Toll-like receptors regulate B cell cytokine production in patients with diabetes.
OBJECTIVE
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
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.
Jagannathan
M
M
Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
McDonnell
M
M
Liang
Y
Y
Hasturk
H
H
Hetzel
J
J
Rubin
D
D
Kantarci
A
A
Van Dyke
T E
TE
Ganley-Leal
L M
LM
Nikolajczyk
B S
BS
D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000276:immunology / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D051193:Toll-Like Receptors / Q000378:metabolism*
D016207:Cytokines; D016209:Interleukin-8; D051193:Toll-Like Receptors; D016753:Interleukin-10
Circulation. 2004 Jul 27;110(4):380-5
15262834
J Immunol. 2009 Dec 1;183(11):7461-70
19917698
J Biol Chem. 1991 Oct 15;266(29):19490-8
1918061
Jpn Heart J. 2003 Jul;44(4):451-61
12906027
Diabetes. 2002 May;51(5):1596-600
11978661
J Immunol. 2007 May 15;178(10):6092-9
17475834
J Immunol. 2002 May 1;168(9):4531-7
11970999
J Periodontol. 2008 Aug;79(8 Suppl):1527-34
18673007
BMC Med Genet. 2008 Feb 25;9:9
18298826
BMC Immunol. 2008 Jul 24;9:39
18652679
Nat Med. 2009 Aug;15(8):921-9
19633657
J Leukoc Biol. 2009 Oct;86(4):1007-16
19589946
Diabetes. 2003 Mar;52(3):812-7
12606524
Nat Med. 2009 Aug;15(8):930-9
19633656
J Diabetes Complications. 2010 May-Jun;24(3):192-8
19395279
Diabetes. 2005 Dec;54 Suppl 2:S11-7
16306328
Infect Immun. 2004 Sep;72(9):5041-51
15321997
Diabetes Care. 2010 Apr;33(4):861-8
20067962
Diabetes. 2007 Aug;56(8):1986-98
17519423
Blood. 2003 Aug 1;102(3):956-63
12689944
Nature. 1997 Oct 9;389(6651):610-4
9335502
Immunity. 2010 Jan 29;32(1):129-40
20079667
Ann N Y Acad Sci. 2004 Dec;1037:170-4
15699513
Nat Med. 2009 Aug;15(8):914-20
19633658
J Clin Invest. 2006 Nov;116(11):3015-25
17053832
J Biol Chem. 2006 Sep 15;281(37):26865-75
16798732
J Immunol. 2008 Apr 1;180(7):4763-73
18354200
Diabetologia. 2007 Jun;50(6):1267-76
17426960
J Leukoc Biol. 2009 Apr;85(4):648-55
19118102
Clin Immunol. 2006 Sep;120(3):272-84
16766226
Diabetes. 1996 Jul;45(7):881-5
8666137
Diabetes. 2002 Apr;51(4):1088-92
11916930
Am J Physiol Endocrinol Metab. 2007 Mar;292(3):E740-7
17090751
J Periodontal Res. 1991 May;26(3 Pt 2):230-42
1679130
Horm Metab Res. 2000 Nov-Dec;32(11-12):537-41
11246821
N Engl J Med. 2007 Apr 12;356(15):1517-26
17429083
Arthritis Rheum. 2003 Mar;48(3):839-45
12632440
J Immunol. 2001 Oct 15;167(8):4494-503
11591776
Nature. 2002 Apr 11;416(6881):603-7
11948342
J Endocrinol. 2008 Dec;199(3):399-406
18787058
Ann Periodontol. 1999 Dec;4(1):1-6
10863370
J Immunol. 2004 Mar 15;172(6):3422-7
15004141
Diabetes. 2003 Jul;52(7):1799-805
12829649
Periodontol 2000. 2007;44:127-53
17474930
Nat Immunol. 2002 Oct;3(10):944-50
12244307
Lancet. 2006 Feb 25;367(9511):668-78
16503465
Vitam Horm. 2006;74:443-77
17027526
Eur J Clin Invest. 2004 Sep;34(9):641-2
15379764