Potential roles of the NFkappaB and glutathione pathways in mature human erythrocytes

• Autorzy: Ghashghaeinia M. , Toulany M. , Saki M. , Rodemann H. P. , Mrowietz U. , Lang F. , Wieder T.
• Języki publikacji: EN

Abstrakty

EN

Anucleated erythrocytes were long considered as oxygen-transporting cells with limited regulatory functions. Components of different nuclear signaling pathways have not been investigated in those cells, yet. Surprisingly, we repeatedly found significant amounts of transcription factors in purified erythrocyte preparations, i.e. nuclear factor κB (NFκB), and major components of the canonical NFκB signaling pathway. To investigate the functional role of NFκB signaling, the effects of the preclinical compounds Bay 11-7082 and parthenolide on the survival of highly purified erythrocytes were investigated. Interestingly, both inhibitors of the NFκB pathway triggered erythrocyte programmed cell death as demonstrated by enhanced phospholipid scrambling (phosphatidylserine exposure) and cell shrinkage. Anucleated erythrocytes are an ideal cellular model allowing the study of nongenomic mechanisms contributing to suicidal cell death. As NFκB inhibitors might also interfere with the anti-oxidative defense systems of the cell, we measured the levels of reduced glutathione (GSH) after challenge with the inhibitors. Indeed, incubation of erythrocytes with Bay 11-7082 clearly decreased erythrocyte GSH levels. In conclusion, the pharmacological inhibitors of the NFκB pathway Bay 11-7082 and parthenolide interfere with the survival of erythrocytes involving mechanisms other than disruption of NFκB-dependent gene expression. Besides affecting erythrocyte survival, NFκB inhibition and induction of erythrocyte phosphatidylserine exposure may influence blood clotting. Future studies will be aimed at discriminating between NFκB-dependent and NFκB-independent GSH-mediated effects of Bay 11-7082 and parthenolide on erythrocyte death.

Słowa kluczowe

EN

glutathione; mature erythrocyte; human erythrocyte; erythrocyte; glycoprotein; nuclear factor-kappaB; calcium; extracellular signal-regulated kinase 2; adhesion molecule; interferon-gamma; interleukin 6; interleukin 8; phosphatidylserine

• Wydawca: -
• Czasopismo: Cellular and Molecular Biology Letters
• Rocznik: 2012
• Tom: 17
• Numer: 1
• Opis fizyczny: p.11-20,fig.,ref.

Twórcy

autor

Ghashghaeinia M.

• Department of Physiology, Eberhard Karls University Tubingen, Gmelinstr. 5, D-72076 Tubingen, Germany

autor

Toulany M.

autor

Saki M.

autor

Rodemann H. P.

autor

Mrowietz U.

autor

Lang F.

autor

Wieder T.

Bibliografia

• 1. Sen, R. and Baltimore, D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46 (1986) 705-716.
• 2. Ghosh, S. and Karin, M. Missing pieces in the NF-kappaB puzzle. Cell 109 Suppl (2002) S81-S96.
• 3. Hayden, M.S. and Ghosh, S. Signaling to NF-kappaB. Genes Dev. 18 (2004) 2195-2224.
• 4. Hayden, M.S. and Ghosh, S. NF-kappaB in immunobiology. Cell. Res. 21 (2011) 223-244.
• 5. Sun, S.C. Non-canonical NF-kappaB signaling pathway. Cell. Res. 21 (2011) 71-85.
• 6. Ghashghaeinia, M., Toulany, M., Saki, M., Bobbala, D., Fehrenbacher, B., Rupec, R., Rodemann, H.P., Ghoreschi, K., Rocken, M., Schaller, M., Lang, F. and Wieder, T. The NFkB pathway inhibitors Bay 11-7082 and parthenolide induce programmed cell death in anucleated Erythrocytes. Cell. Physiol. Biochem. 27 (2011) 45-54.
• 7. Neelam, S., Kakhniashvili, D.G., Wilkens, S., Levene, S.D. and Goodman, S.R. Functional 20S proteasomes in mature human red blood cells. Exp. Biol. Med. (Maywood.) 236 (2011) 580-591.
• 8. Gilmore, T.D. and Herscovitch, M. Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 25 (2006) 6887-6899.
• 9. Pierce, J.W., Schoenleber, R., Jesmok, G., Best, J., Moore, S.A., Collins, T. and Gerritsen, M.E. Novel inhibitors of cytokine-induced IkappaBalpha phosphorylation and endothelial cell adhesion molecule expression show anti-inflammatory effects in vivo. J. Biol. Chem. 272 (1997) 21096-21103.
• 10. Kwok, B.H., Koh, B., Ndubuisi, M.I., Elofsson, M. and Crews, C.M. The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem. Biol. 8 (2001) 759-766.
• 11. Garcia-Pineres, A.J., Castro, V., Mora, G., Schmid,t T.J., Strunck, E., Pahl, H.L. and Merfort, I. Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J. Biol. Chem. 276 (2001) 39713-39720.
• 12. Garcia-Pineres, A.J., Lindenmeyer, M.T. and Merfort, I. Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential. Life Sci. 75 (2004) 841-856.
• 13. Wagner, S., Hofmann, A., Siedle, B., Terfloth, L., Merfort, I. and Gasteiger, J. Development of a structural model for NF-kappaB inhibition of sesquiterpene lactones using self-organizing neural networks. J. Med. Chem. 49 (2006) 2241-2252.
• 14. Foller, M., Bobbala, D., Koka, S., Huber, S.M., Gulbins, E. and Lang, F. Suicide for survival--death of infected erythrocytes as a host mechanism to survive malaria. Cell. Physiol. Biochem. 24 (2009) 133-140.
• 15. Lang, F., Lang, K.S., Lang, P.A., Huber, S.M. and Wieder, T. Mechanisms and significance of eryptosis. Antioxid. Redox. Signal. 8 (2006) 1183-1192.
• 16. Lang, F., Gulbins, E., Lang, P.A., Zappulla, D. and Foller, M. Ceramide in suicidal death of erythrocytes. Cell. Physiol. Biochem. 26 (2010) 21-28.
• 17. Koprowska, K. and Czyz, M. Molecular mechanisms of parthenolide's action: Old drug with a new face. Postepy Hig. Med. Dosw. 64 (2010) 100-114.
• 18. Wen, J., You, K.R., Lee, S.Y., Song, C.H. and Kim, D.G. Oxidative stressmediated apoptosis. The anticancer effect of the sesquiterpene lactone parthenolide. J. Biol. Chem. 277 (2002) 38954-38964.
• 19. Zhang, S., Ong, C.N. and Shen, H.M. Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells. Cancer Lett. 208 (2004) 143-153.
• 20. Pasparakis, M., Luedde, T. and Schmidt-Supprian, M. Dissection of the NF-kappaB signalling cascade in transgenic and knockout mice. Cell Death Differ. 13 (2006) 861-872.
• 21. Snapper, C.M., Zelazowski, P., Rosas, F.R., Kehry, M.R., Tian, M., Baltimore, D. and Sha, W.C. B cells from p50/NF-kappa B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J. Immunol. 156 (1996) 183-191.
• 22. Spinelli, S.L., Casey, A.E., Pollock, S.J., Gertz, J.M., McMillan, D.H., Narasipura, S.D., Mody, N.A., King, M.R., Maggirwar, S.B., Francis, C.W., Taubman, M.B., Blumberg, N. and Phipps, R.P. Platelets and megakaryocytes contain functional nuclear factor-kappaB. Arterioscler. Thromb. Vasc. Biol. 30 (2010) 591-598.
• 23. Morel, O., Jesel, L., Freyssinet, J.M. and Toti, F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler. Thromb. Vasc. Biol. 31 (2011) 15-26.
• 24. Malaver, E., Romaniuk, M.A., D'Atri, L.P., Pozner, R.G., Negrotto, S., Benzadon, R. and Schattner, M. NF-kappaB inhibitors impair platelet activation responses. J. Thromb. Haemost. 7 (2009) 1333-1343.
• 25. Lee, H.S., Kim, S.D., Lee, W.M., Endale, M., Kamruzzaman, S.M., Oh, W.J., Cho, J.Y., Kim, S.K., Cho, H.J., Park, H.J. and Rhee, M.H. A noble function of BAY 11-7082: Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations. Eur. J. Pharmacol. 627 (2010) 85-91.
• 26. Guo, M., Sahni, S.K., Sahni, A. and Francis, C.W. Fibrinogen regulates the expression of inflammatory chemokines through NF-kappaB activation of endothelial cells. Thromb. Haemost. 92 (2004) 858-866.
• 27. Sahler, J., Bernard, J.J., Spinelli, S.L., Blumberg, N. and Phipps, R.P. The Feverfew plant-derived compound, parthenolide enhances platelet production and attenuates platelet activation through NF-kappaB inhibition. Thromb. Res. 127 (2011) 426-434.
• 28. Groenewegen, W.A. and Heptinstall, S. A comparison of the effects of an extract of feverfew and parthenolide, a component of feverfew, on human platelet activity in-vitro. J. Pharm. Pharmacol. 42 (1990) 553-557.
• 29. Matsuda, S., Ikeda, Y., Aoki, M., Toyama, K., Watanabe, K. and Ando, Y. Role of reduced glutathione on platelet functions. Thromb. Haemost. 42 (1979) 1324-1331.
• 30. Fadok, V.A., Bratton, D.L., Rose, D.M., Pearson, A., Ezekewitz, R.A. and Henson, P.M. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405 (2000) 85-90.
• 31. Steffen, P., Jung, A., Nguyen, D.B., Muller, T., Bernhardt, I., Kaestner, L. and Wagner, C. Stimulation of human red blood cells leads to Ca(2+)- mediated intercellular adhesion. Cell. Calcium 50 (2011) 54-61.
• 32. Kaestner, L., Tabellion, W., Lipp, P. and Bernhardt, I. Prostaglandin E2 activates channel-mediated calcium entry in human erythrocytes: an indication for a blood clot formation supporting process. Thromb. Haemost. 92 (2004) 1269-1272.
• 33. Lang, K.S., Roll, B., Myssina, S., Schittenhelm, M., Scheel-Walter, H.G., Kanz, L., Fritz, J., Lang, F., Huber, S.M. and Wieder, T. Enhanced erythrocyte apoptosis in sickle cell anemia, thalassemia and glucose-6- phosphate dehydrogenase deficiency. Cell. Physiol. Biochem. 12 (2002) 365-372.
• 34. Lang, P.A., Kasinathan, R.S., Brand, V.B., Duranton, C., Lang, C., Koka, S., Shumilina, E., Kempe, D.S., Tanneur, V., Akel, A., Lang, K.S., Foller, M., Kun, J.F., Kremsner, P.G., Wesselborg, S., Laufer, S., Clemen, C.S., Herr, C., Noegel, A.A., Wieder, T., Gulbins, E., Lang, F. and Huber, S.M. Accelerated clearance of Plasmodium-infected erythrocytes in sickle cell trait and annexin-A7 deficiency. Cell. Physiol. Biochem. 24 (2009) 415-428.
• 35. Dangel, O. [Wirkung von Stickstoffmonoxid auf die Thrombozytenfunktion von Guanylyl-Cyclase defizienten Mäusen. Lehrstuhl für Pharmakologie und Toxikologie der Fakultät für Medizin] Bochum (2007) 24.