International Immunology Advance Access published online on May 25, 2006
International Immunology, doi:10.1093/intimm/dxl045
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1 Department of Medicinal and Biological Chemistry, College of Pharmacy, 2801 West Bancroft Street, Toledo, OH 43606-3390, USA; Present address: College of Pharmacy, University of Jordan, Amman, Jordan
* To whom correspondence should be addressed. The expression, responsiveness and regulation of mouse Toll-like receptors (TLRs) in bone marrow-derived macrophages (BM- *These authors contributed equally to this study.
Received August 8, 2005
Accepted April 20, 2006
Article
Dysregulated Toll-like receptor expression and signaling in bone marrow-derived macrophages at the onset of diabetes in the non-obese diabetic mouse
Mohammad K. Mohammad 1 *,
Michael Morran 2 *,
Brandon Slotterbeck 2,
Douglas W. Leaman 3,
Yaping Sun 3,
Hermann von Grafenstein 2,
Soon-Cheol Hong 4,
and
Marcia F. McInerney 2 *
2 Department of Medicinal and Biological Chemistry, College of Pharmacy, 2801 West Bancroft Street, Toledo, OH 43606-3390, USA
3 Department of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606-3390, USA
4 Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Walther Oncology Center, Walther Cancer Institute, Indianapolis, IN, USA
Marcia F. McInerney, E-mail: marcia.mcinerney{at}utoledo.edu
Abstract 
) were investigated prior to and following the development of diabetes. Expression of TLR3 and TLR5 was significantly higher in newly diabetic non-obese diabetic (NOD) mice when compared with pre-diabetic and control strains of mice. The TLR3 ligand poly(I)poly(C) triggered up-regulation of its own receptor in NOR and pre-diabetic NOD, but TLR3 was already highly expressed in diabetic NOD mice. Expression levels of TLR3 correlated with poly(I)poly(C)-triggered IFN activity. LPS triggered down-regulation of TLR4 in pre-diabetic NOD, NOR and BALB/c, while levels of TLR4 remained consistently elevated in type 1 diabetic NOD and type 2 diabetic NZL mice. Dysregulation of TLR4 expression in the diabetic state correlated with increased nuclear factor kappa B (NF-
B) activation in response to the TLR4 ligand LPS and higher expression of IL-12p40, tumor necrosis factor 
(TNF), IL-6 and inducible nitric oxide synthase but lowered expression of IL-10. Exposure of bone marrow precursor cells from NOD mice to a hyperglycemic environment during differentiation into macrophages resulted in elevated levels of TLR2 and TLR4 and the cytokine TNF. The results indicate that macrophage precursors are influenced by systemic changes in diabetes favoring altered TLR expression and sensitivity that may influence susceptibility to macrophage-mediated diabetes complications and explain inappropriate responses to infection in diabetes.
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