Knockout of toll-like receptor-4 attenuates the pro-inflammatory state of diabetes

Cytokine. 2011 Sep;55(3):441-5. doi: 10.1016/j.cyto.2011.03.023. Epub 2011 Apr 16.

Abstract

Type 1 diabetes (T1DM) is associated with increased vascular complications and is a pro-inflammatory state. Recent findings have shown increased TLR2 and 4 expression, signaling, ligands, and functional activation in T1DM subjects compared to controls and further accentuated in T1DM with microvascular complications. Thus, the aim of this study was to examine if genetic deficiency of TLR4 attenuates the increased inflammation associated with T1DM using the streptozotocin-induced diabetic mouse model. C57BL/6 and TLR4(-/-) mice were obtained and studied in the native state and following induction of diabetes using streptozotocin. Diabetic (WT+STZ) mice had increased expression of both TLR2 and TLR4, while TLR4(-/-) STZ mice had increased expression only of TLR2, but not TLR4 compared to the non-diabetic mice TLR2 expression was significantly increased with STZ-induced diabetes and was unaffected by knockout of TLR4. Also, levels of MyD88, IRAK-1 protein phosphorylation, Trif, IRF3, and NF-κB activity were significantly reduced in TLR4(-/-) +STZ mice compared to the WT+STZ mice. WT+STZ mice exhibited significantly increased levels of serum and macrophage IL-1β, IL-6, KC/IL-8, IP-10, MCP-1, IFN beta and TNF-α compared to WT mice and this was significantly attenuated in TLR4(-/-) +STZ mice (P<0.01). Thus, TLR4 contributes to the pro-inflammatory state and TLR4KO attenuates inflammation in diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Antigens, Surface / immunology
  • Cytokines / biosynthesis
  • Cytokines / blood
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / chemically induced
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Interferon Regulatory Factor-3 / metabolism
  • Interleukin-1 Receptor-Associated Kinases / metabolism
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / metabolism
  • NF-kappa B / metabolism
  • Signal Transduction
  • Streptozocin / pharmacology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / deficiency
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Antigens, Surface
  • Cytokines
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • TICAM-1 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Streptozocin
  • Interleukin-1 Receptor-Associated Kinases