'Endotoxin tolerance': TNF-alpha hyper-reactivity and tubular cytoresistance in a renal cholesterol loading state

Kidney Int. 2007 Mar;71(6):496-503. doi: 10.1038/sj.ki.5002092. Epub 2007 Jan 17.


The term 'endotoxin tolerance' defines a state in which prior endotoxin (lipopolysaccharide (LPS)) exposure induces resistance to subsequent LPS attack. However, its characteristics within kidney have not been well defined. Hence, this study tested the impact of LPS 'preconditioning' (LPS-PC; 18 or 72 h earlier) on: (i) selected renal inflammatory mediators (tumor necrosis factor (TNF)-alpha, interleukin-10 (IL-10), monocyte chemotactic protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), Toll-like receptor 4 (TLR4); protein or mRNA); (ii) cholesterol homeostasis (a stress reactant); and (iii) isolated proximal tubule (PT) vulnerability to hypoxia or membrane cholesterol (cholesterol oxidase/esterase) attack. Two hours post LPS injection, LPS-PC mice manifested reduced plasma TNF-alpha levels, consistent with systemic LPS tolerance. However, in kidney, paradoxical TNF-alpha hyper-reactivity (protein/mRNA) to LPS existed, despite normal TLR4 protein levels. PT TNF-alpha levels paralleled renal cortical results, implying that PTs were involved. LPS-PC also induced: (i) renal cortical iNOS, IL-10 (but not MCP-1) mRNA hyper-reactivity; (ii), PT cholesterol loading, and (iii) cytoresistance to hypoxia and plasma membrane cholesterol attack. A link between cholesterol homeostasis and cell LPS responsiveness was suggested by observations that cholesterol reductions in HK-2 cells (methylcyclodextrin), or reductions in HK-2 membrane fluidity (A2C), blunted LPS-mediated TNF-alpha/MCP-1 mRNA increases. In sum: (i) systemic LPS tolerance can be associated with renal hyper-responsiveness of selected components within the LPS signaling cascade (e.g., TNF-alpha, iNOS, IL-10); (ii) PT cytoresistance against hypoxic/membrane injury coexists; and (iii) LPS-induced renal/PT cholesterol accumulation may mechanistically contribute to each of these results.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / physiology
  • Cholesterol / pharmacology
  • Cholesterol / physiology*
  • Cytoprotection / drug effects
  • Cytoprotection / physiology*
  • Drug Tolerance / physiology*
  • Endotoxins / adverse effects*
  • Endotoxins / pharmacology
  • Gene Expression Regulation / drug effects
  • Hypoxia / physiopathology
  • Interleukin-10 / genetics
  • Interleukin-10 / physiology
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Kidney Tubules / physiopathology*
  • Lipopolysaccharides / adverse effects*
  • Lipopolysaccharides / pharmacology
  • Male
  • Membrane Fluidity / physiology
  • Mice
  • Mice, Inbred Strains
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / physiology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / physiology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / physiology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology*


  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Endotoxins
  • Lipopolysaccharides
  • RNA, Messenger
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Cholesterol
  • Nitric Oxide Synthase