Toll-like receptors regulate B cell cytokine production in patients with diabetes

Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
Diabetologia (Impact Factor: 6.67). 04/2010; 53(7):1461-71. DOI: 10.1007/s00125-010-1730-z
Source: PubMed

ABSTRACT Understanding cellular and molecular events in diabetes mellitus will identify new approaches for therapy. Immune system cells are important modulators of chronic inflammation in diabetes mellitus, but the role of B cells is not adequately studied. The aim of this work was to define the function of B cells in diabetes mellitus patients through focus on B cell responses to pattern recognition receptors.
We measured expression and function of Toll-like receptors (TLRs) on peripheral blood B cells from diabetes mellitus patients by flow cytometry and multiplexed cytokine analysis. We similarly analysed B cells from non-diabetic donors and periodontal disease patients as comparative cohorts.
B cells from diabetes mellitus patients secrete multiple pro-inflammatory cytokines, and IL-8 production is significantly elevated in B cells from diabetic patients compared with those from non-diabetic individuals. These data, plus modest elevation of TLR surface expression, suggest B cell IL-8 hyperproduction is a cytokine-specific outcome of altered TLR function in B cells from diabetes mellitus patients. Altered TLR function is further evidenced by demonstration of an unexpected, albeit modest 'anti-inflammatory' function for TLR4. Importantly, B cells from diabetes mellitus patients fail to secrete IL-10, an anti-inflammatory cytokine implicated in inflammatory disease resolution, under a variety of TLR-stimulating conditions. Comparative analyses of B cells from patients with a second chronic inflammatory disease, periodontal disease, indicated that some alterations in B cell TLR function associate specifically with diabetes mellitus.
Altered TLR function in B cells from diabetes mellitus patients increases inflammation by two mechanisms: elevation of pro-inflammatory IL-8 and lack of anti-inflammatory/protective IL-10 production.

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Available from: Barbara S Nikolajczyk, Sep 29, 2015
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    • "Macrophages are the predominant participant in innate immune responses of atherosclerosis, acting via receptors. Tolllike receptors (TLRs) are the most characterized innate immune receptors in atherogenesis and type 2 diabetes mellitus [13] [14] [15] [16] [17] [18]. "
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    ABSTRACT: Background: Toll-like receptors, the most characterized innate immune receptors, have recently been demonstrated to play an important role in coronary atherosclerotic disease and diabetes mellitus (DM). TLR3 and TLR4 are known to act as anti-inflammatory and pro-inflammatory factors respectively in multi-factorial inflammatory disease states. However, there is less research about TLR3 and TLR4 expression in percutaneous transluminal coronary intervention (PCI) patients, particularly those with type 2 diabetes mellitus (DM2). Methods: We examined TLR3 and TLR4 expression and their downstream signaling pathway in PCI patients with (n=31) or without (n=32) DM2 compared with controls (n=35). Results: TLR3 and downstream anti-inflammatory factors (IRF-3, INF-β and IL-10) were significantly down-regulated in PCI patients with or without DM2 compared with controls, as determined by the quantification of both mRNA and protein. In contrast, TLR4 and downstream proinflammatory factors (MyD88 and TNF-α) were up-regulated in PCI patients with or without DM2 compared with controls. Conclusions: Patients undergoing PCI were shown to have a TLR-dependent pro-inflammatory state, mediated by a downregulation of TLR3 pathway, and upregulation of TLR4. This occurred in both with or without type 2 diabetes mellitus compared with controls in this research. The inflammatory imbalance observed in PCI patients was exacerbated in patients with DM2, consistent with a likely contribution of DM2 to the inflammatory state of coronary atherosclerotic disease, via impact on the innate immune response. This data supports the potential of TLRs as a novel therapeutic target in diabetics with coronary atherosclerotic disease.
    Immunology Letters 05/2014; 161(1). DOI:10.1016/j.imlet.2014.05.003 · 2.51 Impact Factor
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    • "Moreover, an impaired function of toll-like receptors in B cells from patients with T2D that increases inflammation by the elevation of pro-inflammatory IL-8 and lack of anti-inflammatory/protective IL-10 production has been described (Jagannathan et al., 2010). "
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    ABSTRACT: Inflammation and altered immune response are important components of obesity and contribute greatly to the promotion of obesity-related metabolic complications, especially cancer development. Adipose tissue expansion is associated with increased infiltration of various types of immune cells from both the innate and adaptive immune systems. Thus, adipocytes and infiltrating immune cells secrete pro-inflammatory adipokines and cytokines providing a microenvironment favorable for tumor growth. Accumulation of B and T cells in adipose tissue precedes macrophage infiltration causing a chronic low-grade inflammation. Phenotypic switching toward M1 macrophages and Th1 T cells constitutes an important mechanism described in the obese state correlating with increased tumor growth risk. Other possible synergic mechanisms causing a dysfunctional adipose tissue include fatty acid-induced inflammation, oxidative stress, endoplasmic reticulum stress, and hypoxia. Recent investigations have started to unravel the intricacy of the cross-talk between tumor cell/immune cell/adipocyte. In this sense, future therapies should take into account the combination of anti-inflammatory approaches that target the tumor microenvironment with more sophisticated and selective anti-tumoral drugs.
    Frontiers in Physiology 10/2013; 4:275. DOI:10.3389/fphys.2013.00275 · 3.53 Impact Factor
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    • "More recently, it was reported that Th17 is negatively related to plasma highdensity lipoprotein (HDL) suggesting that HDL modulates T cell polarization in T2DM patients [9]. T2DM patients are skewed towards proinflammatory subsets [10]; however, the relationship of peripheral Th1, Th17, and Treg cells in T2DM with hyperglycemia and dyslipidemia as well as diabetes complications is not fully addressed. "
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    ABSTRACT: This study evaluates peripheral blood T lymphocyte expression of inflammatory and proinflammatory cytokines as well as T regulatory (Treg) (FOXP3+CD25+CD4+) cells in type 2 diabetes (T2DM). Participants included 40 T2DM and 30 healthy control subjects. Twenty-four patients had no complications while 16 were afflicted with coronary heart disease (CHD). Relative to healthy subjects, all T2DM patients showed a significant increase in expression of CD4+IFN- ϒ +, CD4+TNF- α +, and CD4+IL-8+ T cells (P < 0.001) as well as CD4+IL-6+, CD4+IL-1 β +, and IL-17+ T cells (P < 0.05) while the ratios of Treg/Th1(CD4+IFN- ϒ +) and Treg/Th-17(CD4+IL-17+) cells were significantly decreased (P < 0.05 and P < 0.01). T2DM patients with CHD showed a significant increase in CD4+IFN- ϒ +, CD4+TNF- α +, and CD4+IL-17+ T cells and a significant decrease in Treg/Th1 and Treg/IL-17 cells compared to T2DM patients without CHD (P < 0.05). In CHD-afflicted T2DM, HbA1c correlated positively with CD4+IFN- ϒ + T cells (P < 0.01), HDL correlated negatively with each of CD4+IL-8+ T cells and CD4+IL-17+ T cells (P < 0.05), and LDL correlated positively with CD4+IL-1 β + T cells (P < 0.05). Conclusion. This study shows that hyperglycemia and dyslipidemia correlate with increased inflammatory cytokine expression and suggests the involvement of T cells in the development of diabetes and its complications.
    Disease markers 09/2013; 35(4):235-41. DOI:10.1155/2013/931915 · 1.56 Impact Factor
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