Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 7/2010

01-07-2010 | Article

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

Authors: M. Jagannathan, M. McDonnell, Y. Liang, H. Hasturk, J. Hetzel, D. Rubin, A. Kantarci, T. E. Van Dyke, L. M. Ganley-Leal, B. S. Nikolajczyk

Published in: Diabetologia | Issue 7/2010

Login to get access

Abstract

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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.
Literature
1.
King GL (2008) The role of inflammatory cytokines in diabetes and its complications. J Periodontol 79:1527–1534CrossRefPubMed
2.
Duncan BB, Schmidt MI, Pankow JS et al (2003) Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 52:1799–1805CrossRefPubMed
3.
Spranger J, Kroke A, Mohlig M et al (2003) Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 52:812–817CrossRefPubMed
4.
Creely SJ, McTernan PG, Kusminski CM et al (2007) Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 292:E740–E747CrossRefPubMed
5.
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–3025CrossRefPubMed
6.
Page RC (1991) The role of inflammatory mediators in the pathogenesis of periodontal disease. J Periodontal Res 26:230–242CrossRefPubMed
7.
Poggi M, Bastelica D, Gual P et al (2007) C3H/HeJ mice carrying a Toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50:1267–1276CrossRefPubMed
8.
Tsukumo DM, Carvalho-Filho MA, Carvalheira JB et al (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56:1986–1998CrossRefPubMed
9.
Caricilli AM, Nascimento PH, Pauli JR et al (2008) Inhibition of toll-like receptor 2 expression improves insulin sensitivity and signaling in muscle and white adipose tissue of mice fed a high-fat diet. J Endocrinol 199:399–406CrossRefPubMed
10.
11.
Kolz M, Baumert J, Muller M et al (2008) Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol. BMC Med Genet 9:9CrossRefPubMed
12.
Park Y, Park S, Yoo E, Kim D, Shin H (2004) Association of the polymorphism for Toll-like receptor 2 with type 1 diabetes susceptibility. Ann N Y Acad Sci 1037:170–174CrossRefPubMed
13.
Jagannathan M, Hasturk H, Liang Y et al (2009) Toll-like receptor cross talk specifically regulates cytokine production by B cells from chronic inflammatory disease patients. J Immunol 183:7461–7470CrossRefPubMed
14.
Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–607CrossRefPubMed
15.
Bourke E, Bosisio D, Golay J, Polentarutti N, Mantovani A (2003) The toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Blood 102:956–963CrossRefPubMed
16.
Hornung V, Rothenfusser S, Britsch S et al (2002) Quantitative expression of Toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531–4537PubMed
17.
Duddy ME, Alter A, Bar-Or A (2004) Distinct profiles of human B cell effector cytokines: a role in immune regulation? J Immunol 172:3422–3427PubMed
18.
Hanten JA, Vasilakos JP, Riter CL et al (2008) Comparison of human B cell activation by TLR7 and TLR9 agonists. BMC Immunol 9:39CrossRefPubMed
19.
Shin H, Zhang Y, Jagannathan M et al (2009) B cells from periodontal disease patients express surface Toll-like receptor 4. J Leukoc Biol 85:648–655CrossRefPubMed
20.
Noronha AM, Liang Y, Hetzel JT et al (2009) Hyperactivated B cells in human inflammatory bowel disease. J Leukoc Biol 86:1007–1016CrossRefPubMed
21.
Duddy M, Niino M, Adatia F et al (2007) Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol 178:6092–6099PubMed
22.
Blair PA, Norena LY, Flores-Borja F et al (2010) CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 32:129–140CrossRefPubMed
23.
Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM (2002) B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3:944–950CrossRefPubMed
24.
Mauri C, Feldmann M, Williams RO (2003) Down-regulation of Th1-mediated pathology in experimental arthritis by stimulation of the Th2 arm of the immune response. Arthritis Rheum 48:839–845CrossRefPubMed
25.
van Exel E, Gussekloo J, de Craen AJ, Frolich M, Bootsma-Van Der Wiel A, Westendorp RG (2002) Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-Plus Study. Diabetes 51:1088–1092CrossRefPubMed
26.
Lampropoulou V, Hoehlig K, Roch T et al (2008) TLR-activated B cells suppress T cell-mediated autoimmunity. J Immunol 180:4763–4773PubMed
27.
Mealey BL, Ocampo GL (2007) Diabetes mellitus and periodontal disease. Periodontol 2000 44:127–153CrossRefPubMed
28.
Freeman DJ, Norrie J, Caslake MJ et al (2002) C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 51:1596–1600CrossRefPubMed
29.
Rutter MK, Meigs JB, Sullivan LM, D’Agostino RB Sr, Wilson PW (2004) C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation 110:380–385CrossRefPubMed
30.
Armitage GC (1999) Development of a classification system for periodontal diseases and conditions. Ann Periodontol 4:1–6CrossRefPubMed
31.
Golenbock DT, Hampton RY, Qureshi N, Takayama K, Raetz CR (1991) Lipid A-like molecules that antagonize the effects of endotoxins on human monocytes. J Biol Chem 266:19490–19498PubMed
32.
Rao S, Procko E, Shannon MF (2001) Chromatin remodeling, measured by a novel real-time polymerase chain reaction assay, across the proximal promoter region of the IL-2 gene. J Immunol 167:4494–4503PubMed
33.
Ganley-Leal LM, Liu X, Wetzler LM (2006) Toll-like receptor 2-mediated human B cell differentiation. Clin Immunol 120:272–284CrossRefPubMed
34.
Dasu MR, Devaraj S, Park S, Jialal I (2010) Increased Toll-like receptor activation and TLR ligands in recently diagnosed type 2 diabetes subjects. Diabetes Care. doi:10.​2337/​dc09-1799
35.
Marks DJ, Harbord MW, MacAllister R et al (2006) Defective acute inflammation in Crohn’s disease: a clinical investigation. Lancet 367:668–678CrossRefPubMed
36.
Darveau RP, Pham TT, Lemley K et al (2004) Porphyromonas gingivalis lipopolysaccharide contains multiple lipid A species that functionally interact with both toll-like receptors 2 and 4. Infect Immun 72:5041–5051CrossRefPubMed
37.
Senn JJ (2006) Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes. J Biol Chem 281:26865–26875CrossRefPubMed
38.
Winer S, Chan Y, Paltser G et al (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921–929CrossRefPubMed
39.
Feuerer M, Herrero L, Cipolletta D et al (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930–939CrossRefPubMed
40.
Nishimura S, Manabe I, Nagasaki M et al (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914–920CrossRefPubMed
41.
Herder C, Haastert B, Muller-Scholze S et al (2005) Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). Diabetes 54(Suppl 2):S11–S17CrossRefPubMed
42.
Fain JN (2006) Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 74:443–477CrossRefPubMed
43.
Qi X, Li J, Gu J, Li S, Dang Y, Wang T (2003) Plasma levels of IL-8 predict early complications in patients with coronary heart disease after percutaneous coronary intervention. Jpn Heart J 44:451–461CrossRefPubMed
44.
Bruun JM, Pedersen SB, Richelsen B (2000) Interleukin-8 production in human adipose tissue. inhibitory effects of anti-diabetic compounds, the thiazolidinedione ciglitazone and the biguanide metformin. Horm Metab Res 32:537–541CrossRefPubMed
45.
Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389:610–614CrossRefPubMed
46.
Larsen CM, Faulenbach M, Vaag A et al (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 356:1517–1526CrossRefPubMed
47.
Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R (1996) Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45:881–885CrossRefPubMed
48.
Yazdani-Biuki B, Stelzl H, Brezinschek HP et al (2004) Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab. Eur J Clin Invest 34:641–642CrossRefPubMed
Metadata
Title
Toll-like receptors regulate B cell cytokine production in patients with diabetes
Authors
M. Jagannathan
M. McDonnell
Y. Liang
H. Hasturk
J. Hetzel
D. Rubin
A. Kantarci
T. E. Van Dyke
L. M. Ganley-Leal
B. S. Nikolajczyk
Publication date
01-07-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 7/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-010-1730-z

Other articles of this Issue 7/2010

Diabetologia 7/2010 Go to the issue

Article

External validation and optimisation of a model for predicting foot ulcers in patients with diabetes

Article

Beta cell coupling and connexin expression change during the functional maturation of rat pancreatic islets

Article

Differences between amyloid toxicity in alpha and beta cells in human and mouse islets and the role of caspase-3

Article

Hepatocyte nuclear factor (HNF)-4α-driven epigenetic silencing of the human PED gene

Article

Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients

Article

IFN-γ and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits