- Email: [email protected]
Th17 response promotes angiotensin II-induced atherosclerosis
Medical Hypotheses 76 (2011) 593–595
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Th17 response promotes angiotensin II-induced atherosclerosis Xiao-Hong Liu a,1, Qing-wei Ji b,1, Ying Huang c, Qiu-tang Zeng b,⇑ a
Department of Cardiology, ShanXi Provincial People’s Hospital, Taiyuan 030000, China Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China c Department of Ultrasound, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China b
a r t i c l e
i n f o
Article history: Received 12 July 2010 Accepted 6 January 2011
a b s t r a c t Vascular wall chronic inflammation plays a critical role in the development and progression of cardiovascular diseases such as atherosclerosis and hypertension. Circulating and tissue angiotensin II can induce potent inflammatory responses in vascular cells and promotes atherosclerosis, whereas the underlying mechanisms remain uncertain. Several data indicated that the upregulation of Th17 response has been found in the local atherosclerotic lesions and circulating lymphocytes in atherosclerosis prone models and the onset of acute coronary syndrome. Evidence from animal models shown that angiotensin II not only induced the Th1 response, but also amplified Th17 response. In addition, angiotensin II-induced hypertension and vascular dysfunction were abolished by blocking Th17/IL-17 effects. Therefore, we hypothesized that Th17 response may play an important role in angiotensin II-induced atherosclerosis. Ó 2011 Published by Elsevier Ltd.
Introduction Vascular wall chronic inflammation plays a critical role in the development and progression of cardiovascular diseases such as atherosclerosis and hypertension. However, what drives this inflammation and how it is regulated remain uncertain. Increased evidence indicated that CD4+ T lymphocytes (also known as Th cells) are highly involved in atherogenesis [1]. In 1986 Mosmann et al. showed that the functional heterogeneity of murine CD4+ T lymphocytes was due to their different profile of cytokine production [2]. Therefore, CD4+ T lymphocytes were categorized into two main subsets, Th type 1 (Th1) producing high levels of IFN-c and Th type 2 (Th2) producing high levels of IL-4. The finding was also confirmed in humans by Parronchi et al. [3]. Since then, the Th1– Th2 hypothesis has served the immunology community well, particularly in understanding infectious and inflammatory diseases. The upregulation of Th1 response has been found in the local atherosclerotic lesions and circulating lymphocytes in atherosclerosis prone models [4]. The evidence for the role of Th1 cells includes the detection of IFN-c mRNA and protein in atherosclerotic lesions. A direct role in the disease process has been defined in atherosclerosis prone models that IFN-c deficiency or IFN-cR deficiency both attenuated atherosclerosis whereas injection of recombinant IFN-c or the IFN-c-releasing factors IL-12 and IL-18 increased lesion size [5]. In contrast, Th2 and related cytokines have rarely been shown in the local atherosclerotic lesions and had no difference in ⇑ Corresponding author. Tel./fax: +86 27 85726423. 1
E-mail address: [email protected] (Q.-t. Zeng). These authors contributed equally to this work.
0306-9877/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.mehy.2011.01.008
circulation, suggesting that Th1/Th2 imbalance plays an important role in the development and progression of atherosclerosis. Th type 17 (Th17),the third subpopulation of Th cells, was identified in 2005, characterized by the production of IL-17, although it was known that activated CD4+ T lymphocytes can secreted IL-17 [6,7]. Th17 cytokines include IL-17, IL-6, TNF-a, IL-23 and so on. Th17 is induced by transforming growth factor (TGF)-b in combination with IL-6 and amplified and/or stabilized by IL-23. IL-17, also produced by memory CD8+, cdT cells, and neutrophils, acts as a potent proinflammatory mediator and synergizes with TNFa and IL-1. IL-17 has been linked to many autoimmune and inflammatory diseases including atherosclerosis [8]. Recently, several data indicated that Th17 also involved in atherosclerosis and angiotensin II-induced vascular wall inflammation.
Th17 and atherosclerosis We [9] analyzed the concentrations of IL-17 in 58 patients with coronary artery disease and 20 healthy controls in the first time. Our findings pointed towards a role of inflammation in the form of increased activity of IL-17, IL-6 and IL-8 in acute coronary syndromes and thus suggested that IL-17-driven inflammation may play a role in the promotion of clinical instability in patients with coronary artery disease. Our colleagues Cheng et al. [10] found that peripheral Th17 number, Th17 related cytokines (IL-17, IL-6 and IL-23) and transcription factor (RORct) levels significant increased in patients with acute coronary syndrome. The hypothesis posed by them is that Th17/Treg imbalance may play a potential role in plaque destabilization and the onset of ACS. Different findings,
594
X.-H. Liu et al. / Medical Hypotheses 76 (2011) 593–595
however, have revealed in several subsequent researches. For example, Eid et al. [11] found that peripheral Th17 number and IL-17 plasma levels were no difference between subgroups of coronary artery disease, although all of them were significantly higher than those in healthy subjects. After human coronary artery-infiltrating leukocytes were isolated from enzyme-digested, they found that Th17 number and Th1 number were higher in atherosclerotic coronary arteries than those in circulation. Furthermore, IL-17/IFNc double positive T cells were readily detectable within the artery wall. Both IL-17 and IFN-c were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Their finding that blockade of IL-17 signaling reduces IFN-c production in atherosclerotic arteries indicates that IL-17 may promote IFN-c production in addition to IFN-c responses, suggesting additional layers of interaction between these two cytokines. They suggest that antiinflammatory therapeutic strategies need to consider a network of interactive cytokines and chemokines rather than individual proinflammatory factors in isolation. Findings from atherosclerosis prone models seem to support the view that Th17/IL-17 appears to be pathogenic during the development of atherosclerosis. IL-6-deficient LDLR / mice have a small nonsignificant reduction in lesion development, while recombinant IL-6-treated mice may enhance early lesion formation [12,13]. Since IL-6 deficiency means decreased Th17 number and increase IL-6 means up-regulation of Th17 number, these researches mentioned suggested that Th17 may induce the proatherogenic inflammatory process. Though failed to detect Th17 number in spleen through flow cytometric analysis, Xie et al. [14] demonstrated that apoE / mice revealed significantly increased secretion of Th17 related cytokines (IL-17 and IL-6) and expression of RORct levels and obviously decreased number in Treg cells, secretion of Treg related cytokines (TGF-b1) and expression of Foxp3 levels as compared with control. In their opinion, Th17/Treg imbalance also involve in the formation and progression of atherosclerosis in atherosclerosis prone models. It has been reported that Inhibition of IL-17A (also known as IL-17) treated with anti-IL17A Ab markedly reduced atherosclerotic lesion area, maximal stenosis and vulnerability of the lesion in apoE / mice [15]. When different atherogenic cell types such as macrophages and dendritic cells were isolated and stimulated with IL-17A in addition to other inflammatory mediators, they observed that stimulation with IL17A induced proinflammatory changes in several atherogenic cell types and apoptotic cell death in murine cells. The report, therefore, support a pathogenic role of IL-17A in the development of atherosclerosis by way of its widespread effects on atherogenic cells. Blocking IL-17A, however, is not equivalent to inhibiting Th17 cell generation as IL-17A is also produced by several other cell types. In Van Es’ study, transplanted LDLR / mice with IL17R deficient bone marrow induced a sharply reduction in lesion size and macrophage number increased but mast cell number decreased in plaque, suggesting that blocking the downstream effect of Th17/IL-17 also attenuated atherosclerosis in LDLR / mice [16]. IL-18 is produced by monocytes, macrophages, dendritic cells, and several nonhematopoeitic cell types. Being the important cytokine to promote Th1 development, IL-18 is likely to be a key mediator in atherogenic inflammation. In addition, IL-18 increases the expression of certain inflammatory cytokines and MMPs in endothelial cells, SMCs, and macrophages. IL-18 administration did not affect lesion development in apoE / IFN-c / mice, suggesting that IL-18 exerts its main effect in atherosclerosis through the induction of IFN-c [17]. Another study showed that in spite of increased serum cholesterol, reduced atherosclerosis and Th1 activity were observed in apoE / IL-18 / mice, suggesting that inhibition of the IL-18/Th1/interferon-c pathway could be an attractive approach for treatment of atherosclerosis [18]. However,
a recent study argued that IL-18 deficiency also resulted in the progression of atherosclerosis [19]. When they treated apoE / IL-18 / mice with high-cholesterol diet, surprising results were shown that not only serum cholesterol and triglyceride levels were significantly higher in these mice than IL-18 / apoE / mice or IL-18 / apoE / mice on low-cholesterol diet, but also lesion size in aortic arch were significantly increase in these mice compared with controls and these plaques seem to be unstable and prone to rupture. Increased atherosclerosis correlates with enhanced Th17-cells, IL-23-producing vascular smooth muscle cells (VSMC) and macrophages. They pointed out that apoE / IL-18 / mice with high-cholesterol diet accelerate atherosclerosis via the alternative IL-23/Th17 pathway, demonstrating a new role for Th17 in atherosclerosis.
Th17 and angiotensin II The renin–angiotensin system plays a vital role in regulating the physiological processes of the cardiovascular system. Angiotensin II is the major bioactive effector molecule of the renin–angiotensin system and it has both beneficial and pathological effects. The most important effect of angiotensin II was considered to be the most important endogenous regulators of blood pressure. Circulating angiotensin II exerts potent vasoconstrictor effects on resistance arteries. In addition angiotensin II releases aldosterone from the adrenal glands, which in turn enhances renal tubular sodium reabsorbtion resulting in an increase in the effective circulating plasma volume. A large of evidence indicates that angiotensin II is a major contributor to the development and maintenance of renovascular hypertension and the pathogenesis of atherosclerosis [20]. Angiotensin II regulates the growth and migration of smooth muscle cells and fibroblasts, apoptosis of endothelial cells, and differentiation of monocytes into macrophages. Moreover, angiotensin II can induce potent inflammatory responses in vascular cells. For example, chronic infusion of angiotensin II in apoE / mice enhances the vascular expression of TNF-a, IL-6, and IL-1b as well as chemokines and chemokine receptors. In addition, angiotensin II treatment increases atherosclerotic lesion size and promotes unstable plaque phenotype. Angiotensin II can also alter the extracellular matrix remodeling via activation of metalloproteinases and induce a procoagulant state. Both circulating plasma-derived of angiotensin II and tissue-based production of angiotensin II play a pivotal role in those effects mentioned above and those effects may have no relation with blood pressure or plasma cholesterol levels. Besides its inflammatory effects on vascular cells, angiotensin II can also modulate CD4+ T lymphocytes response. Accumulating evidence suggested that angiotensin II can be produced by lymphocytes and trigger the proliferation of splenic lymphocytes through AT1 receptor activation [21–23]. Rats infused with exogenous angiotensin II show an increased IFN-c and an immune switch toward a Th1 response in splenocytes [22]. Similarly, splenocytes from hypertensive hypercholesterolemic apoE / mice with high angiotensin II produce more IFN-c than those from hypertensive mice with normal angiotensin II or normotensive apoE / mice [23] .Furthermore, administration of angiotensin AT1 receptor blockers ameliorated disease and abolished the Th1 response. More recently, Madhur et al. [24] have demonstrated that angiotensin II also induced Th17 response. Th17 number increased 2- to 3-fold in mice with 2 weeks of angiotensin II-induced hypertension. Since they found angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media, IL-17 / mice (C57BL/6J background) were used to determine the effect of IL-17 on blood pressure and vascular function. In the
X.-H. Liu et al. / Medical Hypotheses 76 (2011) 593–595
beginning of the study, the initial hypertensive response to angiotensin II infusion was similar in IL-17 / and C57BL/6J mice. However, blood pressure in IL-17 / mice sharply decreased and was 30-mm Hg lower than in C57BL/6J mice after 4 weeks of angiotensin II infusion. In addition, vascular dysfunction in response to angiotensin II was also abolished in IL-17 / mice, suggesting that Th17/IL-17 are critical for the maintenance of angiotensin II-induced hypertension and vascular dysfunction. Hypothesis and clinical implications Based on these previous studies, we hypothesized that Th17 response may play an important role in angiotensin II-induced atherosclerosis. Atherosclerosis as well as hypertension presents in several forms, some linked to the activation of the renin-angiotensin system and elevated circulating angiotensin II, and some with normal angiotensin II levels. In regards with those atherosclerotic patients accompanied with higher levels circulating angiotensin II, blocking Th17/IL-17 effects might be a therapeutic target for this widespread disease. In addition, modulating Th17 response may be one of anti-atherosclerosis mechanisms of angiotensin AT1 receptor blockers. Conflict of interest statement None declared. References [1] Robertson AK, Hansson GK. T cells in atherogenesis: for better or for worse? Arterioscler Thromb Vasc Biol 2006;26:2421–32. [2] Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone I definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986;136:2348–57. [3] Parronchi P, Macchia D, Piccinni MP, et al. Allergen- and bacterial antigenspecific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci USA 1991;88:4538–42. [4] Lusis AJ. Atherosclerosis. Nature 2000;407:233–41. [5] Harvey EJ, Ramji DP. Interferon-gamma and atherosclerosis: pro- or antiatherogenic? Cardiovasc Res 2005;67:11–20.
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[6] Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6:1123–32. [7] Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133–41. [8] Csiszar A, Ungvari Z. Synergistic effects of vascular IL-17 and TNFalpha may promote coronary artery disease. Med Hypotheses 2004;63:696–8. [9] Hashmi S, Zeng QT. Role of interleukin-17 and interleukin-17-induced cytokines interleukin-6 and interleukin-8 in unstable coronary artery disease. Coron Artery Dis 2006;17:699–706. [10] Cheng X, Yu X, Ding YJ, et al. The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 2008;127:89–97. [11] Eid RE, Rao DA, Zhou J, et al. Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 2009;119:1424–32. [12] Song L, Schindler C. IL-6 and the acute phase response in murine atherosclerosis. Atherosclerosis 2004;177:43–51. [13] Huber SA, Sakkinen P, Conze D, Hardin N, Tracy R. Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1999;19:2364–7. [14] Xie JJ, Wang J, Tang TT, et al. The Th17/Treg functional imbalance during atherogenesis in ApoE( / ) mice. Cytokine 2010;49:185–93. [15] Erbel C, Chen L, Bea F, et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J Immunol 2009;183:8167–75. [16] van Es T, van Puijvelde GH, Ramos OH, et al. Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice. Biochem Biophys Res Commun 2009;388:261–5. [17] Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 2001;89:E41–5. [18] Elhage R, Jawien J, Rudling M, et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc Res 2003;59:234–40. [19] Pejnovic N, Vratimos A, Lee SH, et al. Increased atherosclerotic lesions and Th17 in interleukin-18 deficient apolipoprotein E-knockout mice fed high-fat diet. Mol Immunol 2009;47:37–45. [20] Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006;86:515–81. [21] Nataraj C, Oliverio MI, Mannon RB, et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J Clin Invest 1999;104:1693–701. [22] Shao J, Nangaku M, Miyata T, et al. Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury. Hypertension 2003;42:31–8. [23] Mazzolai L, Duchosal MA, Korber M, et al. Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE / mice. Hypertension 2004;44:277–82. [24] Madhur MS, Lob HE, McCann LA, et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 2010;55:500–7.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Th17 response promotes angiotensin II-induced atherosclerosis Xiao-Hong Liu a,1, Qing-wei Ji b,1, Ying Huang c, Qiu-tang Zeng b,⇑ a
Department of Cardiology, ShanXi Provincial People’s Hospital, Taiyuan 030000, China Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China c Department of Ultrasound, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China b
a r t i c l e
i n f o
Article history: Received 12 July 2010 Accepted 6 January 2011
a b s t r a c t Vascular wall chronic inflammation plays a critical role in the development and progression of cardiovascular diseases such as atherosclerosis and hypertension. Circulating and tissue angiotensin II can induce potent inflammatory responses in vascular cells and promotes atherosclerosis, whereas the underlying mechanisms remain uncertain. Several data indicated that the upregulation of Th17 response has been found in the local atherosclerotic lesions and circulating lymphocytes in atherosclerosis prone models and the onset of acute coronary syndrome. Evidence from animal models shown that angiotensin II not only induced the Th1 response, but also amplified Th17 response. In addition, angiotensin II-induced hypertension and vascular dysfunction were abolished by blocking Th17/IL-17 effects. Therefore, we hypothesized that Th17 response may play an important role in angiotensin II-induced atherosclerosis. Ó 2011 Published by Elsevier Ltd.
Introduction Vascular wall chronic inflammation plays a critical role in the development and progression of cardiovascular diseases such as atherosclerosis and hypertension. However, what drives this inflammation and how it is regulated remain uncertain. Increased evidence indicated that CD4+ T lymphocytes (also known as Th cells) are highly involved in atherogenesis [1]. In 1986 Mosmann et al. showed that the functional heterogeneity of murine CD4+ T lymphocytes was due to their different profile of cytokine production [2]. Therefore, CD4+ T lymphocytes were categorized into two main subsets, Th type 1 (Th1) producing high levels of IFN-c and Th type 2 (Th2) producing high levels of IL-4. The finding was also confirmed in humans by Parronchi et al. [3]. Since then, the Th1– Th2 hypothesis has served the immunology community well, particularly in understanding infectious and inflammatory diseases. The upregulation of Th1 response has been found in the local atherosclerotic lesions and circulating lymphocytes in atherosclerosis prone models [4]. The evidence for the role of Th1 cells includes the detection of IFN-c mRNA and protein in atherosclerotic lesions. A direct role in the disease process has been defined in atherosclerosis prone models that IFN-c deficiency or IFN-cR deficiency both attenuated atherosclerosis whereas injection of recombinant IFN-c or the IFN-c-releasing factors IL-12 and IL-18 increased lesion size [5]. In contrast, Th2 and related cytokines have rarely been shown in the local atherosclerotic lesions and had no difference in ⇑ Corresponding author. Tel./fax: +86 27 85726423. 1
E-mail address: [email protected] (Q.-t. Zeng). These authors contributed equally to this work.
0306-9877/$ - see front matter Ó 2011 Published by Elsevier Ltd. doi:10.1016/j.mehy.2011.01.008
circulation, suggesting that Th1/Th2 imbalance plays an important role in the development and progression of atherosclerosis. Th type 17 (Th17),the third subpopulation of Th cells, was identified in 2005, characterized by the production of IL-17, although it was known that activated CD4+ T lymphocytes can secreted IL-17 [6,7]. Th17 cytokines include IL-17, IL-6, TNF-a, IL-23 and so on. Th17 is induced by transforming growth factor (TGF)-b in combination with IL-6 and amplified and/or stabilized by IL-23. IL-17, also produced by memory CD8+, cdT cells, and neutrophils, acts as a potent proinflammatory mediator and synergizes with TNFa and IL-1. IL-17 has been linked to many autoimmune and inflammatory diseases including atherosclerosis [8]. Recently, several data indicated that Th17 also involved in atherosclerosis and angiotensin II-induced vascular wall inflammation.
Th17 and atherosclerosis We [9] analyzed the concentrations of IL-17 in 58 patients with coronary artery disease and 20 healthy controls in the first time. Our findings pointed towards a role of inflammation in the form of increased activity of IL-17, IL-6 and IL-8 in acute coronary syndromes and thus suggested that IL-17-driven inflammation may play a role in the promotion of clinical instability in patients with coronary artery disease. Our colleagues Cheng et al. [10] found that peripheral Th17 number, Th17 related cytokines (IL-17, IL-6 and IL-23) and transcription factor (RORct) levels significant increased in patients with acute coronary syndrome. The hypothesis posed by them is that Th17/Treg imbalance may play a potential role in plaque destabilization and the onset of ACS. Different findings,
594
X.-H. Liu et al. / Medical Hypotheses 76 (2011) 593–595
however, have revealed in several subsequent researches. For example, Eid et al. [11] found that peripheral Th17 number and IL-17 plasma levels were no difference between subgroups of coronary artery disease, although all of them were significantly higher than those in healthy subjects. After human coronary artery-infiltrating leukocytes were isolated from enzyme-digested, they found that Th17 number and Th1 number were higher in atherosclerotic coronary arteries than those in circulation. Furthermore, IL-17/IFNc double positive T cells were readily detectable within the artery wall. Both IL-17 and IFN-c were produced at higher levels by T cells within cultured atherosclerotic coronary arteries after polyclonal activation than within nondiseased vessels. Their finding that blockade of IL-17 signaling reduces IFN-c production in atherosclerotic arteries indicates that IL-17 may promote IFN-c production in addition to IFN-c responses, suggesting additional layers of interaction between these two cytokines. They suggest that antiinflammatory therapeutic strategies need to consider a network of interactive cytokines and chemokines rather than individual proinflammatory factors in isolation. Findings from atherosclerosis prone models seem to support the view that Th17/IL-17 appears to be pathogenic during the development of atherosclerosis. IL-6-deficient LDLR / mice have a small nonsignificant reduction in lesion development, while recombinant IL-6-treated mice may enhance early lesion formation [12,13]. Since IL-6 deficiency means decreased Th17 number and increase IL-6 means up-regulation of Th17 number, these researches mentioned suggested that Th17 may induce the proatherogenic inflammatory process. Though failed to detect Th17 number in spleen through flow cytometric analysis, Xie et al. [14] demonstrated that apoE / mice revealed significantly increased secretion of Th17 related cytokines (IL-17 and IL-6) and expression of RORct levels and obviously decreased number in Treg cells, secretion of Treg related cytokines (TGF-b1) and expression of Foxp3 levels as compared with control. In their opinion, Th17/Treg imbalance also involve in the formation and progression of atherosclerosis in atherosclerosis prone models. It has been reported that Inhibition of IL-17A (also known as IL-17) treated with anti-IL17A Ab markedly reduced atherosclerotic lesion area, maximal stenosis and vulnerability of the lesion in apoE / mice [15]. When different atherogenic cell types such as macrophages and dendritic cells were isolated and stimulated with IL-17A in addition to other inflammatory mediators, they observed that stimulation with IL17A induced proinflammatory changes in several atherogenic cell types and apoptotic cell death in murine cells. The report, therefore, support a pathogenic role of IL-17A in the development of atherosclerosis by way of its widespread effects on atherogenic cells. Blocking IL-17A, however, is not equivalent to inhibiting Th17 cell generation as IL-17A is also produced by several other cell types. In Van Es’ study, transplanted LDLR / mice with IL17R deficient bone marrow induced a sharply reduction in lesion size and macrophage number increased but mast cell number decreased in plaque, suggesting that blocking the downstream effect of Th17/IL-17 also attenuated atherosclerosis in LDLR / mice [16]. IL-18 is produced by monocytes, macrophages, dendritic cells, and several nonhematopoeitic cell types. Being the important cytokine to promote Th1 development, IL-18 is likely to be a key mediator in atherogenic inflammation. In addition, IL-18 increases the expression of certain inflammatory cytokines and MMPs in endothelial cells, SMCs, and macrophages. IL-18 administration did not affect lesion development in apoE / IFN-c / mice, suggesting that IL-18 exerts its main effect in atherosclerosis through the induction of IFN-c [17]. Another study showed that in spite of increased serum cholesterol, reduced atherosclerosis and Th1 activity were observed in apoE / IL-18 / mice, suggesting that inhibition of the IL-18/Th1/interferon-c pathway could be an attractive approach for treatment of atherosclerosis [18]. However,
a recent study argued that IL-18 deficiency also resulted in the progression of atherosclerosis [19]. When they treated apoE / IL-18 / mice with high-cholesterol diet, surprising results were shown that not only serum cholesterol and triglyceride levels were significantly higher in these mice than IL-18 / apoE / mice or IL-18 / apoE / mice on low-cholesterol diet, but also lesion size in aortic arch were significantly increase in these mice compared with controls and these plaques seem to be unstable and prone to rupture. Increased atherosclerosis correlates with enhanced Th17-cells, IL-23-producing vascular smooth muscle cells (VSMC) and macrophages. They pointed out that apoE / IL-18 / mice with high-cholesterol diet accelerate atherosclerosis via the alternative IL-23/Th17 pathway, demonstrating a new role for Th17 in atherosclerosis.
Th17 and angiotensin II The renin–angiotensin system plays a vital role in regulating the physiological processes of the cardiovascular system. Angiotensin II is the major bioactive effector molecule of the renin–angiotensin system and it has both beneficial and pathological effects. The most important effect of angiotensin II was considered to be the most important endogenous regulators of blood pressure. Circulating angiotensin II exerts potent vasoconstrictor effects on resistance arteries. In addition angiotensin II releases aldosterone from the adrenal glands, which in turn enhances renal tubular sodium reabsorbtion resulting in an increase in the effective circulating plasma volume. A large of evidence indicates that angiotensin II is a major contributor to the development and maintenance of renovascular hypertension and the pathogenesis of atherosclerosis [20]. Angiotensin II regulates the growth and migration of smooth muscle cells and fibroblasts, apoptosis of endothelial cells, and differentiation of monocytes into macrophages. Moreover, angiotensin II can induce potent inflammatory responses in vascular cells. For example, chronic infusion of angiotensin II in apoE / mice enhances the vascular expression of TNF-a, IL-6, and IL-1b as well as chemokines and chemokine receptors. In addition, angiotensin II treatment increases atherosclerotic lesion size and promotes unstable plaque phenotype. Angiotensin II can also alter the extracellular matrix remodeling via activation of metalloproteinases and induce a procoagulant state. Both circulating plasma-derived of angiotensin II and tissue-based production of angiotensin II play a pivotal role in those effects mentioned above and those effects may have no relation with blood pressure or plasma cholesterol levels. Besides its inflammatory effects on vascular cells, angiotensin II can also modulate CD4+ T lymphocytes response. Accumulating evidence suggested that angiotensin II can be produced by lymphocytes and trigger the proliferation of splenic lymphocytes through AT1 receptor activation [21–23]. Rats infused with exogenous angiotensin II show an increased IFN-c and an immune switch toward a Th1 response in splenocytes [22]. Similarly, splenocytes from hypertensive hypercholesterolemic apoE / mice with high angiotensin II produce more IFN-c than those from hypertensive mice with normal angiotensin II or normotensive apoE / mice [23] .Furthermore, administration of angiotensin AT1 receptor blockers ameliorated disease and abolished the Th1 response. More recently, Madhur et al. [24] have demonstrated that angiotensin II also induced Th17 response. Th17 number increased 2- to 3-fold in mice with 2 weeks of angiotensin II-induced hypertension. Since they found angiotensin II infusion increased IL-17 production from T cells and IL-17 protein in the aortic media, IL-17 / mice (C57BL/6J background) were used to determine the effect of IL-17 on blood pressure and vascular function. In the
X.-H. Liu et al. / Medical Hypotheses 76 (2011) 593–595
beginning of the study, the initial hypertensive response to angiotensin II infusion was similar in IL-17 / and C57BL/6J mice. However, blood pressure in IL-17 / mice sharply decreased and was 30-mm Hg lower than in C57BL/6J mice after 4 weeks of angiotensin II infusion. In addition, vascular dysfunction in response to angiotensin II was also abolished in IL-17 / mice, suggesting that Th17/IL-17 are critical for the maintenance of angiotensin II-induced hypertension and vascular dysfunction. Hypothesis and clinical implications Based on these previous studies, we hypothesized that Th17 response may play an important role in angiotensin II-induced atherosclerosis. Atherosclerosis as well as hypertension presents in several forms, some linked to the activation of the renin-angiotensin system and elevated circulating angiotensin II, and some with normal angiotensin II levels. In regards with those atherosclerotic patients accompanied with higher levels circulating angiotensin II, blocking Th17/IL-17 effects might be a therapeutic target for this widespread disease. In addition, modulating Th17 response may be one of anti-atherosclerosis mechanisms of angiotensin AT1 receptor blockers. Conflict of interest statement None declared. References [1] Robertson AK, Hansson GK. T cells in atherogenesis: for better or for worse? Arterioscler Thromb Vasc Biol 2006;26:2421–32. [2] Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone I definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986;136:2348–57. [3] Parronchi P, Macchia D, Piccinni MP, et al. Allergen- and bacterial antigenspecific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci USA 1991;88:4538–42. [4] Lusis AJ. Atherosclerosis. Nature 2000;407:233–41. [5] Harvey EJ, Ramji DP. Interferon-gamma and atherosclerosis: pro- or antiatherogenic? Cardiovasc Res 2005;67:11–20.
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[6] Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005;6:1123–32. [7] Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005;6:1133–41. [8] Csiszar A, Ungvari Z. Synergistic effects of vascular IL-17 and TNFalpha may promote coronary artery disease. Med Hypotheses 2004;63:696–8. [9] Hashmi S, Zeng QT. Role of interleukin-17 and interleukin-17-induced cytokines interleukin-6 and interleukin-8 in unstable coronary artery disease. Coron Artery Dis 2006;17:699–706. [10] Cheng X, Yu X, Ding YJ, et al. The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 2008;127:89–97. [11] Eid RE, Rao DA, Zhou J, et al. Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation 2009;119:1424–32. [12] Song L, Schindler C. IL-6 and the acute phase response in murine atherosclerosis. Atherosclerosis 2004;177:43–51. [13] Huber SA, Sakkinen P, Conze D, Hardin N, Tracy R. Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1999;19:2364–7. [14] Xie JJ, Wang J, Tang TT, et al. The Th17/Treg functional imbalance during atherogenesis in ApoE( / ) mice. Cytokine 2010;49:185–93. [15] Erbel C, Chen L, Bea F, et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J Immunol 2009;183:8167–75. [16] van Es T, van Puijvelde GH, Ramos OH, et al. Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice. Biochem Biophys Res Commun 2009;388:261–5. [17] Mallat Z, Corbaz A, Scoazec A, et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 2001;89:E41–5. [18] Elhage R, Jawien J, Rudling M, et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc Res 2003;59:234–40. [19] Pejnovic N, Vratimos A, Lee SH, et al. Increased atherosclerotic lesions and Th17 in interleukin-18 deficient apolipoprotein E-knockout mice fed high-fat diet. Mol Immunol 2009;47:37–45. [20] Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006;86:515–81. [21] Nataraj C, Oliverio MI, Mannon RB, et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J Clin Invest 1999;104:1693–701. [22] Shao J, Nangaku M, Miyata T, et al. Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury. Hypertension 2003;42:31–8. [23] Mazzolai L, Duchosal MA, Korber M, et al. Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE / mice. Hypertension 2004;44:277–82. [24] Madhur MS, Lob HE, McCann LA, et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 2010;55:500–7.