Regulation of lipopolysaccharide-induced inflammatory response and endotoxemia by beta-arrestins

J Cell Physiol. 2010 Nov;225(2):406-16. doi: 10.1002/jcp.22289.

Abstract

Beta-arrestins are scaffolding proteins implicated as negative regulators of TLR4 signaling in macrophages and fibroblasts. Unexpectedly, we found that beta-arrestin-1 (beta-arr-1) and -2 knockout (KO) mice are protected from TLR4-mediated endotoxic shock and lethality. To identify the potential mechanisms involved, we examined the plasma levels of inflammatory cytokines/chemokines in the wild-type (WT) and beta-arr-1 and -2 KO mice after lipopolysaccharide (LPS, a TLR4 ligand) injection. Consistent with lethality, LPS-induced inflammatory cytokine levels in the plasma were markedly decreased in both beta-arr-1 and -2 KO, compared to WT mice. To further explore the cellular mechanisms, we obtained splenocytes (separated into CD11(b+) and CD11(b-) populations) from WT, beta-arr-1, and -2 KO mice and examined the effect of LPS on cytokine production. Similar to the in vivo observations, LPS-induced inflammatory cytokines were significantly blocked in both splenocyte populations from the beta-arr-2 KO compared to the WT mice. This effect in the beta-arr-1 KO mice, however, was restricted to the CD11(b-) splenocytes. Our studies further indicate that regulation of cytokine production by beta-arrestins is likely independent of MAPK and IkappaBalpha-NFkappaB pathways. Our results, however, suggest that LPS-induced chromatin modification is dependent on beta-arrestin levels and may be the underlying mechanistic basis for regulation of cytokine levels by beta-arrestins in vivo. Taken together, these results indicate that beta-arr-1 and -2 mediate LPS-induced cytokine secretion in a cell-type specific manner and that both beta-arrestins have overlapping but non-redundant roles in regulating inflammatory cytokine production and endotoxic shock in mice.

Publication types

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

MeSH terms

  • Animals
  • Arrestins / genetics
  • Arrestins / metabolism*
  • CD11 Antigens / metabolism
  • Cell Culture Techniques
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Endotoxemia / metabolism*
  • Gene Expression Regulation
  • Inflammation / chemically induced*
  • Lipopolysaccharides / toxicity*
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Signal Transduction
  • Spleen / cytology
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • beta-Arrestin 1
  • beta-Arrestins

Substances

  • Arrb1 protein, mouse
  • Arrestins
  • CD11 Antigens
  • Cytokines
  • Lipopolysaccharides
  • NF-kappa B
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • beta-Arrestin 1
  • beta-Arrestins
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Mitogen-Activated Protein Kinase Kinases