Interaction of IL-6 and TNF-α contributes to endothelial dysfunction in type 2 diabetic mouse hearts

Abstract

ObjectivesInflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), are individually considered as important contributors to endothelial dysfunction in obesity and type 2 diabetes (T2D). However, their interactions in coronary arteriole endothelial dysfunction are uncertain. Therefore, this study aimed to determine the effects of TNF-α and IL-6 interactions on coronary endothelial dysfunction in experimental T2D.MethodsThe studies used wild type (WT), diabetic mice (db/db), db/db null for TNF (dbTNF-/dbTNF-), and db/db mice treated with neutralizing antibody to IL-6 (anti-IL-6). Endothelium-dependent (acetylcholine [ACh], or luminal flow-induced shear stress) and endothelium-independent (sodium nitroprusside [SNP]) vasodilation of isolated and pressurized coronary arterioles were determined. Quantitative PCR, Western blot, and immunofluorescence staining were utilized for mechanistic studies.ResultsRelative to WT, arteriolar dilation to both ACh and flow was attenuated in db/db mice and dbTNF-/dbTNF-. Treatment of dbTNF-/dbTNF- and db/db mice with anti-IL-6 improved arteriolar dilation compared to db/db mice. Immunofluorescence staining illustrated localization of IL-6 within the endothelial cells of coronary arterioles. In db/db mice, mRNA and protein expression of IL-6 and superoxide (O2-) production were higher, but reduced by anti-IL-6 treatment. Also, in db/db mice, mRNA and protein expression of TNF-α suppressed by the anti-IL-6 treatment and the reduced expression of mRNA and protein expression of IL-6 by the genetic deletion of TNF-α both supported a reciprocal regulation between TNF-α and IL-6. Superoxide dismutase 2 (SOD2) expression and phosphorylation of eNOS (p-eNOS/eNOS) were lower in db/db mice coronary arterioles and were restored in db/db+Anti-IL-6 and dbTNF-/dbTNF- mice.ConclusionThe interactions between TNF-α and IL-6 exacerbate oxidative stress and reduce phosphorylation of eNOS, thereby contributing to coronary endothelial dysfunction in T2D mice.

Complexity of TNF-α Signaling in Heart Disease

“…In this mechanism, both TNFRs are also critically engaged in the process of diapedesis [ 137 ]. TNF-α is also known to increase ROS levels and decrease nitric oxide production in blood vessels, which can lead to endothelial dysfunction: an initial step in atherogenesis [ 138 ]. In this process, TNF-α-induced ROS production depends on the activation of NADH oxidase [ 139 , 140 ].…”

Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target

“…There are multiple mechanisms that play a role in the development of COPD, atherosclerosis and T2D including: altered function of cells such as endothelial cell and neutrophils [23][24][25]; mitochondrial defects [26]; metabolic changes [27]; increased age [25,28]; and increased inflammation [29,30]. Despite overlapping mechanisms and risk factors, targeting a known manifestation of one disease does not always improve outcomes in another.…”

“…TNF-α is implicated in insulin resistance and β-islet cell dysfunction in murine models, suggesting that IL-1β and TNF-α treatment result in a loss of the transcription factor FoxO1, which is required for maintaining β-cell identity (figure 2b) [104,105]. TNF-α murine knockout models are more resistant to developing atherosclerosis [106], emphysema [107], endothelial dysfunction in diabetes [24] and late-stage diabetic retinopathy [108]. Neutrophils isolated from patients with T2D release larger amounts of proinflammatory cytokines, including TNF-α and IL-6 at baseline and in response to lipopolysaccharide (LPS) stimulation (figure 2c) [39].…”

Potential therapeutic effects of endothelial cells trans-differentiated from Wharton’s Jelly-derived mesenchymal stem cells on altered vascular functions in aged diabetic rat model

“…Moreover, TNF-α interacts with IL-6 resulting in exacerbation of oxidative stress and reduction in eNOS phosphorylation. This interaction has been shown to contribute strongly to endothelial dysfunction in type II diabetes [36]. Furthermore, IL-6 induced oxidative stress and endothelial dysfunction was attributable to the increase in the expression of vascular angiotensin II type 1 (AT1) receptors.…”