Dataset Information

Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is increasing worldwide, and it is associated with increased risk of coronary artery disease (CAD). For T2DM patients, the main surgical intervention for CAD is autologous saphenous vein grafting. However, T2DM patients have increased risk of saphenous vein graft failure (SVGF). While the mechanisms underlying increased risk of vascular disease in T2DM are not fully understood, hyperglycaemia, insulin resistance, and hyperinsulinaemia have been shown to contribute to microvascular damage, whereas clinical trials have reported limited effects of intensive glycaemic control in the management of macrovascular complications. This suggests that factors other than glucose exposure may be responsible for the macrovascular complications observed in T2DM. SVGF is characterised by neointimal hyperplasia (NIH) arising from endothelial cell (EC) dysfunction and uncontrolled migration and proliferation of vascular smooth muscle cells (SMCs). This is driven in part by proinflammatory cytokines released from the activated ECs and SMCs, particularly interleukin 6 (IL-6). IL-6 stimulation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT) pathway is a key mechanism through which EC inflammation, SMC migration, and proliferation are controlled and whose activation might therefore be enhanced in patients with T2DM. In this review, we investigate how proinflammatory cytokines, particularly IL-6, contribute to vascular damage resulting in SVGF and how suppression of proinflammatory cytokine responses via targeting the JAK/STAT pathway could be exploited as a potential therapeutic strategy. These include the targeting of suppressor of cytokine signalling (SOCS3), which appears to play a key role in suppressing unwanted vascular inflammation, SMC migration, and proliferation.

SUBMITTER: Moshapa FT

PROVIDER: S-EPMC6334365 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundCell-to-cell heterogeneity is an inherent feature of multicellular organisms and is central in all physiological and pathophysiological processes including cellular signal transduction. The cytokine IL-6 is an essential mediator of pro- and anti-inflammatory processes. Dysregulated IL-6-induced intracellular JAK/STAT signalling is associated with severe inflammatory and proliferative diseases. Under physiological conditions JAK/STAT signalling is rigorously controlled and timely orchestrated by regulatory mechanisms such as expression of the feedback-inhibitor SOCS3 and activation of the protein-tyrosine phosphatase SHP2 (PTPN11). Interestingly, the function of negative regulators seems not to be restricted to controlling the strength and timely orchestration of IL-6-induced STAT3 activation. Exemplarily, SOCS3 increases robustness of late IL-6-induced STAT3 activation against heterogenous STAT3 expression and reduces the amount of information transferred through JAK/STAT signalling.MethodsHere we use multiplexed single-cell analyses and information theoretic approaches to clarify whether also SHP2 contributes to robustness of STAT3 activation and whether SHP2 affects the amount of information transferred through IL-6-induced JAK/STAT signalling.ResultsSHP2 increases robustness of both basal, cytokine-independent STAT3 activation and early IL-6-induced STAT3 activation against differential STAT3 expression. However, SHP2 does not affect robustness of late IL-6-induced STAT3 activation. In contrast to SOCS3, SHP2 increases the amount of information transferred through IL-6-induced JAK/STAT signalling, probably by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells. These effects are independent of SHP2-dependent MAPK activation.ConclusionIn summary, the results of this study extend our knowledge of the functions of SHP2 in IL-6-induced JAK/STAT signalling. SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information. Plain English summary Cells within a multicellular organism communicate with each other to exchange information about the environment. Communication between cells is facilitated by soluble molecules that transmit information from one cell to the other. Cytokines such as interleukin-6 are important soluble mediators that are secreted when an organism is faced with infections or inflammation. Secreted cytokines bind to receptors within the membrane of their target cells. This binding induces activation of an intracellular cascade of reactions called signal transduction, which leads to cellular responses. An important example of intracellular signal transduction is JAK/STAT signalling. In healthy organisms signalling is controlled and timed by regulatory mechanisms, whose activation results in a controlled shutdown of signalling pathways. Interestingly, not all cells within an organism are identical. They differ in the amount of proteins involved in signal transduction, such as STAT3. These differences shape cellular communication and responses to intracellular signalling. Here, we show that an important negative regulatory protein called SHP2 (or PTPN11) is not only responsible for shutting down signalling, but also for steering signalling in heterogeneous cell populations. SHP2 increases robustness of STAT3 activation against variable STAT3 amounts in individual cells. Additionally, it increases the amount of information transferred through JAK/STAT signalling by increasing the dynamic range of pathway activation in heterogeneous cell populations. This is an amazing new function of negative regulatory proteins that contributes to communication in heterogeneous multicellular organisms in health and disease. Video Abstract.

Dataset Information

Therapeutic Targeting of the Proinflammatory IL-6-JAK/STAT Signalling Pathways Responsible for Vascular Restenosis in Type 2 Diabetes Mellitus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets