Increased Th1 and suppressed Th2 serum cytokine levels in subjects with diabetic coronary artery disease

Madhumitha, Haridoss; Mohan, Viswanathan; Deepa, Mohan; Babu, Subash; Aravindhan, Vivekanandhan

doi:10.1186/1475-2840-13-1

Cited by 96 publications

(86 citation statements)

References 28 publications

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“…[28][29][30][31] Notably, both T2DM patients and those with CV disease are characterized by increased systemic LGI, and T2DM patients with CV complications have the highest cumulative inflammatory score. 32,34,78 The relevance of inflammation as a contributing factor to CV events is supported by the following evidence. First, mouse models that involve lack of a pro-inflammatory gene are protected against the atherosclerotic process and cardiac hypertrophy and develop fewer CV diseases overall.…”

Section: Plaque Instabilitymentioning

confidence: 88%

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Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

Prattichizzo

Nigris

Micheloni

et al. 2018

Diabetes Obesity Metabolism

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Recent clinical trials have demonstrated a strong cardiovascular (CV) protective effect of sodium/glucose cotransporter (SGLT) 2 inhibitors, a recently introduced class of hypoglycaemic agents. The improvement in glycated haemoglobin and other conventional risk factors explains only a portion of the observed reduction in CV risk. A relevant feature of SGLT2-inhibitor-treated diabetic patients is the increase in circulating levels of ketone bodies, which has been proposed to mediate part of the beneficial effects of this class of drugs, mainly through their bioenergetic properties. However, ketone bodies are emerging as potent anti-inflammatory molecules, and inflammation is a recognized risk factor for the development of CV events. In this framework, we hypothesize that, through their unique mechanism of action and by increasing circulating ketone bodies, SGLT2 inhibitors indirectly target the IL-1β pathway and thus produce a consistent amelioration of low-grade inflammation, a clinically relevant phenomenon in diabetic patients with high CV risk. This attenuation could slow the progression of CV disease and especially the atherosclerotic process, which is sensitive to environmental changes, even over a short time period. To test this conceptual structure, it would be necessary to measure circulating pro-inflammatory molecules in patients treated with SGLT inhibitors. The addition of inflammatory markers to the list of clinical data measured in FDA-requested, large CV outcome trials could provide supplementary information regarding potential secondary effects of new anti-hyperglycaemic drugs, considering that the inflammatory process is an often neglected cornerstone of CV diseases.

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Section: Plaque Instabilitymentioning

confidence: 88%

“…A comprehensive review on the topic is beyond the scope of this manuscript . Notably, both T2DM patients and those with CV disease are characterized by increased systemic LGI, and T2DM patients with CV complications have the highest cumulative inflammatory score …”

Section: Effect Of Lgi On the Atherosclerotic Process And Hearth Failmentioning

confidence: 99%

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

Prattichizzo

Nigris

Micheloni

et al. 2018

Diabetes Obesity Metabolism

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“…Endothelial cells cultured in high glucose demonstrate abnormal cell cycles, slow replication and increase in apoptosis [20]. All these pathways lead to increased oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Cyclophilin A enhances macrophage differentiation and lipid uptake in high glucose conditions: a cellular mechanism for accelerated macro vascular disease in diabetes mellitus

Ramachandran

Anandan

2016

Cardiovasc Diabetol

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BackgroundVascular disease in diabetes is initiated by monocyte adhesion to vascular endothelium, transmigration and formation of foam cells. Increasing clinical evidence supports a role for the secretory protein, cyclophilin A in diabetic vascular disease. The means by which cyclophilin A contributes to vascular lesion development in diabetes is however largely unknown.MethodsIn this study we investigated using THP1 cells and human monocytes whether cyclophilin A under hyperglycemic conditions, functions in the inflammatory cascade as a chemoattractant and increases lipid uptake by formation of foam cells invitro. We developed an invitro model of monocytes cultured in 20 mm glucose (high glucose) equivalent to 360 mg/dL of plasma glucose levels. These monocytes were then differentiated into macrophages using PMA and subsequently transformed to lipid laden foam cells using oxidized low density lipoproteins in the presence and absence of cyclophilin A. This cellular model was used to study monocyte to macrophage differentiation, transmigration and foam cell formation. A similar cellular model using siRNA mediated transient elimination of the cyclophilin A gene as well as chemical inhibitors were used to further confirm the role of cyclophilin A in the differentiation and foam cell formation process.ResultsCyclophilin A effectively increased migration of high glucose treated monocytes to the endothelial cell monolayer (p < 0.0001). In the presence of cyclophilin A, differentiated macrophages, when treated with oxLDL had a 36 percent increase in intracellular lipid accumulation (p = 0.01) when compared to cells treated with oxLDL alone. An increased flux of reactive oxygen species was also observed (p = 0.01). Inflammatory cytokines such as TNF-α, MCP-1 and cyclophilin A were significantly increased. Silencing cyclophilin A in THP-1 cells and human monocytes using siRNA or chemical inhibitor, TMN355 resulted in decrease in lipid uptake by 65–75% even after exposure to oxidized LDL. The expression of scavenger receptors expressed during differentiation process, CD36 and LOX-1 were decreased (p < 0.0001). Levels of extracellular cyclophilin A and other inflammatory cytokines such as TNF-α and MCP-1also significantly reduced.ConclusionsTaken together, we describe here a possible cellular basis by which cyclophilin A may accelerate atherogenesis in diabetes mellitus.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0467-5) contains supplementary material, which is available to authorized users.

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“…We next examined the responsiveness of human activated CD8 T cells to various doses of IL-12. Human activated CD8 T cells were pretreated with a range of physiological doses of IL-12 [25-27], washed, and stimulated through the TCR. Following TCR stimulation, we found that pretreatment with doses of 5-70 ng/mL of IL-12 results in augmented TCR–induced IFN-γ production in comparison to cells treated in media alone; however, there were no significant differences in the potentiation of IFN-γ production between any of the doses (Fig.…”

Section: Resultsmentioning

confidence: 99%

Pretreatment of activated human CD8 T cells with IL-12 leads to enhanced TCR-induced signaling and cytokine production

Vacaflores

Freedman

Chapman

et al. 2017

Molecular Immunology

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During the immune response to pathogens and autoantigens, CD8 T cells are exposed to numerous inflammatory agents including the cytokine IL-12. Previous studies have focused on how IL-12 regulates T cell functions when present during or after the activation of the T cell receptor (TCR). However, recent studies suggest that prior exposure to IL-12 also alters the TCR responsiveness of murine T cells. Whether similar phenomena occur in human activated CD8 T cells and the mechanisms mediating these effects remain unexplored. In this study, we observed that pretreatment of human activated CD8 T cells with IL-12 results in increased cytokine mRNA and protein production following subsequent TCR challenge. The potentiation of TCR-mediated cytokine release was transient and required low doses of IL-12 for at least 24 hours. Mechanistically, prior exposure to IL-12 increased the TCR induced activation of select MAPKs and AKT without altering the activation of more proximal TCR signaling molecules, suggesting that the IL-12 mediated changes in TCR signaling are responsible for the increased production of cytokines. Our data suggest that prior treatment with IL-12 potentiates human CD8 T cell responses at sites of infection and inflammation, expanding our understanding of the function of this clinically important cytokine.

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Increased Th1 and suppressed Th2 serum cytokine levels in subjects with diabetic coronary artery disease

Cited by 96 publications

References 28 publications

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

Cyclophilin A enhances macrophage differentiation and lipid uptake in high glucose conditions: a cellular mechanism for accelerated macro vascular disease in diabetes mellitus

Pretreatment of activated human CD8 T cells with IL-12 leads to enhanced TCR-induced signaling and cytokine production

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