肝醣合成酶激酶-3beta(GSK-3beta)，屬於Serine/Threonine kinase並可調控蛋白質生成、細胞生長、分化、凋亡及發炎反應。我們先前的研究指出丙型干擾素 (IFN-gamma) 誘導發炎反應中肝醣合成酶激酶-3beta扮演重要的角色，但其活化的機制仍不清楚。以干擾子及抑制劑的實驗證實抑制肝醣合成酶激酶-3beta的活性能夠降低丙型干擾素所造成的一氧化氮及細胞激素的產生。本研究中，我們進一步探討肝醣合成酶激酶-3beta的活化機制。在丙型干擾素的刺激下，蛋白質去磷酸酶 (phosphatase) 會降低肝醣合成酶激酶-3beta絲胺酸9的位點磷酸化而proline-rich tyrosine kinase 2 (Pyk2) 會增加肝醣合成酶激酶-3beta酪氨酸216的位點磷酸化，進而活化肝醣合成酶激酶-3beta。神經醯胺 (ceramide) 可能參與活化蛋白質去磷酸酶，因此，我們加以探討神經醯胺扮演的角色。實驗顯示透過中性神經磷質水解酶 (neutral sphingomyelinase) 降解生成的神經醯胺進而調控了肝醣合成酶激酶-3beta的活化。丙型干擾素刺激活化巨噬細胞的訊息傳遞中，phosphatidylcholine-specific phospholipase C (PC-PLC), protein kinase C (PKC)以及Src等調節作用將可活化了Pyk2以及肝醣合成酶激酶-3beta。活化PC-PLC, Pyk2和肝醣合成酶激酶-3beta係由丙型干擾素接受器第二型 (IFNGR2) 活化Jak2所調控。有趣的是，我們的結果也顯示了中性神經磷質水解酶也會調控Jak2, PC-PLC, PKC以及cytosolic PLA2 (cPLA2)。cPLA2也扮演調控活化肝醣合成酶激酶-3beta的角色。此外，活化nuclear factor kappa B (NF-kB) 的訊號中,是透過肝醣合成酶激酶-3beta調節Jak2進而影響dsRNA-dependent kinase-IkB kinase-inhibitor of NF-kB。並且，肝醣合成酶激酶-3beta透過抑制Src homology-2 domain-containing phosphatase 2而活化Jak2到NF-kB的訊息傳遞。綜合以上的結果顯示，丙型干擾素的刺激下，PC-PLC, cPLA2以及神經醯胺這些生物脂質可活化肝醣合成酶激酶-3beta。

Glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine kinase, regulates protein synthesis, cell growth, differentiation, apoptosis, and inflammation. Our current studies show the key role for GSK-3beta in interferon-gamma (IFN-gamma-induced inflammation; however, the activation of GSK-3beta remains unclear. Treating cells with GSK-3beta inhibitor and short interfering RNA showed a decrease on IFN-gamma-induced inflammatory responses, including nitric oxide biosynthesis and cytokine production. In this study, we further investigate the mechanism of GSK-3beta activation. After IFN-gamma stimulation, protein phosphatase (PPase) mediated GSK3beta dephosphorylation at Ser9 and proline-rich tyrosine kinase 2 (Pyk2) mediated GSK-3betaphosphorylation at Tyr216. Since okadaic acid-sensitive PPases were activated by ceramide, results demonstrated that IFN-gamma induced ceramide generation. Furthermore, neutral sphingomyelinase (SMase) was required for GSK-3beta activation. In IFN-gamma-stimulated macrophages, Pyk2 and GSK-3beta were sequentially activated through phosphatidylcholine-specific phospholipase C (PC-PLC)-, protein kinase C (PKC)-, and Src-regulated pathways. Activation of PC-PLC, Pyk2, and GSK-3beta by IFN-gamma was mediated via IFN-gamma receptor 2 (IFNGR2)-associated Jak2-regulated but IFNGR1-independent pathway. Further results demonstrated that IFN-gamma-elicited neutral SMase was also regulated by Jak2, PC-PLC, PKC, and cytosolic PLA2 (cPLA2). cPLA2 was essential for IFN-gamma-induced GSK-3beta dephosphorylation (Ser9). In addition, activation of nuclear factor kappa B (NF-kB) via dsRNA-dependent kinase-IkB kinase-inhibitor of NF-kB axis was regulated by Jak2 as well as GSK-3beta. Interestingly, GSK-3beta regulated Jak2-NF-kB signaling through inhibiting Src homology-2 domain-containing phosphatase 2. Taken together, these results demonstrate the novel role for GSK-3beta that activated by bioactive lipids, including PC-PLC, cPLA2, and ceramide.

Anderson, R.J. (2007). Kidney in sepsis. Crit. Care Med. 35, 2223-2224.
Amano, F., and Noda, T. (1995). Improved detection of nitric oxide radical (NO.) production in an activated macrophage culture with a radical scavenger, carboxy PTIO and Griess reagent. FEBS letters 368, 425-428.
Asai, K., Kato, H., Kimura, S., Mukai, S., Kawahito, Y., Sano, H., Kondo, M., Akaogi, K., and Hirose, K. (1996). Induction of gene expression for nitric oxide synthase by immunomodulating drugs in the RAW264.7 murine macrophage cell line. Cancer Immunol Immunother 42, 275-279.
Bach, E.A., Aguet, M., and Schreiber, R.D. (1997). The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 15, 563-591.
Baud, L., Oudinet, J.P., Bens, M., Noe, L., Peraldi, M.N., Rondeau, E., Etienne, J., and Ardaillou, R. (1989). Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 35, 1111-1118.
Bao, Z., Lim, S., Liao, W., Lin, Y., Thiemermann, C., Leung, B.P., and Wong, W.S. (2007). Glycogen synthase kinase-3beta inhibition attenuates asthma in mice. Am J Respir Crit Care Med 176, 431-438.
Barid, I., and Sosroseno, W. (2002). The effect of parachlorophenol and camphorated parachlorophenol on nitric oxide production by a murine macrophage cell line, RAW264.7. Journal of oral science 44, 155-159.
Beaulieu, J.M., Marion, S., Rodriguiz, R.M., Medvedev, I.O., Sotnikova, T.D., Ghisi, V., Wetsel, W.C., Lefkowitz, R.J., Gainetdinov, R.R., and Caron, M.G. (2008). A -arrestin 2 signaling complex mediates lithium action on behavior. Cell 132, 125-136.
Beurel, E., and Jope, R.S. (2008). Differential regulation of STAT family members by glycogen synthase kinase-3. The Journal of biological chemistry.
Beurel, E., and Jope, R.S. (2009). Glycogen synthase kinase-3 promotes the synergistic action of interferon-gamma on lipopolysaccharide-induced IL-6 production in RAW264.7 cells. Cellular signalling 21, 978-985.
Beaulieu, J.M., Sotnikova, T.D., Yao, W.D., Kockertiz, L., Woodgett, J.R., Gainetdinov, R.R., and Caron, M.G. (2004). Lithium antagonizes dopamine-dependent behaviors mediated by an Akt/glycogen synthase kinase 3 signaling cascade. Proc. Natl. Acad. Sci. 101, 5099-5104.
Bhat, R.V., Leonov, S., Luthman, J., Scott, C.W., and Lee, C.M. (2002). Interactions between GSK3beta and caspase signalling pathways during NGF deprivation induced cell death. J. Alzheimers Dis. 4, 291-301.
Bickler, P.E., and Fahlman, C.S. (2006). The inhaled anesthetic, isoflurane, enhances Ca2+-dependent survival signaling in cortical neurons and modulates MAP kinases, apoptosis proteins and transcription factors during hypoxia. Anesthesia and analgesia 103, 419-429, table of contents.
Bijur, G.N., De Sarno, P., and Jope, R.S. (2000). Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium. J. Biol. Chem. 275, 7583-7590.
Biron, K.K. (2006). Antiviral drugs for cytomegalovirus diseases. Antiviral research 71, 154-163.
Burnham, C.A., Shokoples, S.E., and Tyrrell, G.J. (2007). Invasion of HeLa cells by group B streptococcus requires the phosphoinositide-3-kinase signalling pathway and modulates phosphorylation of host-cell Akt and glycogen synthase kinase-3. Microbiology (Reading, England) 153, 4240-4252.
Chang, Y.J., Holtzman, M.J., and Chen, C.C. (2004). Differential role of Janus family kinases (JAKs) in interferon-gamma-induced lung epithelial ICAM-1 expression: involving protein interactions between JAKs, phospholipase
Cohen, P., and Frame, S. (2001). The renaissance of GSK-3. Nat. Rev. Mol. Cell Biol. 2, 769-776.
Cross, D.A., Alessi, D.R., Cohen, P., Andjelkovich, M., and Hemmings, B.A. (1995). Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785-789.
Cunningham, P.N., Dyanov, H.M., Park, P., Wang, J., Newell, K.A., and Quigg, R.J. (2002). Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney. J. Immunol. 168, 5817-5823.
Cunningham, P.N., Wang, Y., Guo, R., He, G., and Quigg, R.J. (2004). Role of Toll-like receptor 4 in endotoxin-induced acute renal failure. J. Immunol. 172, 2629-2635.
Cuzzocrea, S., Malleo, G., Genovese, T., Mazzon, E., Esposito, E., Muia, C., Abdelrahman, M., Di Paola, R., and Thiemermann, C. (2007a). Effects of glycogen synthase kinase-3beta inhibition on the development of cerulein-induced acute pancreatitis in mice. Crit. Care Med 35, 2811-2821.
Cuzzocrea, S., Mazzon, E., Di Paola, R., Muia, C., Crisafulli, C., Dugo, L., Collin, M., Britti, D., Caputi, A.P., and Thiemermann, C. (2006). Glycogen synthase kinase-3beta inhibition attenuates the degree of arthritis caused by type II collagen in the mouse. Clin. Immunol. 120, 57-67.
Cuzzocrea, S., Mazzon, E., Esposito, E., Muia, C., Abdelrahman, M., Di Paola, R., Crisafulli, C., Bramanti, P., and Thiemermann, C. (2007b). Glycogen synthase kinase-3beta inhibition attenuates the development of ischaemia/reperfusion injury of the gut. Intensive Care Med. 33, 880-893.
de Visser, K.E., Eichten, A., and Coussens, L.M. (2006). Paradoxical roles of the immune system during cancer development. Nat. Rev. Cancer 6, 4-37.
Demarchi, F., Bertoli, C., Sandy, P., and Schneider, C. (2003). Glycogen synthase kinase-3 beta regulates NF-kappa B1/p105 stability. The Journal of biological chemistry 278, 39583-39590.
Deng, J., Kohda, Y., Chiao, H., Wang, Y., Hu, X., Hewitt, S.M., Miyaji, T., McLeroy, P., Nibhanupudy, B., Li, S., et al. (2001). Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int. 60, 2118-2128.
De Sarno, P., Axtell, R.C., Raman, C., Roth, K.A., Alessi, D.R., and Jope, R.S. (2008). Lithium prevents and ameliorates experimental autoimmune encephalomyelitis. J Immunol 181, 338-345.
Deb, A., Haque, S.J., Mogensen, T., Silverman, R.H., and Williams, B.R. (2001). RNA-dependent protein kinase PKR is required for activation of NF-kappa B by IFN-gamma in a STAT1-independent pathway. J Immunol 166, 6170-6180.
Decker, T., and Kovarik, P. (2000). Serine phosphorylation of STATs. Oncogene 19, 2628-2637.
Gil, J., Alcami, J., and Esteban, M. (2000). Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex. Oncogene 19, 1369-1378.
Gough, D.J., Levy, D.E., Johnstone, R.W., and Clarke, C.J. (2008). IFNgamma signaling-does it mean JAK-STAT? Cytokine Growth Factor Rev 19, 383-394.
Donnelly, R.P., Freeman, S.L., and Hayes, M.P. (1995). Inhibition of IL-10 expression by IFN-gamma up-regulates transcription of TNF-alpha in human monocytes. J Immunol 155, 1420-1427.
Dugo, L., Abdelrahman, M., Murch, O., Mazzon, E., Cuzzocrea, S., and Thiemermann, C. (2006a). Glycogen synthase kinase-3beta inhibitors protect against the organ injury and dysfunction caused by hemorrhage and resuscitation. Shock 25, 485-491.
Dugo, L., Collin, M., Allen, D.A., Murch, O., Foster, S.J., Yaqoob, M.M., and Thiemermann, C. (2006b). Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: role of glycogen synthase kinase-3beta inhibition. Crit. Care Med 34, 1489-1496.
Dugo, L., Collin, M., Allen, D.A., Patel, N.S., Bauer, I., Mervaala, E., Louhelainen, M., Foster, S.J., Yaqoob, M.M., and Thiemermann, C. (2007a). Inhibiting glycogen synthase kinase 3beta in sepsis. Novartis Found. Symp. 280, 128-142; discussion 142-146, 160-164.
Dugo, L., Collin, M., Allen, D.A., Patel, N.S., Bauer, I., Mervaala, E.M., Louhelainen, M., Foster, S.J., Yaqoob, M.M., and Thiemermann, C. (2005). GSK-3beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat. Crit. Care Med. 33, 1903-1912.
Dugo, L., Collin, M., and Thiemermann, C. (2007b). Glycogen synthase kinase 3beta as a target for the therapy of shock and inflammation. Shock 27, 113-123.
Endo, H., Nito, C., Kamada, H., Nishi, T., and Chen, P.H. (2006). Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 26, 1479-1489.
Frame, S., and Cohen, P. (2001). GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1-16.
Giannopoulou, M., Dai, C., Tan, X., Wen, X., Michalopoulos, G.K., and Liu, Y. (2008). Hepatocyte growth factor exerts its anti-inflammatory action by disrupting nuclear factor-B signaling. Am. J. Pathol. 173, 30-41.
Gong, R., Rifai, A., and Dworkin, L.D. (2005). Activation of PI3K-Akt-GSK3beta pathway mediates hepatocyte growth factor inhibition of RANTES expression in renal tubular epithelial cells. Biochem. Biophys. Res. Commun. 330, 27-33.
Gong, R., Rifai, A., and Dworkin, L.D. (2006a). Anti-inflammatory effect of hepatocyte growth factor in chronic kidney disease: targeting the inflamed vascular endothelium. J. Am. Soc. Nephrol. 17, 2464-2473.
Gong, R., Rifai, A., and Dworkin, L.D. (2006b). Hepatocyte growth factor suppresses acute renal inflammation by inhibition of endothelial E-selectin. Kidney Int. 69, 1166-1174.
Gong, R., Rifai, A., Ge, Y., Chen, S., and Dworkin, L.D. (2008). Hepatocyte growth factor suppresses proinflammatory NFkappaB activation through GSK3beta inactivation in renal tubular epithelial cells. J. Biol. Chem 283, 7401-7410.
Guo, R., Wang, Y., Minto, A.W., Quigg, R.J., and Cunningham, P.N. (2004). Acute renal failure in endotoxemia is dependent on caspase activation. J. Am. Soc. Nephrol. 15, 3093-3102.
Gupta, A., Berg, D.T., Gerlitz, B., Sharma, G.R., Syed, S., Richardson, M.A., Sandusky, G., Heuer, J.G., Galbreath, E.J., and Grinnell, B.W. (2007). Role of protein C in renal dysfunction after polymicrobial sepsis. J. Am. Soc. Nephrol. 18, 860-867.
Haefner, B. (2003). A model for NF-kappa B regulation by GSK-3 beta. Drug Discov Today 8, 1062-1063.
Halfter, U.M., Derbyshire, Z.E., and Vaillancourt, R.R. (2005). Interferon-gamma-dependent tyrosine phosphorylation of MEKK4 via Pyk2 is regulated by annexin II and SHP2 in keratinocytes. The Biochemical journal 388, 17-28.
Held, T.K., Weihua, X., Yuan, L., Kalvakolanu, D.V., and Cross, A.S. (1999). Gamma interferon augments macrophage activation by lipopolysaccharide by two distinct mechanisms, at the signal transduction level and via an autocrine mechanism involving tumor necrosis factor alpha and interleukin-1. Infect Immun 67, 206-212.
Herrero, C., Hu, X., Li, W.P., Samuels, S., Sharif, M.N., Kotenko, S., and Ivashkiv, L.B. (2003). Reprogramming of IL-10 activity and signaling by IFN-gamma. J Immunol 171, 5034-5041.
Henriksen, E.J. and Dokken, B.B. (2006). Role of glycogne synthase kinase-3 in insulin resisitance and type 2 diabetes. Curr. Drug Targets 7, 1435-1441.
Hetman, M., Cavanaugh, J.E., Kimelman, D., and Xia, Z. (2000). Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J. Neurosci. 20, 2567-2574.
Hetman, M., Hsuan, S.L., Habas, A., Higgins, M.J., and Xia, Z. (2002). ERK1/2 antagonizes glycogen synthase kinase-3beta-induced apoptosis in cortical neurons. J. Bio. Chem. 277, 49577-49584.
Hoeflich, K.P., Luo, J., Rubie, E.A., Tsao, M.S., Jin, O., and Woodgett, J.R. (2000). Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406, 86-90.
Hongisto, V., Smeds, N., Brecht, S., Herdegen, T., Courtney, M.J., and Coffey, E.T. (2003). Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol. Cell. Biol. 23, 6027-6036.
Hooper, C., Killick, R., and Lovestone, S. (2008). The GSK3 hypothesis of Alzheimer's disease. J. Neurochem. 104, 1433-1439.
Hotchkiss, R.S., and Karl, I.E. (2003). The pathophysiology and treatment of sepsis. N. Engl J. Med. 348, 138-150.
Hu, X., Paik, P.K., Chen, J., Yarilina, A., Kockeritz, L., Lu, T.T., Woodgett, J.R., and Ivashkiv, L.B. (2006). IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 24, 563-574.
Huang, H.C., and Klein, P.S. (2006). Multiple roles for glycogen synthase kinase-3 as a drug target in Alzheimer's disease. Curr. Drug Targets 7, 1389-1397.
Ivaska, J., Nissinen, L., Immonen, N., Erikson, J.E., Kähäri, V.M., and Heino, J. (2002). Integrin alpha2beta1 promotes activation of protein phosphatase 2A and dephosphorylation of Akt and glycogen synthase kinase 3 beta. Mol. Cell. Biol. 22, 1352-1359.
Jo, S.K., Cha, D.R., Cho, W.Y., Kim, H.K., Chang, K.H., Yun, S.Y., and Won, N.H. (2002). Inflammatory cytokines and lipopolysaccharide induce Fas-mediated apoptosis in renal tubular cells. Nephron 91, 406-415.
Johns, D.G., and Webb, R.C. (1998). TNF-alpha-induced endothelium-independent vasodilation: a role for phospholipase A2-dependent ceramide signaling. The American journal of physiology 275, H1592-1598.
Jope, R.S., and Bijur, G.N. (2002). Mood stabilizers, glycogen synthase kinase-3beta and cell survival. Mol. Psychiatry 7 Suppl 1, S35-45.
Jope, R.S., and Johnson, G.V. (2004). The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci. 29, 95-102.
Jope, R.S., Yuskaitis, C.J., and Beurel, E. (2007). Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem. Res. 32, 577-595.
Karehed, K., Dimberg, A., Dahl, S., Nilsson, K., and Oberg, F. (2007). IFN-gamma-induced upregulation of Fcgamma-receptor-I during activation of monocytic cells requires the PKR and NFkappaB pathways. Mol Immunol 44, 615-624.
Khan, R.Z., and Badr, K.F. (1999). Endotoxin and renal function: perspectives to the instanding of septic acute renal failure and toxic shock. Nephrol. Dial. Transplant. 14, 814-818.
King, T.D., Bijur, G.N., and Jope, R.S. (2001). Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium. Brain Res. 919, 106-114.
Klover, P.J., Zimmers, T.A., Koniaris, L.G., and Mooney, R.A. (2003). Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52, 2784-2789.
Knotek, M., Rogachev, B., Wang, W., Ecder, T., Melnikov, V., Gengaro, P.E., Esson, M., Edelstein, C.L., Dinarello, C.A., and Schrier, R.W. (2001). Endotoxemic renal failure in mice: Role of tumor necrosis factor independent of inducible nitric oxide synthase. Kidney Int. 59, 2243-2249.
Kockeritz, L., Doble, B., Patel, S., and Woodgett, J.R. (2006). Glycogen synthase kinase-3--an overview of an over-achieving protein kinase. Curr Drug Targets 7, 1377-1388.
Koide, N., Narita, K., Kato, Y., Sugiyama, T., Chakravortty, D., Morikawa, A., Yoshida, T., and Yokochi, T. (1999). Expression of Fas and Fas ligand on mouse renal tubular epithelial cells in the generalized shwartzman reaction and its relationship to apoptosis. Infect. and Immun. 67, 4112-4118.
Koide, N., Mu, M.M., Hassan, F., Islam, S., Tumurkhuu, G., Dagvadorj, J., Naiki, Y., Mori, I., Yoshida, T., and Yokochi, T. (2007). Lipopolysaccharide enhances interferon-gamma-induced nitric oxide (NO) production in murine vascular endothelial cells via augmentation of interferon regulatory factor-1 activation. J Endotoxin Res 13, 167-175.
Krebs, D.L., and Hilton, D.J. (2000). SOCS: physiological suppressors of cytokine signaling. J Cell Sci 113 ( Pt 16), 2813-2819.
Kumar, A., Haque, J., Lacoste, J., Hiscott, J., and Williams, B.R. (1994). Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc Natl Acad Sci U S A 91, 6288-6292.
Liao, X., Zhang, L., Thrasher, J.B., Du, J., and Li, B. (2003). Glycogen synthase kinase-3beta suppression eliminates tumor necrosis factor-related apoptosis-inducing ligand resistance in prostate cancer. Molecular cancer therapeutics 2, 1215-1222.
Li, X., Bijur, G.N., and Jope, R.S. (2002). Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord. 4, 137-144.
Lin, C.F., Chen, C.L., Chiang, C.W., Jan, M.S., Huang, W.C., and Lin, Y.S. (2007). Glycogen synthase kinase-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. J. Cell Sci. 120, 2935-2943.
Lin, C.F., Tsai, C.C., Huang, W.C., Wang, C.Y., Tseng, H.C., Wang, Y., Kai, J.I., Wang, S.W., and Cheng, Y.L. (2008). IFN-gamma synergizes with LPS to induce nitric oxide biosynthesis through glycogen synthase kinase-3-inhibited IL-10. Journal of cellular biochemistry 105, 746-755.
Loberg, R.D., Vesely, E., and Brosius, F.C., 3rd (2002). Enhanced glycogen synthase kinase-3beta activity mediates hypoxia-induced apoptosis of vascular smooth muscle cells and is prevented by glucose transport and metabolism. J. Biol. Chem. 277, 41667-41673.
Loisa, P., Rinne, T., Laine, S., Hurme, M., and Kaukinen, S. (2003). Anti-inflammatory cytokine response and the development of multiple organ failure in severe sepsis. Acta. Anaesth. Scand. 47, 319-325.
Lovell, M.A., Xiong, S., Xie, C., Davies, P., and Markesbery, W.R. (2004). Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. J Alzheimers Dis 6, 659-671; discussion 673-681.
Manthey, C.L., and Schuchman, E.H. (1998). Acid sphingomyelinase-derived ceramide is not required for inflammatory cytokine signalling in murine macrophages. Cytokine 10, 654-661.
Marshall, J.C., Vincent, J.L., Fink, M.P., Cook, D.J., Rubenfeld, G., Foster, D., Fisher, C.J., Jr., Faist, E., and Reinhart, K. (2003). Measures, markers, and mediators: toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis Roundtable, Toronto, Ontario, Canada, October 25-26, 2000. Crit. Care Med. 31, 1560-1567.
Martin, G.S., Mannino, D.M., Eaton, S., and Moss, M. (2003). The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546-1554.
Martin, M., Rehani, K., Jope, R.S., and Michalek, S.M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6, 777-784.
Martinez, A., Alonso, M., Castro, A., Perez, C., and Moreno, F.J. (2002). First non-ATP competitive glycogen synthase kinase 3  (GSK-3) inhibitors: thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer’s disease. J. Med. Chem. 45, 1292-1299.
Matsuoka, Y., Picciano, M., Malester, B., LaFrancois, J., Zehr, C., Daeschner, J.M., Olschowka, J.A., Fonseca, M.I., O'Banion, M.K., Tenner, A.J., et al. (2001). Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease. Am. J. Pathol. 158, 1345-1354.
Mendes, C.T., Mury, F.B., de Sa Moreira, E., Alberto, F.L., Forlenza, O.V., Dias-Neto, E., and Gattaz, W.F. (2009). Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease. European archives of psychiatry and clinical neuroscience 259, 16-22.
Messmer, U.K., Briner, V.A., and Pfeilschifter, J. (1999). Tumor necrosis factor-alpha and lipopolysaccharide induce apoptotic cell death in bovine glomerular endothelial cells. Kidney Int. 55, 2322-2337.
Moore, K.W., de Waal Malefyt, R., Coffman, R.L., and O'Garra, A. (2001). Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683-765.
Mora, A., Sabio, G., Risco, A.M., Cuenda, A., Alonso, J.C., Soler, G., and Centeno, F. (2002). Lithium blocks the PKB and GSK3 dephosphorylation induced by ceramide through protein phosphatase-2A. Cellular signalling 14, 557-562.
Nadiri, A., Wolinski, M.K., and Saleh, M. (2006). The inflammatory caspase: key players in the host response to pathogenic invasion and sepsis. J. Immunol. 177, 4239-4245.
Neveu, H., Kleinknecht, D., Brivet, F., Loirat, P., and Landais, P. (1996). Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol. Dial. Transplant. 11, 293-299.
Obligado, S.H., Ibraghimov-Beskrovnaya, O., Zuk, A., Meijer, L., and Nelson, P.J. (2008). CDK/GSK-3 inhibitors as therapeutic agents for parenchymal renal diseases. Kidney Int. 73, 684-690.
O'Farrell, A.M., Liu, Y., Moore, K.W., and Mui, A.L. (1998). IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways. EMBO J. 17, 1006-1018.
Ortiz A, Justo P, Sanz A, Lorz C, and Egido J. (2003). Targeting apoptosis in acute tubular injury. Biochem. Pharmacol. 66, 1589-1594.
Ortiz-Arduan, A., Danoff, T.M., Kalluri, R., Gonzalez-Cuadrado, S., Karp, S.L., Elkon, K., Egido, J., and Neilson, E.G. (1996). Regulation of Fas and Fas ligand expression in cultured murine renal cells and in the kidney during endotoxemia. Am. J. Physiol. 271, F1193-1201.
Ougolkov, A.V., Fernandez-Zapico, M.E., Savoy, D.N., Urrutia, R.A., and Billadeau, D.D. (2005). Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res 65, 2076-2081.
Ougolkov, A.V., and Billadeau, D.D. (2006). Targeting GSK-3: a promising approach for cancer therapy? Future Oncol. 2, 91-100.
Pahan, K., Sheikh, F.G., Khan, M., Namboodiri, A.M., and Singh, I. (1998). Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes. The Journal of biological chemistry 273, 2591-2600.
Pap, M., and Cooper, G.M. (1998). Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J. Bio. Chem. 273, 19929-19932.
Pap, M., and Cooper, G.M. (2002). Role of translation initiation factor 2B in control of cell survival by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta signaling pathway. Mol. Cell. Biol. 22, 578-586.
Pickup, J.C. (2004). Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27, 813-823.
Platanias, L.C. (2005). Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat Rev Immunol 5, 375-386.
Plotnikov, E.Y., Kazachenko, A.V., Vyssokikh M.Y., et al. (2007) The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney. Kidney Int. 72, 1493-1502.
Poljakovic, M., Nygren, J.M., and Persson, K. (2003). Signalling pathways regulating inducible nitric oxide synthase expression in human kidney epithelial cells. Eur. J. Pharmacol. 469, 21-28.
Polychronopoulos, P., Magiatis, P., Skaltsounis A.L., Myrianthopoulos, V., Mikros, E., Tarricone, A., Musacchio, A., Roe, S.M., Pearl, L., Leost, M., et al. (2004). J. Med. Chem. 47, 935-946.
Reynolds, J.L., Ignatowski, T.A., Sud, R., and Spengler, R.N. (2005). An antidepressant mechanism of desipramine is to decrease tumor necrosis factor-alpha production culminating in increases in noradrenergic neurotransmission. Neuroscience 133, 519-531.
Ring, D. B., Johnson, K. W., Henriksen, E. J., Nuss J. M., Goff, D., Kinnick, T. R., Ma, S. T., Reeder, J. W., Samuels, I., Slabiak, T., et al. (2003). Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52, 588-595.
Rossig, L., Badorff, C., Holzmann, Y., Zeiher, A.M., and Dimmeler, S. (2002). Glycogen synthase kinase-3 couples Akt-dependent signaling to the regulation of p21Cip1 degradation. J. Bio. Chem. 277, 9684-9689.
Russell, J.A. (2006). Management of sepsis. N. Engl. J. Med. 355, 1699-1713.
Ryves, W.J., and Harwood A.J. (2001). Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem. Biophys. Res. Commun. 280, 720-725.
Ruvolo, P.P., Deng, X., Ito, T., Carr, B.K., and May, W.S. (1999). Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. The Journal of biological chemistry 274, 20296-20300.
Ruvolo, P.P. (2001). Ceramide regulates cellular homeostasis via diverse stress signaling pathways. Leukemia 15, 1153-1160.
Sands, W.A., Clark, J.S., and Liew, F.Y. (1994). The role of a phosphatidylcholine-specific phospholipase C in the production of diacylglycerol for nitric oxide synthesis in macrophages activated by IFN-gamma and LPS. Biochem Biophys Res Commun 199, 461-466.
Sastre, M., Klockgether, T., and Heneka, M.T. (2006). Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int. J. Dev. Neurosci. 24, 167-176.
Sayas, C.L., Ariaens, A., Ponsioen, B., and Moolenaar, W.H. (2006). GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction. Molecular biology of the cell 17, 1834-1844.
Schaper, F., Gendo, C., Eck, M., Schmitz, J., Grimm, C., Anhuf, D., Kerr, I.M., and Heinrich, P.C. (1998). Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression. The Biochemical journal 335 ( Pt 3), 557-565.
Schiepers, O.J., Wichers, M.C., and Maes, M. (2005). Cytokines and major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 201-217.
Schmidt, C., Hocherl, K., and Bucher, M. (2007a). Cytokine-mediated regulation of urea transporters during experimental endotoxemia. Am. J. Physiol. 292, F1479-F1489.
Schmidt, C., Hocherl, K., and Bucher, M. (2007b). Regulation of renal glucose transporters during severe inflammation. Am. J. Physiol. 292, F804-F811.
Schmidt, C., Hocherl, K., Schweda, F., and Bucher, M. (2007c). Proinflammatory cytokines cause down-regulation of renal chloride entry pathways during sepsis. Crit. Care Med. 35, 2110-2119.
Schrier, R.W., and Wang, W. (2004). Acute renal failure and sepsis. N. Engl. J. Med. 351, 159-169.
Schoenborn, J.R., and Wilson, C.B. (2007). Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol 96, 41-101.
Schroder, K., Hertzog, P.J., Ravasi, T., and Hume, D.A. (2004). Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol 75, 163-189.
Schwabe, R.F., and Brenner, D.A. (2002). Role of glycogen synthase kinase-3 in TNF-alpha-induced NF-kappaB activation and apoptosis in hepatocytes. American journal of physiology 283, G204-211.
Sebaldt, R.J., Prpic, V., Hollenbach, P.W., Adams, D.O., and Uhing, R.J. (1990). IFN-gamma potentiates the accumulation of diacylglycerol in murine macrophages. J Immunol 145, 684-689.
Seeling J.M., Miller, J.R., Gil, R., Moon, R.T., White, R., and Virshup, D.M. (1999). Regulation of beta-Catenin signaling by the B56 subunit of protein phosphatase 2A. Science. 283, 2089-2091.
Somervaille, T.C., Linch, D.C., and Khwaja, A. (2001). Growth factor withdrawal from primary human erythroid progenitors induces apoptosis through a pathway involving glycogen synthase kinase-3 and Bax. Blood 98, 1374-1381.
Song, M.M., and Shuai, K. (1998). The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. The Journal of biological chemistry 273, 35056-35062.
Song, G.Y., Chung, C.S., Chaudry, I.H., and Ayala, A. (1999). What is the role of interleukin 10 in polymicrobial sepsis: anti-inflammatory agent or immunosuppressant? Surgery 126, 378-383.
Song, L., De Sarno, P., and Jope, R.S. (2002). Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation. J. Biol. Chem. 277, 44701-44708.
Soos, T.J., Meijer, L., and Nelson, P.J. (2006). CDK/GSK-3 inhibitors as a new approach for the treatment of proliferative renal diseases. Drug News Perspect. 19, 325-328.
Su, Q., Wang, S., Baltzis, D., Qu, L.K., Raven, J.F., Li, S., Wong, A.H., and Koromilas, A.E. (2007). Interferons induce tyrosine phosphorylation of the eIF2alpha kinase PKR through activation of Jak1 and Tyk2. EMBO Rep 8, 265-270.
Takada, Y., Fang, X., Jamaluddin, M.S., Boyd, D.D., and Aggarwal, B.B. (2004). Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. J. Biol. Chem. 279, 39541-39554.
Testard, A., Loge, C., Leger, B., Robert, J.M., Lozach, O., Blairvacq, M., Meijer, L., Thiery, V., and Besson, T. (2006). Thiazolo[5,4-f]quinazolin-9-ones, inhibitors of glycogen synthase kinase-3. Bioorganic & medicinal chemistry letters 16, 3419-3423.
Thadhani, R., Pascual, M., and Bonventre, J.V. (1996). Acute renal failure. N. Engl. J. Med. 334, 1448-1460.
Trinchieri, G., and Sher, A. (2007). Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7, 179-190.
Tsai, C.C., Lin, C.F. (2009) Glycogen Synthase Kinase-3 Facilitates IFN--induced STAT1 Activation by Regulating Src Homology-2 Domain-containing Phosphatase 2. J.Immunol.
Uchino, S., Kellum, J.A., Bellomo, R., Doig, G.S., Morimatsu, H., Morgera, S., Schetz, M., Tan, I., Bouman, C., Macedo, E., et al. (2005). Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294, 813-818.
Uysal, K.T., Wiesbrock, S.M., Marino, M.W., and Hotamisligil, G.S. (1997). Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610-614.
van der Poll, T., Marchant, A., Buurman, W.A., Berman, L., Keogh, C.V., Lazarus, D.D., Nguyen, L., Goldman, M., Moldawer, L.L., and Lowry, S.F. (1995). Endogenous IL-10 protects mice from death during septic peritonitis. J. Immunol. 155, 5397-5401.
Visnjic, D., Batinic, D., and Banfic, H. (1997). Arachidonic acid mediates interferon-gamma-induced sphingomyelin hydrolysis and monocytic marker expression in HL-60 cell line. Blood 89, 81-91.
Wan, L., Bagshaw, S.M., Langenberg, C., Saotome, T., May, C., and Bellomo, R. (2008). Pathophysiology of septic acute kidney injury: what do we really know? Crit. Care Med. 36, S198-S203.
Wan, L., Bellomo, R., Di Giantomasso, D., and Ronco, C. (2003). The pathogenesis of septic acute renal failure. Curr. Opin. Crit. Care 9, 496-502.
Wang, Q.M., Fiol, C.J., DePaoli-Roach, A.A., and Roach, P.J. (1994). Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. The Journal of biological chemistry 269, 14566-14574.
Wang, L., Tassiulas, I., Park-Min, K.H., Reid, A.C., Gil-Henn, H., Schlessinger, J., Baron, R., Zhang, J.J., and Ivashkiv, L.B. (2008). 'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nat Immunol 9, 186-193.
Watanabe, M.A., Rodrigues Souza, L., Murad, J.M., and De Lucca, F.L. (2003). Antitumor activity induced by regulatory RNA: possible role of RNA-dependent protein kinase and nuclear factor-kappaB. Eur J Pharmacol 465, 205-210.
Watcharasit, P., Bijur, G.N., Song, L., Zhu, J., Chen, X., and Jope, R.S. (2003). Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the action of p53. J. Bio. Chem. 278, 48872-48879.
Wen, Z., Zhong, Z., and Darnell, J.E., Jr. (1995). Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241-250.
Whittle, B.J., Varga, C., Posa, A., Molnar, A., Collin, M., and Thiemermann, C. (2006). Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3beta. Br. J. Pharmacol. 147, 575-582.
Wong, A.H., Durbin, J.E., Li, S., Dever, T.E., Decker, T., and Koromilas, A.E. (2001). Enhanced antiviral and antiproliferative properties of a STAT1 mutant unable to interact with the protein kinase PKR. The Journal of biological chemistry 276, 13727-13737.
Woodgett, J.R., and Ohashi, P.S. (2005). GSK3: an in-Toll-erant protein kinase? Nat. Immunol. 6, 751-752.
Wu, X., Guo, R., Wang, Y., and Cunningham, P.N. (2007). The role of ICAM-1 in endotoxin-induced acute renal failure. Am. J. Physiol. 293, F1262-F1271.
Yin, T., Shen, R., Feng, G.S., and Yang, Y.C. (1997). Molecular characterization of specific interactions between SHP-2 phosphatase and JAK tyrosine kinases. The Journal of biological chemistry 272, 1032-1037.
You, M., Yu, D.H., and Feng, G.S. (1999). Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol Cell Biol 19, 2416-2424.
Zhang, Y.J., Xu, Y.F., Liu, Y.H., Yin, J., and Wang, J.Z. (2005). Nitric oxide induces tau hyperphosphorylation via glycogen synthase kinase-3beta activation. FEBS letters 579, 6230-6236.
Zamanian-Daryoush, M., Mogensen, T.H., DiDonato, J.A., and Williams, B.R. (2000). NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaB-inducing kinase and IkappaB kinase. Mol Cell Biol 20, 1278-1290.
Zamorano, J., Rivas, M.D., Garcia-Trinidad, A., Qu, C.K., and Keegan, A.D. (2003). Phosphatidylcholine-specific phospholipase C activity is necessary for the activation of STAT6. J Immunol 171, 4203-4209.