17Beta-estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage

Mol Immunol. 2007 Mar;44(9):2165-72. doi: 10.1016/j.molimm.2006.11.019. Epub 2006 Dec 19.


Although studies have shown that 17beta-estradiol (estradiol) normalized Kupffer cell function following trauma-hemorrhage, the mechanism by which E2 maintains immune function remains unclear. Activation of Toll-like receptor 4 (TLR4) initiates an inflammatory cascade, involving activation of p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and nuclear factor-kappaB (NF-kappaB). This leads to the release of proinflammatory cytokines. Thus, we hypothesized that the salutary effects of estradiol on Kupffer cell function following trauma-hemorrhage are mediated via negative regulation of TLR4-dependent p38 MAPK and NF-kappaB. TLR4 mutant (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to trauma-hemorrhage (mean BP 35+/-5 mmHg approximately 90 min, then resuscitation) or sham operation. Administration of estradiol following trauma-hemorrhage in wild type mice decreased Kupffer cell TLR4 expression as well as prevented the phosphorylation of p38 MAPK and NF-kappaB. This was accompanied by normalization of Kupffer cell production capacities of IL-6, TNF-alpha, macrophage inflammatory protein (MIP)-1alpha, and MIP-2 and the decrease in plasma cytokine levels. In contrast, TLR4 mutant mice did not exhibit the increase in Kupffer cell p38 MAPK and NF-kappaB activation, cytokine production, or the increase in circulating cytokine levels following trauma-hemorrhage. No difference was observed in activation of PI3K among groups. These results suggest that the protective effect of estradiol on Kupffer cell function is mediated via downregulation of TLR4-dependent p38 MAPK and NF-kappaB signaling following trauma-hemorrhage, which prevents the systemic release of cytokines.

Publication types

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

MeSH terms

  • Animals
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CXCL2
  • Cytokines / biosynthesis*
  • Cytokines / blood
  • Down-Regulation / drug effects*
  • Estradiol / pharmacology*
  • Hemorrhage / chemically induced
  • Hemorrhage / immunology
  • Inflammation
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / blood
  • Kupffer Cells / drug effects*
  • Kupffer Cells / enzymology*
  • Macrophage Inflammatory Proteins / biosynthesis
  • Macrophage Inflammatory Proteins / blood
  • Mice
  • Monokines / biosynthesis
  • Monokines / blood
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Toll-Like Receptor 4 / genetics*
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / blood
  • Wounds and Injuries / chemically induced
  • Wounds and Injuries / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Chemokine CCL3
  • Chemokine CCL4
  • Chemokine CXCL2
  • Cytokines
  • Interleukin-6
  • Macrophage Inflammatory Proteins
  • Monokines
  • NF-kappa B
  • RNA, Messenger
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • Estradiol
  • Phosphatidylinositol 3-Kinases
  • p38 Mitogen-Activated Protein Kinases