting of IL-17RA and IL-17RC and to lesser extent to IL-17 RB, IL-17RD and IL-17RE [3, 11]. The IL-17 RA and IL-17-RC are type I transmembrane proteins receptors with intracellular sequences termed SEFIR [3, 11]. IL-27RC are polymorphic and 90 different variants upon alternative splicing [3, 11]. After ligand binding, the intracellular IL-17 signaling cascade include subsequent activation of several downstream pathways. One such pathway involves the adaptor protein nuclear factor (NF)- activator 1 (Act-1) [3, 11] that binds with SEFIR. The complex activates TNF receptor associated factors (TRAF) 3 and 6 and transforming growth factor activated kinase (TAK)1 which in turn mediate the activation of transcription factors such as NF- and CCAAT/enhancer binding protein (C/EBP) and C/EBP- [3, 11]. The members of the mitogen-activated protein (MAP) kinase family, such as cJun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 are also involved in IL-17-induced cytokine production [3, 11]. Another pathway reported in human airway epithelial cells is Act-1-independent and involves Janus kinase (JAK) 1 and phosphatidylinositol 3kinase (PI3K), followed by the inactivation of glycogen synthase kinase (GSK)-3 and PI3K gene products [3, 11]. Cell activation upon IL-17 stimulation induces the release of secondary, proinflammatory chemokines and growth factors in most mesenchymal cells leading to the recruitment and © 2009 Bentham Science Publishers Ltd.

2 Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 2

accumulation of neutrophils at the site of inflammation in the organ [1-16]. IIL-17A and IL-17F are key molecules for the recruitment, activation and migration of neutrophils,B cell differentiation and promote transcription and secretion of: IL-6, IL-8, IL-22, IL-26, GM-CSF, M-CSF, CXC chemokine ligand 1 and 10, CC chemokine ligand 20 and metalloproteinases [1-6]. Th17 cells have been suggested to play an important role in responses against extracellular Gram-negative bacteria and fungi, in which granulocyte infiltration is highly protective. Despite the fact that IL-17 appears to play a modest role in protecting host against intracellular mycobacterium, its production is increased during infection with Klebsiella pneumoniae, Bacteroides fragilis, Citrobacter rodentium, Escherichia coli, Borrelia burgdoferi and fungal species [16, 19, 20]. Patients with a deficiency of the IL-12p40 subunit, or with a deficiency of IL-12R 1, have an impaired synthesis of IL-12 and IL-23, making them more susceptible to mycobacterial disease and infections with nontyphoidal Salmonellae [1-6, 19,20. The lack of IL-17 protein is an insufficient differentiation and maturation of Th-17 cells when IL-23 is also absent [1-9]. Animal models of infection with Gram-negative and Gram-positive bacteria, in addition to Mycoplasma pneumoniae and certain protozoa, that IL-17 contributes to host defense against these microbes through its promoting effects on neutrophil recruitment and activation and the subsequent enhanced clearance of the pathogens [15]. IL-17 also up regulates the expression of antimicrobial molecules, such as -defensins, in the lung, skin and gut [1922]. However, the efficiency of IL-17 driven responses depends on pathogen burden [1-3]. High pathogen burden seems to down regulate IL-12, up regulate IL-6, IL-21 and TGF-, and in consequence induce overproduction of IL-23 and IL-17 which may result in severe tissue inflammatory pathology rather than protection [1-4].

Sanctis et al.

In addition to infections, Th17 cells play an important role in the induction and propagation of autoimmunity in various animal models [1-6, 17]. IL-17 deficient mice or mice treated with an IL-17 receptor antagonist are resistant to the development of collagen induced arthritis and they develop experimental autoimmune encephalitis (EAE) with delayed onset and reduced severity compared to wild type mice[17]. Administration of an IL-17 blocking antibody in mice immunized with a myelin antigen prevents chemokine expression in the brain and the subsequent development of EAE [17]. These data supported the idea that IL-17 is involved in the pathogenesis of several autoimmune diseases in mice and possibly also in humans. The generation of Th17 in murine and human cells is different [1-4] Fig. (1). Human Th17 cells were shown to be derived from memory, not naïve, T cells [1-4]. Experimental in vitro data co-stimulating human T CD4+ naïve T lymphocytes with cytokines as: IL-1 and IL-6, IL-6 and TGF-, IL-23, IL-1 or IL-23, are not sufficient to induce development of IL-17 producing cells [1-10]. A more effective strategy is to stimulate dendritic cells by muramyl-peptide, which enhances IL-23 and IL-1 production [3, 11]. In humans, TGF- is important but not necessary for Th17 differentiation suggesting that pharmacological modulation of this cytokine will not provide a substantial benefit in autoimmune diseases [1-3]. IL-17 levels have been detected in sera and diseased tissues in several autoimmune diseases such as: systemic lupus erythematosus, systemic sclerosis, multiple sclerosis, Crohn disease. Interestingly, IL-17 was present in the sera, synovial fluid, and synovial biopsies of most patients with rheumatoid arthritis (RA) was not detected in the tissue and sera of osteoarthritis patients [1-6, 23]. In a recent study in RA patients, the frequency of Th17 cells was significantly decreased in the joints as compared

Fig. (1). Generation of Th17 The figure illustrates the generation of Th17. The inhibitors are in the box.

Modulation of Th-17

Table 1.

Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 2 3

Pharmacological Modulation of TH17 Name

Effect

References

Monoclonal anti IL-17

Block IL-17

[29-33]

Soluble IL-17 receptor fusion protein

Block IL-17

[34-43]

Blockage of p40 IL12/IL23 receptor

Inhibit IL-23

[44-48]

Etanercept

Blocks TNF, inflammation

[50-52]

Apilimod mesylate

Regulates IL-23 production.

[53-54]

Retinoic acid

Generates Th2 differentiation

[56-59]

Retinoids: Tamibarotene (AM80), tretinoin (ATRA)

Inhibit RORt

[56]

Retinoids: tarazotene

Modulates local IL-17 production

[56]

Retinoids: 9 cis-retinoic acid, fenretidine, lycopene

Dow regulate CCR7 and CXCR4 receptors and IL17

[24, 56, 60]

NSAID

Inhibit COX-2 and IL-23

[61-67]

Resolvin 1

Blocks IL-23 generation

[68]

Simvastatin

Inhibit ROR

[69-72]

Sphingosine 1P

Block IL17 induction

[74]

Rapamycin

Down regulate Th17 inducing Treg

[79-82]

Prednisolone/prednisolone

Partial inhibitors of Th17

[82-84]

MAP inhibitors

Inhibit IL-6

[86-88]

Macrolides

Decrease IL-8

[89-90]

Aryl receptor antagonist CH-223191

Inhibits Th17 generation

[94]

shown to ameliorate the exacerbated inflammatory response in Cftr-KO mice infected with Pseudomonas aeruginosa and consequently allows for a more efficient clearance of the pathogen [24], This suggests that the reduction of the inflammatory response of may promote a more efficient pathogen clearance and decrease fibrosis in the lungs of patients with cystic fibrosis [24]. The role of endogenous IL-17 in allergen-induced eosinophilia is more controversial [6]. Since IL-4 down regulates IL-17 secretion, it is suspected that this cytokine is responsible for the decrease in Th17 in the local allergen response. Nonetheless, in the resolution of allergic reaction or in the maintenance of the inflammatory reaction induced by the allergen, IL-17 could play a role such as it has been proposed for autoimmune diseases [1-6]. In graft versus host disease, IL-17 seems to play a major role generating cell recruitment and eventually causes transplant rejection [25]. The role of CD8+ and CD4+ in the inflammatory site are crucial for this phenomenon [1-6, 17, 25-28]. The use of cyclosporine A and leflunomide in patients with RA has provided evidence that suggesting that these drugs may modulate IL-17, increasing Treg and consequently protecting the transplant [25,26]. PHARMACOLOGICAL INTERVENTION OF THE IL17 PATHWAY IN HUMAN DISEASE The strategies to moderate IL-17 effects involve modulation of cytokines that induce IL-17 expression such as IL1, IL-6, IL-12, and IL-23, blocking IL-17 activity, interfering with IL-17 of IL-17 to its receptors and interfering with IL-17 signal transduction upstream or downstream of its pathways. Direct Neutralization or Deactivation of IL- 17

with peripheral blood, in contrast Th1 cells were more abundant in the joints than in peripheral blood [3, 23]. In patients with asthma, IL-17 is moderately increased in lung tissue, bronchoalveolar lavage (BAL) fluid, sputum and blood which is also the case for neutrophils [1-6]. IL-17 seems to be a key cytokine in tobacco-induced chronic obstructive pulmonary disease and in patients with frequent infections and decreased pathogen clearance [1-6]. In similar fashion, patients with cystic fibrosis with ongoing exacerbations caused by Pseudomonas aeruginosa have elevated levels of IL-23 and IL-17 in BAL fluid when compared with control subjects [1-6]. Down regulation of IL-17 may be important pharmacological task in order to decrease the pathogenic effect of IL-17 in COPD and cystic fibrosis [3]. Interestingly, IL-17 levels were decreased 2.9 times when Cftr-KO mice were treated with fenretinide [N(4-hydroxyphenyl)-retinamide, 4-HPR] [24]. Fenretinide,has also been

A monoclonal anti-IL-17 antibody has been used in murine models of autoimmune arthritis and encephalomyelitis successfully [3, 23]. The antibody prevents reactivation of experimental arthritis, joint inflammation and bone erosion by decreasing RANKL and IL-1 levels [3, 23, 2832]. In patients with Crohn’s disease and psoriasis, who are resistant to current therapies, trials are underway using the antibody treatment [3, 29-33] Table 1. However, no data on the pharmokinetic and the efficacy of these therapies have been published up to date [3]. A soluble IL-17-receptor-Ig fusion protein, an autovaccine targeting IL-17 and a soluble form of IL-17 RC receptor, which binds IL-17 (and IL- 17F) have also been studied [3, 34-43]. In similar fashion to other fusion proteins, several important issues of ligand binding, pharmacokinetics have to be addressed and have yet to be published [3, 33-43]. Indirect Inhibition of IL-17 Production by Modulation of IL-23 Pathway A hopeful therapeutic approach to reduce IL-17 production in autoimmune diseases is IL-23 inhibition [3, 44-48]. Up to date, this approach has been based either on inhibition of IL-23 transcription, blocking the p40 subunit (shared with IL-12) or use of antagonists [3, 44-48]. A fusion


protein consisting of the IL-12-IL-23p40 subunit fused to the constant region of immunoglobulin IgG2b suppresses the inflammatory activity of mononuclear cells in the lamina propria from patients with Crohn’s disease in vitro [3]. No clinical studies of this fusion protein have been performed, to our knowledge, so its potential in vivo remains to be evaluated. In contrast, the antibody against the p40 subunit can be effective in models of gut and skin inflammation [3, 44-49]. The safety and efficacy of the anti-p40 antibody was evaluated in a double blind Phase II clinical trial with using the antibody intravenously once weekly for 7 weeks in 79 patients with Crohn’s disease [46-47]. The Crohn’s disease activity index score indicated clinical improvement, without increase in infections, after only 3 weeks of treatment and up to 18 weeks after the termination of treatment. A follow-up study on colectomy specimens obtained from 15 patients with disease and 10 ulcerative colitis patients indicated that a single-dose treatment with the anti-p40 antibody substantially down regulates the secretion of IL-6, IL-12, IL-23 and IL-17 only in mononuclear cells in the lamina propria of Crohn’s disease from active mucosal lesions but not in patients with ulcerative colitis [46,47]. The potential therapeutic efficacy in Phase I clinical studies evaluated shortterm safety, pharmacokinetics and clinical response to this antibody in patients with psoriasis [48,49]. Anti-p40 antibody decreases the expression of IL-12p40 and that of IL-23p19 (i.e. the unique subunit for IL-23) in patients who responded clinically to treatment. [46-49]. The results from a placebo-controlled, double-blind, parallel-group Phase II study enrolling 320 patients with moderate-to-severe psoriasis at 46 sites worldwide indicate that the clinical efficacy of the anti-p40 antibody is dose dependent [46-49]. Etanercept, a TNF-receptor-Ig fusion protein, leads to the inhibition of multiple molecular pathways in the downstream cellular signaling of TNF including IL-23 and consequently IL-17 [50-52]. These results indicate that an important mechanism of action of etanercept is to reduce the production of proinflammatory cytokines by dendritic cells, which results in subsequent inhibition of the activity in Th17 cells [50-52]. No report, to our knowledge, has compared the effects of different fusion proteins on IL-17 production in different human pathologies and studies are required to address this issue for the diversity of diseases in which the cytokine is involved. Apilimod Mesylate A promising drug, apilimod mesylate (AM), has been show to down to regulate in vitro production of IL-12 and IL-23 in human peripheral blood mononuclear cells [53-55]. AM, in a mouse macrophage cell line, inhibits IL-12 and IL23 transcription by blocking c-Rel translocation, without affecting the translocation of the other NF- family members to the nucleus [53,54]. The promising results in rodent models of inflammatory bowel disease have also prompted clinical trials with this drug [3]. In a Phase I/II clinical study, 73 patients with active Crohn’s disease received oral AM in a dose ranging from 14 to 70 mg either once or twice daily for up to 28 days [53]. The results demonstrated that AM is well tolerated and clinically effective in patients receiving higher doses (i.e. 35 mg once or twice daily and 70 mg once daily) of the drug. Altogether,

Sanctis et al.

Phase II clinical trials with AM have now been started in patients with Crohn’s disease, rheumatoid arthritis (RA) (in combination with methotrexate), multiple sclerosis (MS), common variable immunodeficiency, autoimmune uveoretinitis and psoriasis [53-55]. Effect of Retinoids on IL-17 and Th17 The stimulation of retinoic acid receptor (RAR), using all-trans retinoic acid (the largest and most important vitamin A metabolite) or synthetic analogs has been shown to inhibit IL-17 and promote Th2 differentiation [56-59]. It is known from studies on mice that all-trans retinoic acid inhibits Th-17 differentiation independently of IL-2 by enhancing TGF--driven signaling and inhibiting the expression of IL-6 and IL-23 receptors and consequently generate FoxP3 regulatory T cells [56-59]. Interestingly, these regulatory T cells may be driven to Th17 when they are stimulated by IL-1 and IL-2 [56]. Several retinoids have been used in the clinic with different affinities to retinoid receptors (RAR or RXR, retinoid X receptor) [56]. Experiments in vitro have shown that tamibarotene (AM80), a retinoid used to treat acute promyelocytic leukemia (APL), Kaposi’s sarcoma as well as psoriasis (binds preferentially RAR more than RAR), was shown to down regulate retinoid orphan nuclear receptor RORt expression and consequently inhibit IL-17 and Th17 [56]. A similar effect has been proposed for tretinoin (all- trans retinoic acid, ATRA), a drug used in APL and acne, although AM80 has been shown to be more potent probably due to lack of specificity of ATRA in the binding of RAR receptors [56]. On the other hand tarazotene, a RAR agonist, used to treat acne could modulate IL-17 local production [56]. Other retinoids, 9 cis-retinoic acid, lycopene and fenretidine (4HRP) have been shown to modulate RAR and peroxisome proliferator-activating receptor (PPAR); however, recent evidence suggest that these retinoids can modulate dendritic cell activation and Th-17 recruitment by down regulating of chemokine receptors in CCR7, CXCR4 [56, 60]. Thus, retinoids already used in the clinic may be useful down modulating IL-17 secretion and consequently Th-17 generation and function. Effects of Cytosolic Phospholipase A2 Inhibition on Th17 Of cytosolic phospholipase A2 (cPLA2) has been shown to prevent experimental autoimmune encephalitis by blocking Th1 and Th17 generation in mice [61]. In humans, prostaglandin E2 (PGE2) was shown to enhance IL-12/IL-23 secretion by dendritic cells favoring Th-17 generation [6264]. The effect is dependent on PGE2 binding to EP2/EP4 receptors enhancing cAMP and PKA signaling [65-67]. Thus, in inflammatory diseases, the increase in pro-inflammatory cytokines, mainly TNF, along with the increased transcription and activity of cPLA2, COX2 and NOS2 induces PGE2 which in turn promotes Th-17 and consequently enhances the inflammatory pathway [1-3]. Th-17 sustains the inflammatory response and consequently the use of NSAIDs which target COX2 along with IL-17 inhibitors may a useful combination for autoimmune diseases as well as cancer therapy [61-67].

Modulation of Th-17


Effects of Resolvin E1 and Lipid Mediators on Regulation of IL17 Resolvin E1, a product of omega-3 fatty acids, was found to reduce airway inflammation and promote its resolution in a mouse model of allergic airway inflammation [68]. Resolvin E1 blocks IL-23 secretion from dendritic cells. consequently decreases increasing in the BAL fluid [68]. The down regulation of IL-23 is due to the generation of lipoxin A4 by esolvin E1 [68]. Inhibitors of the cholesterol synthesis like simvastatin have been widely used as anti-inflammatory drugs [69-72]. Simvastatin was shown in vitro to decrease IL-6 and IL-23 transcription and secretion while simultaneously up regulating the transcription and secretion of IFN-, IL-4 and IL27 in monocytes derived from relapsing, remitting (RR) MS patients and from healthy controls [69-72]. In addition, simvastatin directly inhibits the expression of retinoid orphan receptors (RORCvar2 in human and ROR-t in mice) and prevents the transcription of IL-17 in activated CD4 cells from both RR MS patients and controls [70]. Simvastatin can also attenuate the release of neutrophilic and remodeling factors from primary bronchial epithelial cells suggesting that the decrease of the inflammatory response following treatment is due to an improvement in multiple parameters [71]. Moreover, pravastatin, which also is used for controlling cholesterol levels in patients, has also been shown to attenuate the allergic airway inflammation by suppressing antigen sensitization, IL-17 and antigen presentation in the lungs of mice with allergic asthma [73]. Other lipid mediators have been implicated in IL-17 transcription, secretion and Th17 generation [1-3]. Sphingosine-1-phosphate by binding to sphingosine-1-phosphate 1 receptor blocks the alternative signaling to generate Th17 [74]. It has been suggested that the mechanism by which the sphingosine-1-phosphate analog FTY720 causes immunosuppression is by blocking IL-17 generation [74]. On the other hand, -galactosyl ceramide and anti-CD3 are able to induce IL-17 in a subset of NKT1.1 (neg) iNKT cell population contributing to neutrophils recruitment in a murine model of pulmonary infiltration [75-76]. These data imply that the levels of NKT cells from the subpopulation involved in chronic inflammatory responses can be modulated by drugs that decrease IL-17 production [74-78]. A recent report also suggests that a subpopulation of NK cells produce IL-17 so in similar fashion as NKT cells, these cells may regulate IFN production and other crucial events in the immune response [77-78]. Other Indirect Ways of IL-17 Modulation (IL-15, Rapamycin, Glucocorticoids) The production of IL-17 can also be modulated by IL-15 since induces IL-17 production by CD4+ cells through PI3K and NF-kB signaling pathways and promotes IL-23 R expression [79]. Notably, this effect can be blocked by calcineurin inhibitors like cyclosporin A [79-82]. ndotoxininduced IL-17 production and the associated accumulation of bronchoalveolar neutrophils can be selectively inhibited by a calcineurin phosphatase inhibitor in the lungs of mice [80, 82]. Furthermore, Rapamycin has also been shown to down regulate IL-17 and generate FoxP3 regulatory T cells from

Th17 cells suggesting that an optimal pharmacological effect of these drugs is dependent upon the decrease in Th17 and the increase in Treg [82]. Glucocorticoids are, by themselves, not sufficient to decrease IL-17 production by T cells [3-4]. The use of calcineurin inhibitors increases the effect of glucocorticoids and consequently decreases inflammatory responses in different models [3, 82-84]. The use of prednisolone and dexamethasone are able to decrease TNF levels and the life span of neutrophils. However, these drugs are unable to completely block STAT 3 activation which seems to be responsible for the maintenance of Th17 [83-85]. In a murine model of glucocorticoid resistance, IL-17 is responsible for neutrophil accumulation in the lungs of mice treated with endotoxin. This effect can be efficiently blocked by rapamycin [85]. Since MAP kinases are part of the signal transduction generated upon IL-17 binding, the inhibition of these kinases in human bronchial epithelial (HBE) cells leads to the attenuated release of proinflammatory cytokines in response to IL-17 [3-4, 86-88]. Thus, an inhibitor of the p38 kinase blocks the release of IL-6, IL-8 and Gro- in addition to another potent neutrophil chemo-attractant, GCP-2[3-4, 8688]. Although not as potent and efficient as the p38 inhibitor, an ERK kinase inhibitor substantially attenuates the release of IL- 8 and IL-6 from these cells supporting the hypothesis that this particular MAP kinase is involved in IL-17 signaling [3-4, 86-88]. Nevertheless, certain antibiotics, such as the macrolides azithromycin and erythromycin, dosedependently decrease the IL-17-induced IL-8 release in these cells [89-90]. The mostly likely method of action involves the reduction of MAP kinase activation (i.e. p38, ERK and JNK) and by reducing oxidative stress. Dioxin Receptors and IL-17 Recently, the aryl hydrocarbon receptor has been shown to induce Th17 [91-94]. The role of endogenous ligand of this receptor as well as the presence of aromatic amino acids in the media condition IL-17 production [94]. Modulation of these receptors may be important for controlling inflammatory response and chronic diseases. CURRENT & FUTURE DEVELOPMENTS Several options could be used to modulate IL-17 in autoimmune and severe allergic diseases as it has been illustrated in this review; however, more studies are required to analyze and monitor the potential effects of IL-17 and its family of cytokines. Lately, pharmacogenomics have been widely used in order to have a more efficient and directed therapy for certain diseases. It is important to note that few reports have dealt with polymorphism of IL-17 and their receptors along with other members of both families. It would be interesting to assess the genetic background of different populations and probably these genes are important candidates for primary immunodeficiency. In case of specific immunodeficiency, the pharmacological modulation of IL-12 and IL-17 signaling can be crucial to promote immune responses.


It may be concluded that pharmacological modulation of Th17 has been successful by different drugs in chronic diseases as Chron disease, psoriasis, and RA. It is possible that we are only beginning to analyze the possible potential therapies that modulate IL-17 and consequently Th17. Grant support from FONACIT for all the co-authors G2005000389, UCV-Sociedad PSU 09-00-6144-2005, CDCH PI 09-00-6010-2005 (JBDS), PG 09-00-6785-07 (JBDS), PG 09-006599-2006 (JVG). Grants: ICC09-0219-2008 (JBDS) ICC09-0242-2008 (JVG). Presented in part at the First International Congress on Design and Drug Discovery, Dubai February 2008, with the financial support of CDCHUCV ICC09-0582 -2007 (JBDS) ICC09-0652-2007 (JVG).

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CONFLICT OF INTEREST None of the authors is involved in any approved or submitted patent which would focus on the regulation of IL17 or TH17 and therefore the authors declare no conflict of interest in relation to this review. REFERENCES [1] [2] [3] [4] [5] [6]

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