Interleukin-12p35 knockout promotes macrophage differentiation, aggravates vascular dysfunction, and elevates blood pressure in angiotensin II-infused mice

Ye, Jing; Qu, Bin; Huang, Ying; Lin, Yingzhong; Chen, Jiangbin; Liu, Ling; Shi, Ying; Wang, Yuan; Wang, Menglong; Zeng, Tao; Wang, Zhen; Hu, Haiying; Xu, Yao; Shi, Lei; Ye, Di; Liu, Jianfang; Jiang, Huimin; Wan, Jun; Ji, Qingwei

doi:10.1093/cvr/cvy263

Cited by 48 publications

(73 citation statements)

References 52 publications

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“…Under the action of external factors, vascular SMCs convert 9 Mediators of Inflammation to the secretory type, with reduced SM22α expression and increased OPN expression [12]. Systolic dysfunction caused by phenotypic transformation of smooth muscle is the fundamental cause of hypertension, and one of the important factors inducing its transformation is inflammatory response [12]. In the present study, we found that IL-9 KO reduced aortic OPN expression, whereas it increased SM22α levels.…”

Section: Cd4+ T Helper (Th) Cells Include Regulatory T Cells (Treg) Asupporting

confidence: 49%

“…Normal vascular SMCs are mainly contractile, with a high expression of SM22α and low expression of OPN. Under the action of external factors, vascular SMCs convert 9 Mediators of Inflammation to the secretory type, with reduced SM22α expression and increased OPN expression [12]. Systolic dysfunction caused by phenotypic transformation of smooth muscle is the fundamental cause of hypertension, and one of the important factors inducing its transformation is inflammatory response [12].…”

Section: Cd4+ T Helper (Th) Cells Include Regulatory T Cells (Treg) Amentioning

confidence: 99%

“…IL-17 treatment can even lead to hypertension without Ang II infusion in wild-type (WT) mice [11]. Knockout of IL-12p35, the subunit shared by IL-12 and IL-35, significantly elevated blood pressure in Ang II-infused mice; treatment with IL-12, a proinflammatory cytokine, rather than the anti-inflammatory cytokine IL-35, surprisingly reduced Ang II-induced hypertension in mice [12]. However, the effects of IL-10 on hypertension are still controversial, and both the anti-and the prohypertensive roles have been reported in previous studies [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

Yang

Tang

Zhai

et al. 2020

Mediators of Inflammation

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Background. Multiple interleukin (IL) family members were reported to be closely related to hypertension. We aimed to investigate whether IL-9 affects angiotensin II- (Ang II-) induced hypertension in mice. Methods. Mice were treated with Ang II, and IL-9 expression was determined. In addition, effects of IL-9 knockout (KO) on blood pressure were observed in Ang II-infused mice. To determine whether the effects of IL-9 on blood pressure was mediated by the signal transducer and activator of the transcription 3 (STAT3) pathway, Ang II-treated mice were given S31-201. Furthermore, circulating IL-9 levels in patients with hypertension were measured. Results. Ang II treatment increased serum and aortic IL-9 expression in a dose-dependent manner; IL-9 levels were the highest in the second week and continued to remain high into the fourth week after the treatment. IL-9 KO downregulated proinflammatory cytokine expression, whereas it upregulated anti-inflammatory cytokine levels, relieved vascular dysfunction, and decreased blood pressure in Ang II-infused mice. IL-9 also reduced smooth muscle 22α (SM22α) expression and increased osteopontin (OPN) levels both in mice and in vitro. The effects of IL-9 KO on blood pressure and inflammatory response were significantly reduced by S31-201 treatment. Circulating IL-9 levels were significantly increased in patients with the hypertension group than in the control group, and elevated IL-9 levels positively correlated with both systolic blood pressure and diastolic blood pressure in patients with hypertension. Conclusions. IL-9 KO alleviates inflammatory response, prevents phenotypic transformation of smooth muscle, reduces vascular dysfunction, and lowers blood pressure via the STAT3 pathway in Ang II-infused mice. IL-9 might be a novel target for the treatment and prevention of clinical hypertension.

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Section: Cd4+ T Helper (Th) Cells Include Regulatory T Cells (Treg) Asupporting

confidence: 49%

Section: Cd4+ T Helper (Th) Cells Include Regulatory T Cells (Treg) Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

Yang

Tang

Zhai

et al. 2020

Mediators of Inflammation

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“…Bone marrow‐derived Mø were obtained from C57BL/6 mice and prepared as previously described (Lake et al, 1994; Ye et al, 2019). The Mø were cultured in RPMI‐1640 with 10% fetal bovine serum (both from Gibco) in an environment with 5% CO 2 at 37°C and then treated with saline and DOX (1 µM).…”

Section: Methodsmentioning

confidence: 99%

Anti‐interleukin‐5‐neutralizing antibody attenuates caradiac injury and cadiac dysfunction by aggravating the inflammatory response in doxorubicin‐treated mice

Xian

Zhan

Yang

et al. 2020

Cell Biology International

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Previous studies have demonstrated that interleukins (ILs) are closely associated with doxorubicin (DOX)-induced cardiac injury. IL-5 is an important member of the IL family, and this study was performed to investigate whether IL-5 affects DOX-induced cardiac injury and its underlying mechanisms. The cardiac IL-5 expression was first detected and the results showed that cardiac IL-5 levels were significantly lower in DOX-treated mice, and IL-5 was mainly derived from cardiac macrophage (Mø). In addition, some DOX-treated mice received an injection of anti-IL-5-neutralizing antibody (nAb), and we found that treatment with a mouse anti-IL-5 nAb significantly upregulated the levels of myocardial injury markers, aggravated cardiac dysfunction, increased M1 macrophage (Mø1) and decreased M2 macrophage (Mø2) differentiation, and promoted apoptotic marker expression. Furthermore, the effect of mouse IL-5 nAb on DOX-induced Mø differentiation and its role on mouse cardiomyocyte (MCM) cells apoptosis were detected in vitro, and the results exhibited that mouse IL-5 nAb promoted Mø1 differentiation but inhibited Mø2 differentiation in vitro and alleviated apoptosis in MCM cells. Our results found a mouse anti-IL-5 nAb-aggravated DOX-induced cardiac injury and dysfunction by alleviating the inflammatory response and myocardial cell apoptosis. (L. L.), and yingzhonglin@126.com (Y. L.) Abbreviations: ANOVA, analysis of variance; Arg-1, arginase-1; CK-MB, creatine kinase myocardial-bound; DOX, doxorubicin; ELISA, enzyme-linked immunosorbent assay; HE, hematoxylin and eosin; HR, heart rate; IFN-γ, interferon γ; ILs, interleukins; IL-5R, IL-5 receptors; iNOS, inducible nitric oxide synthase; JAK1/2, Janus Kinase 1/2; LDH, lactate dehydrogenase; LV, left ventricle; LVEF, left ventricle ejection fraction; LVEDP, left ventricular enddiastolic pressure; LVFS, left ventricle fractional shortening; LVSP, left ventricular systolic pressure; Mø, macrophage; MCMs, mouse cardiomyocytes; Mø1, M1 macrophage; Mø2, M2 macrophage; nAb, neutralizing antibody; PBS, phosphate-buffered saline; SDS, sodium dodecyl sulfate; STAT1/5, signal transducer and activator of transcription 1/5; SMCs, smooth muscle cells; SD, standard deviation; TNF-α, tumor necrosis factor α; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling; WT, wild-type; +dP/dt max, maximal slope of the systolic pressure increment; −dP/dt max, maximal slope of the diastolic pressure decrement

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“…Induce and promote th17 differentiation IL-27 alone has no apparent stimulatory properties, collaboration with other ILs promote or inhibit T cell differentiation and proliferation Promote Treg activity, suppress the Teff cell (Th1, and Th17 ) activity Ma and Trinchieri, 2001;Kastelein et al, 2007;Collison and Vignali, 2008;Vignali et al, 2008;Cox et al, 2011;Vignali and Kuchroo, 2012;Wojno and Hunter, 2012;Sun et al, 2015 Regulation of inflammation Except inflammatory environment induced by DOX or Ang II, all play pro-inflammatory role Always play a proinflammatory roles, no anti-inflammatory effects had been reported Not only play an anti-inflammatory role, but also play a proinflammatory effects, may be associated with inflammatory microenvironment Always relieves the inflammatory response Davenport and Tipping, 2003;Vignali and Kuchroo, 2012;Jin et al, 2012;Koltsova et al, 2012;Li et al, 2012;Yan et al, 2012;Jääskeläinen et al, 2013;Abbas et al, 2015;Subramanian et al, 2015;Sun et al, 2015;Andrews et al, 2016;Tao et al, 2016;Hu et al, 2016;Gregersen et al, 2017;Fatkhullina et al, 2018;Ye et al, 2018b;Jia et al, 2019;Liu et al, 2019;Vargas-Alarcón et al, 2019;Ye et al, 2019 family members have significantly higher levels of expression in patients with atherosclerosis and coronary artery disease, and are closely related to the progression of these diseases.…”

Section: Induce Th1 and Mø1 Differentiationmentioning

confidence: 99%

Roles and Mechanisms of Interleukin-12 Family Members in Cardiovascular Diseases: Opportunities and Challenges

Wang

et al. 2020

Front. Pharmacol.

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Cardiovascular diseases represent a complex group of clinical syndromes caused by a variety of interacting pathological factors. They include the most extensive disease population and rank first in all-cause mortality worldwide. Accumulating evidence demonstrates that cytokines play critical roles in the presence and development of cardiovascular diseases. Interleukin-12 family members, including IL-12, IL-23, IL-27 and IL-35, are a class of cytokines that regulate a variety of biological effects; they are closely related to the progression of various cardiovascular diseases, including atherosclerosis, hypertension, aortic dissection, cardiac hypertrophy, myocardial infarction, and acute cardiac injury. This paper mainly discusses the role of IL-12 family members in cardiovascular diseases, and the molecular and cellular mechanisms potentially involved in their action in order to identify possible intervention targets for the prevention and clinical treatment of cardiovascular diseases.

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Interleukin-12p35 knockout promotes macrophage differentiation, aggravates vascular dysfunction, and elevates blood pressure in angiotensin II-infused mice

Cited by 48 publications

References 52 publications

Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

Anti‐interleukin‐5‐neutralizing antibody attenuates caradiac injury and cadiac dysfunction by aggravating the inflammatory response in doxorubicin‐treated mice

Roles and Mechanisms of Interleukin-12 Family Members in Cardiovascular Diseases: Opportunities and Challenges

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