In vivo Effects of Cortistatin on Kupffer Cells Function in Endotoxemic Rats

Kupffer cells comprise the largest population of fixed tissue macrophages in the body and the first macrophages to contact noxious materials (bacteria, viruses, and tumor cells) that enter circulation via the portal vein. Activated by endotoxemia, Kupffer cells secrete a wide variety of biologically active compounds including reactive oxygen species (e.g., superoxide, hydrogen peroxide), nitric oxide, eicosanoids, and cytokines (e.g., TNF-, IL-6, IL-10, IL-12, TGF-1). These molecules are important in orchestrating the anti-infectious process; however, their excessive production may lead to severe immunopathology such as endotoxic shock. Cortistatin is a recently discovered cyclic neuropeptide which shows a high homology with somatostatin and binds to all five somatostatin receptors and therefore, some of the somatostatin immunomodulatory actions could be shared by cortistatin. Although a recent report shows that cortistatin down-regulates the production of cytokines by endotoxin-activated peritoneal macrophages in mice, functional heterogeneity exists in macrophages from different tissues. Therefore, it is necessary to further characterize the cortistatin effects on Kuffer cells. In addition, the in vivo effects of cortistatin on Kupffer cells in endotoxemia have not ever been reported. This study will disclose the mechanisms of how in vivo cortistatin modulates Kupffer cell functions in endotoxemia. The findings may lead us to the eventual development of an effective therapy for infection. Our preliminary results demonstrate in vitro cortistatin effects on Kupffer cells. In vitro results may be different from the in vivo findings. In addition, the in vivo effects of cortistatin on Kupffer cells in endotoxemia have not ever been reported. Our general hypothesis is that in vivo treatment with cortistatin suppresses Kupffer cell function in endotoxemia. To test our hypotheis, we will obtain Kupffer cells from cortistatin-treated endotoxemic rats and study the release of nitric oxide, TNF-, IL-6, IL-10, and TGF-1 by Kupffer cells. Secondly, the expression of these cytokines mRNAs will be studied using semi-quantitative RT-PCR. Then we will examine the mechanisms of cortistatin effects on Kupffer cells, including cAMP, PGE2, cAMP, COX-1, COX-2, leukotriene B4, NFB and IB, mitogen-activated protein kinases, and suppressor of cytokine signaling (SOCS) proteins. Since cortistatin possibly affects Kupffer cell function through interfering with the expression of CD14 and TLR4 on Kupffer cells, CD14 and TLR4 expression will also be examined. This study will disclose in vivo cortistatin effects on Kupffer cell function in endotoxemic rats. In addition, the mechanisms of cortistatin effects on Kupffer cells in endotoxemia will also be elucidated, and therefore leads to the eventual development of effective therapy for infection and inflammatory diseases.

Project ID:PC10008-0755
External Project ID:NSC100-2314-B182A-078