|Year : 2016 | Volume
| Issue : 3 | Page : 125-129
Assessment of serum interleukins-17 and 1β levels in hypertensive patients treated with angiotensin converting enzyme and/or angiotensin II receptor blockers
Adil H Alhusseiny1, Marwan S. M. Al-Nimer2
1 Department of Medicine, College of Medicine, Diyala University, Diyala, Iraq
2 Department of Pharmacology, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
|Date of Web Publication||14-Dec-2016|
Marwan S. M. Al-Nimer
Department of Pharmacology, College of Medicine, Al-Mustansiriya University, P.O. Box 14132, Baghdad
Source of Support: None, Conflict of Interest: None
Background: Low-grade inflammation plays a role in pathogenesis of hypertension. Some of antihypertensive agents have anti-inflammatory effects. Aims: This study aimed to compare the serum levels of interleukin-17 (IL-17) and IL-1β in hypertensive patients treated with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers with untreated hypertensive patients. Settings and Design: This observational study was carried in Departments of Medicine, College of Medicine, Diyala University in Iraq from June 2014 to December 2014. Materials and Methods: A total of 78 hypertensive patients treated with ACEIs and/or ARBs, and another 28 newly diagnosed hypertensive patients (without treatment at the time of admission into the study) were included in the study. Anthropometric measurements and the laboratory measurements included fasting serum lipid profile, and serum IL-1β and IL-17 levels as proinflammatory markers. Statistical Analysis: All calculations and analysis were made using Excel 2003 and SPSS program (version 17) for Windows. Results: There are nonsignificant differences in the anthropometric and lipid profile measurements between treated and untreated hypertensive patients. The blood pressure of patients treated with ARBs and/or ACEIs is significantly lower than the corresponding level of untreated patients but still higher than the cut-off level of 140/90 mmHg. Nonsignificant low serum IL-17 levels observed in treated hypertensive patients compared with untreated hypertensive patients. Significant inverse correlation between serum IL-17 with systolic (r = −0.420, P < 0.02) and diastolic (r = 0.491, P < 0.01) blood pressure observed in patients treated with ACEIs. Conclusions: We conclude that hypertensive patients treated with ACEIs and/or ARBs drugs showed inconsistent serum levels of IL-1β and IL-17 and a paradox is observed in the relation between these cytokines levels and blood pressure measurements.
Keywords: Angiotensin, cytokines, hypertension, paradox
|How to cite this article:|
Alhusseiny AH, Al-Nimer MS. Assessment of serum interleukins-17 and 1β levels in hypertensive patients treated with angiotensin converting enzyme and/or angiotensin II receptor blockers. Saudi J Health Sci 2016;5:125-9
|How to cite this URL:|
Alhusseiny AH, Al-Nimer MS. Assessment of serum interleukins-17 and 1β levels in hypertensive patients treated with angiotensin converting enzyme and/or angiotensin II receptor blockers. Saudi J Health Sci [serial online] 2016 [cited 2017 Oct 19];5:125-9. Available from: http://www.saudijhealthsci.org/text.asp?2016/5/3/125/195814
| Introduction|| |
Low-grade inflammation plays a role in the pathogenesis of hypertension.  T-lymphocyte (Th17) produces interleukin-17 (IL-17) which has a proinflammatory role and involved in many overzealous inflammatory conditions and autoimmune disorders in humans. IL-17 up-regulates the gene expression and progression of local inflammation by stimulating the production of IL-6 and nitric oxide (NO), and potentiating the actions of the inflammatory cytokines; IL-1β and tumor necrosis factor (TNF-α). ,, The TNF-α cytokine involved in the pathogenesis of hypertension through its interaction with angiotensin II which is the later induced hypertension.  Angiotensin II infusion markedly increased the levels of IL-17 in the thoracic aorta of mice and altered the vascular reactivity.  Animal treated with IL-17 for 1 week showed an increase in systolic blood pressure associated with diminished NO-dependent relaxation process.  Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor-2 blockers (ATRBs) that used in the management of hypertension were interacted with the production of IL-17. Experimental evidence showed that captopril (an ACEI) induced expression of IL-17 by T cells parasitized by Trypansoma cruzi while telmisartan (a ATRB) reduced the serum level of IL-17 in KK-Ay mice that represent an animal model of insulin resistance in type 2 diabetes.  In vitro study, both ACEIs and ATRBs reduced the secretion of IL-1β from polymorphonuclear leukocytes of hypertensive patients.  The rational of this study is to assess the effect of ACEIs and ATRBs in hypertensive patients via their actions on the IL-17. Therefore, this study aimed to measure the serum levels of IL-17 and IL-1β in hypertensive patients treated with ACEIs or ATRBs.
| Materials and Methods|| |
This study was carried in Department of Medicine, College of Medicine, Diyala University in Iraq from June 2014 to December 2014. A consent form obtained from each patient before the admission to the study. This study was conducted according to the ethical guidelines constructed by the Scientific Committee of the Institute in which the treatment or using device should not be harmful to the patient, and the patient is free to decline from the study or to refuse for study admission.
The patients were recruited from the Consultant Clinics at The General Teaching Hospital, where patients routinely followed up. Inclusion criteria were patients with essential hypertension taking antihypertensive therapy in the form of ACEIs and or angiotensin receptor blocking agents. The exclusion criteria included secondary hypertension, diabetes mellitus, chronic liver diseases, renal disorders, autoimmune diseases, and drug intake, for example, nonsteroidal anti-inflammatory drugs.
A total number of 78 hypertensive patients treated with ACEIs and/or ARBs and another 28 newly diagnosed hypertensive patients (without treatment at the time of admission into the study) were included in the study. The patients sub-grouped according to the therapeutic regimen into:
- Group I (n = 28): Hypertensive patients without medications at the time of study
- Group II (n = 37): Hypertensive patients treated with one generic agent related to ARBs
- Group III (n = 31): Hypertensive patients treated with one generic agent related to ACEIs
- Group IV (n = 10): Hypertensive patients treated with combined ARBS and ACEIs.
Demographic data, medical history, and treatment were obtained from each patient. Modifiable risk factors, events or complications, and current therapy were recorded. A person who reported smoking on admission was defined as a current smoker. The anthropometric measurements including height (m), weight (kg), and waist circumference (cm) were measured. The body mass index (BMI) and waist/height ratios were calculated. The blood pressure (mmHg) was measured on sitting position, and the mean of three readings was taken. The difference between systolic and diastolic blood pressure represented the pulse pressure, and the mean arterial blood pressure is equal to diastolic blood pressure +⅓ pulse pressure.
Peripheral venous blood was drawn immediately after admission into tubes, then the samples were centrifuged at 2500 rpm for 10 min, and the sera were separated for determination of fasting lipid profile and IL-1β and IL-17.
The determinants of lipid profile included fasting serum total cholesterol (TC), triglycerides (TG), high-density-lipoprotein-cholesterol (HDL-c). The LDL-c lipoprotein (low-density lipoprotein cholesterol, LDL-c) is determined by using the equation: TC − (HDL-c + TG/5). The atherogenic index (AI) was calculated by estimating the log of the ratio TGs to HDL values. Quantitative determination of serum IL-1β and IL-17 was carried on using the enzyme-linked immunosorbent assay technique. The serum levels of IL-1β and IL-17 expressed as pg/ml. The data are present as a number, percentage, mean ± standard deviation (standard error mean) or median. Unpaired Student's t-test was used to evaluate differences between the two groups, one-way ANOVA test to evaluate the differences between groups and the simple correlation test was applied for the association between the independent and dependent factors. For all tests, a two-tailed P ≤ 0.05 is a cutoff level of statistically significant. All calculations were made using Excel 2003 and SPSS program (version 17, IBM corporation, USA) for Windows.
| Results|| |
[Table 1] shows the characteristics of the study. The overall ratio of men to women is 0.376 (29 men: 77 women). There is nonsignificant difference between patients groups regarding the age. The majority of patients are Arab while the ethnicity of Kurds constituted 6.6% (7 out of 106 patients). The patients with black race constituted 1.9% (2 out of 106). [Table 2] shows the anthropometric measurements of patients. There were nonsignificant differences between treated and nontreated groups in respect to BMI and waist circumference. Waist to height ratio is significantly higher in treated groups compared with nontreated group. [Table 2] shows wide range difference in duration of hypertension while there is no difference in the duration of drug intake. The blood pressure is significantly less in treated groups compared with nontreated group. Despite medical therapy, the blood pressure in treated group patients is still higher than the cutoff levels of <140 mmHg systolic and <90 mmHg diastolic blood pressure [Table 2].
[Table 2] shows that the mean values of fasting serum lipid profile and AI are nonsignificantly differed in treated groups compared with nontreated group. The mean value of AI in Groups III and IV is less than nontreated group whereas in Group II is higher. [Table 3] shows wide variation in the serum levels of IL-1β and IL-17 in hypertensive patients. Undetected serum IL-1β levels observed in five out of 28 patients (17.9%) of untreated hypertensive patients (Group I) and to be 32.4%, 32.3%, and 20% of patients belonged to Groups II, III, and IV, respectively [Table 3]. The mean serum level of IL-1β in untreated hypertensive patients do not significantly differ from the corresponding level in treated hypertensive patients. The mean serum levels of IL-17 in Group I are nonsignificantly higher than corresponding levels in treated hypertensive patients [Table 3]. The undetected level of serum IL-17 is observed in 17.9% of Group I patients compared with 10.8%, 3.2%, and 10% of Groups II, III, and IV, respectively. [Table 4] shows that the correlations of IL-1β or IL-17 with the blood pressure do not follow a specific pattern in each studied group, and a paradox pattern was observed. In Group I, the significant inverse correlation between systolic blood pressure and IL-1β while in Group II a significant positive correlation between IL-1β and diastolic blood pressure observed. In Group III, significant inverse correlations between IL-17 with systolic and diastolic blood pressures while in the Group IV the inverse correlations with IL-1β [Table 4].
| Discussion|| |
The results of this study show that hypertensive patients treated with ACEIs and/or ATRBs are still having high blood pressure, and their serum IL-1β and IL-17 levels are inconsistently differed from those of untreated patients. The results of this study are not influenced with the risk, or confounding factors that related to hypertension as the BMI and fasting serum lipid profile did not show a significant difference between the studied groups. The duration of hypertension and the duration of using the medications may influence the effect of antihypertensive drugs on the inflammatory biomarkers. There is evidence that the association of hypertension and inflammatory cytokines level is inconsistent. Recently, Mirhafez et al.  reported that the serum concentration levels of IL-1α but not IL-1β is increased in hypertension, and it is considered as an independent predictor of a high systolic but not diastolic blood pressure. Other study reported that detection of IL-1β in the serum of hypertensive patients indicated arterial stiffness by the evidence of increased arterial pulse wave velocity.  Inconsistent changes of serum IL-1β levels that reported in our study confirmed other previous studies. In different experimental and in vitro studies that both ARBs and ACEIs significantly reduced the production of IL-1β. ,, Therefore, it is possible to suggest that the effect of these medications on the production of IL-1β is related to the pathological conditions, and this explains why the serum level of IL-1β in treated hypertension (Groups II, III, and IV) did not differ from the corresponding level of nontreated hypertensive patients (Group I). Moreover, the variability in the significant correlations between IL-1β with systolic or diastolic blood pressure may lead us to suggest that IL-1β is not the only proinflammatory biomarker that involved in the pathogenesis of hypertension and ARBs, and/or ACEIs are not specifically inhibit the production of IL-1β. ,,, The mean serum level of IL-17 in untreated hypertension is nonsignificantly higher than the corresponding mean level of treated hypertensive patients. Recent study claims that the significant increase levels of IL-17 are linked with prehypertension state and with systolic blood pressure.  Moreover, there is a wide variation in the serum level of IL-17 of each studied group, and this explains the nonsignificant differences between these groups. IL-17 is a cytokine that contributed to hypertension and nonsignificant effect of the ACEIs and/or ARBs on the serum IL-17 levels explain the high blood pressure in treated groups. , The significant inverse correlations between serum IL-17 levels with systolic or diastolic blood pressure in Group III may due to the presence of other vasopressors other than angiotensin II that not affected by ACEIs.  It is important to mention here that angiotensin II-mediated the immune response of Th17 in the lymphoid immune system, that is, the relationship between angiotensin II and IL-17 is not a simple one. Therefore, it is possible to attribute the significant inverse correlations to the paradoxical effect of ACEIs.  One of the limitations of this study is a small sample size of Group IV and the variability in the generic drugs that used in each treated group that may influence the results.
| Conclusion|| |
We conclude that hypertensive patients treated with ACEIs and/or ARBs showed inconsistent serum levels of IL-1β and IL-17 and paradoxical correlations between IL-1β and IL-17 levels with the blood pressure measurements.
The authors would like to thank the authority of College of Medicine, Diyala University for their help and support this study.
Financial support and sponsorship
College of Medicine, Diyala University.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Schiffrin EL. Immune mechanisms in hypertension and vascular injury. Clin Sci (Lond) 2014;126:267-74.
Ogura H, Murakami M, Okuyama Y, Tsuruoka M, Kitabayashi C, Kanamoto M, et al.
Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 2008;29:628-36.
Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med 2009;361:888-98.
Ruddy MJ, Wong GC, Liu XK, Yamamoto H, Kasayama S, Kirkwood KL, et al.
Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem 2004;279:2559-67.
Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al.
Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med 2007;204:2449-60.
Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, et al.
Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 2010;55:500-7.
Nguyen H, Chiasson VL, Chatterjee P, Kopriva SE, Young KJ, Mitchell BM. Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. Cardiovasc Res 2013;97:696-704.
Coelho dos Santos JS, Menezes CA, Villani FN, Magalhães LM, Scharfstein J, Gollob KJ, et al.
Captopril increases the intensity of monocyte infection by Trypanosoma cruzi
and induces human T helper type 17 cells. Clin Exp Immunol 2010;162:528-36.
Ohshima K, Mogi M, Jing F, Iwanami J, Tsukuda K, Min LJ, et al.
Roles of interleukin 17 in angiotensin II type 1 receptor-mediated insulin resistance. Hypertension 2012;59:493-9.
Nemati F, Rahbar-Roshandel N, Hosseini F, Mahmoudian M, Shafiei M. Anti-inflammatory effects of anti-hypertensive agents: Influence on interleukin-1ß secretion by peripheral blood polymorphonuclear leukocytes from patients with essential hypertension. Clin Exp Hypertens 2011;33:66-76.
Mirhafez SR, Mohebati M, Feiz Disfani M, Saberi Karimian M, Ebrahimi M, Avan A, et al.
An imbalance in serum concentrations of inflammatory and anti-inflammatory cytokines in hypertension. J Am Soc Hypertens 2014;8:614-23.
Barbaro NR, Fontana V, Modolo R, De Faria AP, Sabbatini AR, Fonseca FH, et al
. Increased arterial stiffness in resistant hypertension is associated with inflammatory biomarkers. Blood Press 2014;25:1-7.
Zhang W, Zhao H, Peng X, Cheng T, Zhang X. Low-dose captopril inhibits wear debris-induced inflammatory osteolysis. J Int Med Res 2011;39:798-804.
Pang T, Wang J, Benicky J, Sánchez-Lemus E, Saavedra JM. Telmisartan directly ameliorates the neuronal inflammatory response to IL-1ß partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation 2012;9:102.
Krishnan SM, Sobey CG, Latz E, Mansell A, Drummond GR. IL-1ß and IL-18: Inflammatory markers or mediators of hypertension? Br J Pharmacol 2014;171:5589-602.
Miguel-Carrasco JL, Zambrano S, Blanca AJ, Mate A, Vázquez CM. Captopril reduces cardiac inflammatory markers in spontaneously hypertensive rats by inactivation of NF-kB. J Inflamm (Lond) 2010;7:21.
Manabe S, Okura T, Watanabe S, Fukuoka T, Higaki J. Effects of angiotensin II receptor blockade with valsartan on pro-inflammatory cytokines in patients with essential hypertension. J Cardiovasc Pharmacol 2005;46:735-9.
Li QZ, Deng Q, Li JQ, Yi GH, Zhao SP. Valsartan reduces interleukin-1beta secretion by peripheral blood mononuclear cells in patients with essential hypertension. Clin Chim Acta 2005;355:131-6.
Yao W, Sun Y, Wang X, Niu K. Elevated serum level of interleukin 17 in a population with prehypertension. J Clin Hypertens (Greenwich) 2015;17:770-4.
Harrison DG. The immune system in hypertension. Trans Am Clin Climatol Assoc 2014;125:130-8.
Majeed B, Tawinwung S, Eberson LS, Secomb TW, Larmonier N, Larson DF. Interleukin-2/anti-interleukin-2 immune complex expands regulatory T Cells and reduces angiotensin II-induced aortic stiffening. Int J Hypertens 2014;2014:126365.
[Table 1], [Table 2], [Table 3], [Table 4]