| First Author | Hsieh YC | Year | 2007 |
| Journal | Mol Immunol | Volume | 44 |
| Issue | 9 | Pages | 2165-72 |
| PubMed ID | 17182102 | Mgi Jnum | J:117916 |
| Mgi Id | MGI:3697983 | Doi | 10.1016/j.molimm.2006.11.019 |
| Citation | Hsieh YC, et al. (2007) 17beta-Estradiol downregulates Kupffer cell TLR4-dependent p38 MAPK pathway and normalizes inflammatory cytokine production following trauma-hemorrhage. Mol Immunol 44(9):2165-72 |
| abstractText | 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+/-5mmHg approximately 90min, 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. |
