Mechanism of Cortistatin Modulatory Effects on Kupffer Cells

  • Chao, Tzu-Chieh (PI)
  • Lin, Jen-Der (CoPI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details


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. On activation, 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-α, IL-6, IL-10, IL-12, TGF-β1). These molecules play a major role in orchestrating the anti-infectious process; however, their excessive production may lead to severe immunopathology such as endotoxic shock. To prevent deleterious endotoxin activation, a number of signaling mechanisms are evoked. 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 literature demonstrates cortistatin down-regulates the production of TNF-α, IL-6, IL-10, 1L-12, MIP-2, and RANTES by endotoxin-activated macrophages in mice, The effects of cortistatin on Kupffer cells have not ever been reported. Our general hypothesis is that cortistatin suppresses Kupffer cell function. Our preliminary results demonstrate cortistatin treatment inhibits production of nitric oxide and TNF-α by rat Kupffer cells, suggesting that cortistatin is an anti-inflammatory peptide. The mechanism of cortistatin modulatory effects on macrophage function is not clear. Our specific hypothesis is that cortistatin inhibits Kupffer cell function through the following mechanisms: 1. Inhibition of effecter molecules (nitric oxide and cytokines in this study) at translational or transcriptional levels. 2. Production of anti-inflammatory cytokines, mainly IL-10 and TGF-β1. 3. Down-regulation of surface TLR4 expression. 4. Modulating Kupffer cell function through arachidonic acid pathway, including cAMP, prostaglandin E2 or leukotriene B4. 5. Inhibition of translocation of NFκB. 6. Inhibition of mitogen-activated protein kinases (MAPKs) activity, including ERKs, JNKs, and p38 MAPK. 7. Transcriptional induction of negative regulators, such as suppressors of cytokine signaling 1 and 3 (SOCS1 and 3). To test our hypothesis, Kupffer cells isolated from male Sprague-Dawley rats will be treated with cortistatin in the presence or absence of 0.1 μg/ml of LPS. Then, nitric oxide and cytokines will be determined. Expression of cell surface TLR4, intracellular cAMP, prostaglandin E2, leukotriene B4, expression of COX-1 and COX-2, SOCS1 and SOCS3, translocation of NFκB, cytoplasmic IκB and phosphorylated IκB will be studied. Mitogen-activated protein kinases (MAPKs), including p38MAPK, JNK, phosphorylated JNK, ERK, phosphorylated ERK, and MKP-1 will also be studied. This study will disclose the mechanisms of how cortistatin modulates Kupffer cell function. The findings may lead us to the eventual development of effective therapy for infection.

Project IDs

Project ID:PC9709-0949
External Project ID:NSC97-2314-B182-008-MY2
Effective start/end date01/08/0831/07/09


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