The Phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 modulates cytokine expression in macrophages via p50 nuclear factor kappa B inhibition, in a PI3K-independent mechanism

Biochemical Pharmacology

Volumn 83, Issue 1, 2012, Pages 106-114

  Avni, Dorit ^a   Glucksam, Yifat ^a   Zor, Tsaffrir ^a  

^a TEL AVIV UNIVERSITY   (Israel)

Author keywords

LY294002; LY303511; Macrophages; p50 NF kappa B; Phosphatidylinositol 3 kinase

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 10; LIPOPOLYSACCHARIDE; LY 303511; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; TRANSCRIPTION FACTOR RELA; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; WORTMANNIN;

ANIMAL CELL; ARTICLE; CYTOKINE PRODUCTION; DELETION MUTANT; HUMAN; HUMAN CELL; MACROPHAGE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REPORTER GENE;

ANIMALS; CELL LINE; CHROMONES; CYTOKINES; GENE EXPRESSION REGULATION; HUMANS; INTERLEUKIN-10; MACROPHAGES; MICE; MORPHOLINES; NF-KAPPA B P50 SUBUNIT; PHOSPHATIDYLINOSITOL 3-KINASES;

EID: 81855161724     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2011.09.025     Document Type: Article

References (72)

1. M.S. Hayden, and S. Ghosh Shared principles in NF-kappaB signaling Cell 132 3 2008 344 362
2. S. Vallabhapurapu, and M. Karin Regulation and function of NF-kappaB transcription factors in the immune system Annu Rev Immunol 27 2009 693 733
3. J. Bohuslav, V.V. Kravchenko, G.C. Parry, J.H. Erlich, S. Gerondakis, and N. Mackman Regulation of an essential innate immune response by the p50 subunit of NF-kappaB J Clin Invest 102 9 1998 1645 1652
4. H. Liu, P. Sidiropoulos, G. Song, L.J. Pagliari, M.J. Birrer, and B. Stein TNF-alpha gene expression in macrophages: regulation by NF-kappa B is independent of c-Jun or C/EBP beta J Immunol 164 8 2000 4277 4285
5. J. Yao, N. Mackman, T.S. Edgington, and S.T. Fan Lipopolysaccharide induction of the tumor necrosis factor-alpha promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-kappaB transcription factors J Biol Chem 272 28 1997 17795 17801
6. M.J. May, and S. Ghosh Rel/NF-kappa B and I kappa B proteins: an overview Semin Cancer Biol 8 2 1997 63 73
7. S. Cao, X. Zhang, J.P. Edwards, and D.M. Mosser NF-kappaB1 (p50) homodimers differentially regulate pro-and anti-inflammatory cytokines in macrophages J Biol Chem 281 36 2006 26041 26050
8. D. Kong, and T. Yamori Phosphatidylinositol 3-kinase inhibitors: promising drug candidates for cancer therapy Cancer Sci 99 9 2008 1734 1740
9. E.H. Walker, M.E. Pacold, O. Perisic, L. Stephens, P.T. Hawkins, and M.P. Wymann Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine Mol Cell 6 4 2000 909 919
10. B. Salh, R. Wagey, A. Marotta, J.S. Tao, and S. Pelech Activation of phosphatidylinositol 3-kinase, protein kinase B, and p70 S6 kinases in lipopolysaccharide-stimulated Raw 264.7 cells: differential effects of rapamycin, Ly294002, and wortmannin on nitric oxide production J Immunol 161 12 1998 6947 6954
11. Y.H. Kim, K.H. Choi, J.W. Park, and T.K. Kwon LY294002 inhibits LPS-induced NO production through a inhibition of NF-kappaB activation: independent mechanism of phosphatidylinositol 3-kinase Immunol Lett 99 1 2005 45 50
12. C.J. Vlahos, W.F. Matter, K.Y. Hui, and R.F. Brown A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4- one (LY294002) J Biol Chem 269 7 1994 5241 5248
13. H.D. Brightbill, S.E. Plevy, R.L. Modlin, and S.T. Smale A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages J Immunol 164 4 2000 1940 1951
14. E.R. Smith, P.L. Jones, J.M. Boss, and A.H. Merrill Jr. Changing J774A.1 cells to new medium perturbs multiple signaling pathways, including the modulation of protein kinase C by endogenous sphingoid bases J Biol Chem 272 9 1997 5640 5646
15. M. Goldsmith, D. Avni, G. Levy-Rimler, R. Mashiach, O. Ernst, and M. Levi A ceramide-1-phosphate analogue, PCERA-1, simultaneously suppresses tumour necrosis factor (TNF)-α and induces interleukin (IL)-10 production in activated macrophages Immunology 127 2009 103 115
16. T. Zor, and Z. Selinger Linearization of the Bradford protein assay increases its sensitivity: theoretical and experimental studies Anal Biochem 236 2 1996 302 308
17. O. Ernst, and T. Zor Linearization of the bradford protein assay J Vis Exp 38 2010 10.3791/1918 http://www.jove.com/index/details.stp?id=1918
18. M. Goldsmith, D. Avni, O. Ernst, Y. Glucksam, G. Levy-Rimler, and M.M. Meijler Synergistic IL-10 induction by LPS and the ceramide-1-phosphate analog PCERA-1 is mediated by the cAMP and p38 MAP kinase pathways Mol Immunol 46 10 2009 1979 1987
19. M. Martin, K. Rehani, R.S. Jope, and S.M. Michalek Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3 Nat Immunol 6 8 2005 777 784
20. S.K. Biswas, and E. Lopez-Collazo Endotoxin tolerance: new mechanisms, molecules and clinical significance Trends Immunol 30 10 2009 475 487
21. T.W. Poh, S. Huang, J.L. Hirpara, and S. Pervaiz LY303511 amplifies TRAIL-induced apoptosis in tumor cells by enhancing DR5 oligomerization, DISC assembly, and mitochondrial permeabilization Cell Death Differ 14 10 2007 1813 1825
22. T.W. Poh, and S. Pervaiz LY294002 and LY303511 sensitize tumor cells to drug-induced apoptosis via intracellular hydrogen peroxide production independent of the phosphoinositide 3-kinase-Akt pathway Cancer Res 65 14 2005 6264 6274
23. K. Shenoy, Y. Wu, and S. Pervaiz LY303511 enhances TRAIL sensitivity of SHEP-1 neuroblastoma cells via hydrogen peroxide-mediated mitogen-activated protein kinase activation and up-regulation of death receptors Cancer Res 69 5 2009 1941 1950
24. V. Kolenko, T. Bloom, P. Rayman, R. Bukowski, E. Hsi, and J. Finke Inhibition of NF-kappa B activity in human T lymphocytes induces caspase-dependent apoptosis without detectable activation of caspase-1 and-3 J Immunol 163 2 1999 590 598
25. S.G. Pereira, and F. Oakley Nuclear factor-kappaB1: regulation and function Int J Biochem Cell Biol 40 8 2008 1425 1430
26. G. Powis, R. Bonjouklian, M.M. Berggren, A. Gallegos, R. Abraham, and C. Ashendel Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3- kinase Cancer Res 54 9 1994 2419 2423
27. M.P. Wymann, G. Bulgarelli-Leva, M.J. Zvelebil, L. Pirola, B. Vanhaesebroeck, and M.D. Waterfield Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction Mol Cell Biol 16 4 1996 1722 1733
28. C. Platzer, C. Meisel, K. Vogt, M. Platzer, and H.D. Volk Up-regulation of monocytic IL-10 by tumor necrosis factor-alpha and cAMP elevating drugs Int Immunol 7 4 1995 517 523
29. S.K. Polumuri, V.Y. Toshchakov, and S.N. Vogel Role of phosphatidylinositol-3 kinase in transcriptional regulation of TLR-induced IL-12 and IL-10 by Fc gamma receptor ligation in murine macrophages J Immunol 179 1 2007 236 246
30. S.Y. Cho, S.J. Park, M.J. Kwon, T.S. Jeong, S.H. Bok, and W.Y. Choi Quercetin suppresses proinflammatory cytokines production through MAP kinases andNF-kappaB pathway in lipopolysaccharide-stimulated macrophage Mol Cell Biochem 243 1-2 2003 153 160
31. Y. Ishikawa, H. Sugiyama, E. Stylianou, and M. Kitamura Bioflavonoid quercetin inhibits interleukin-1-induced transcriptional expression of monocyte chemoattractant protein-1 in glomerular cells via suppression of nuclear factor-kappaB J Am Soc Nephrol 10 11 1999 2290 2296
32. S. Kastenbauer, and H.W. Ziegler-Heitbrock NF-kappaB1 (p50) is upregulated in lipopolysaccharide tolerance and can block tumor necrosis factor gene expression Infect Immun 67 4 1999 1553 1559
33. M.A. Collart, P. Baeuerle, and P. Vassalli Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B Mol Cell Biol 10 4 1990 1498 1506
34. J. Wang, X. Wang, S. Hussain, Y. Zheng, S. Sanjabi, and F. Ouaaz Distinct roles of different NF-kappa B subunits in regulating inflammatory and T cell stimulatory gene expression in dendritic cells J Immunol 178 11 2007 6777 6788
35. J. Wessells, M. Baer, H.A. Young, E. Claudio, K. Brown, and U. Siebenlist BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages J Biol Chem 279 48 2004 49995 50003
36. E.K. Choi, H.J. Park, J.S. Ma, H.C. Lee, H.C. Kang, and B.G. Kim LY294002 inhibits monocyte chemoattractant protein-1 expression through a phosphatidylinositol 3-kinase-independent mechanism FEBS Lett 559 1-3 2004 141 144
37. H. Sun, B. Xu, E. Sheveleva, and Q.M. Chen LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism Toxicol Appl Pharmacol 232 1 2008 25 32
38. K. Yamaguchi, S.H. Lee, J.S. Kim, J. Wimalasena, S. Kitajima, and S.J. Baek Activating transcription factor 3 and early growth response 1 are the novel targets of LY294002 in a phosphatidylinositol 3-kinase-independent pathway Cancer Res 66 4 2006 2376 2384
39. P. Liu, B. Xu, J. Li, and H. Lu LY294002 inhibits leukemia cell invasion and migration through early growth response gene 1 induction independent of phosphatidylinositol 3-kinase-Akt pathway Biochem Biophys Res Commun 377 1 2008 187 190
40. C.H. Tsai-Morris, X.M. Cao, and V.P. Sukhatme 5′ flanking sequence and genomic structure of Egr-1, a murine mitogen inducible zinc finger encoding gene Nucleic Acids Res 16 18 1988 8835 8846
41. G. Liang, C.D. Wolfgang, B.P. Chen, T.H. Chen, and T. Hai ATF3 gene. Genomic organization, promoter, and regulation J Biol Chem 271 3 1996 1695 1701
42. T. Martin, P.M. Cardarelli, G.C. Parry, K.A. Felts, and R.R. Cobb Cytokine induction of monocyte chemoattractant protein-1 gene expression in human endothelial cells depends on the cooperative action of NF-kappa B and AP-1 Eur J Immunol 27 5 1997 1091 1097
43. W. Xiao, D.R. Hodge, L. Wang, X. Yang, X. Zhang, and W.L. Farrar Co-operative functions between nuclear factors NFkappaB and CCAT/enhancer- binding protein-beta (C/EBP-beta) regulate the IL-6 promoter in autocrine human prostate cancer cells Prostate 61 4 2004 354 370
44. L.J. Crofford, B. Tan, C.J. McCarthy, and T. Hla Involvement of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression by interleukin-1 in rheumatoid synoviocytes Arthritis Rheum 40 2 1997 226 236
45. M. Brodsky, G. Halpert, M. Albeck, and B. Sredni The anti-inflammatory effects of the tellurium redox modulating compound, AS101, are associated with regulation of NFkappaB signaling pathway and nitric oxide induction in macrophages J Inflamm (Lond) 7 1 2010 3
46. Z. Yu, W. Zhang, and B.C. Kone Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB Biochem J 367 Pt 1 2002 97 105
47. Y.J. Kang, B.A. Wingerd, T. Arakawa, and W.L. Smith Cyclooxygenase-2 gene transcription in a macrophage model of inflammation J Immunol 177 11 2006 8111 8122
48. M. Guha, and N. Mackman The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells J Biol Chem 277 35 2002 32124 32132
49. G.J. Brunn, J. Williams, C. Sabers, G. Wiederrecht, J.C. Lawrence Jr., and R.T. Abraham Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002 EMBO J 15 19 1996 5256 5267
50. R.A. Izzard, S.P. Jackson, and G.C. Smith Competitive and noncompetitive inhibition of the DNA-dependent protein kinase Cancer Res 59 11 1999 2581 2586
51. M.D. Jacobs, J. Black, O. Futer, L. Swenson, B. Hare, and M. Fleming Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002 J Biol Chem 280 14 2005 13728 13734
52. S.P. Davies, H. Reddy, M. Caivano, and P. Cohen Specificity and mechanism of action of some commonly used protein kinase inhibitors Biochem J 351 Pt 1 2000 95 105
53. S.I. Gharbi, M.J. Zvelebil, S.J. Shuttleworth, T. Hancox, N. Saghir, and J.F. Timms Exploring the specificity of the PI3K family inhibitor LY294002 Biochem J 404 1 2007 15 21
54. N. Andina, S. Didichenko, J. Schmidt-Mende, C.A. Dahinden, and H.U. Simon Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade initiated by IL-5 in eosinophils J Allergy Clin Immunol 123 3 2009 603 611
55. F. Demarchi, C. Bertoli, P. Sandy, and C. Schneider Glycogen synthase kinase-3 beta regulates NF-kappa B1/p105 stability J Biol Chem 278 41 2003 39583 39590
56. J.A. McElhinny, S.A. Trushin, G.D. Bren, N. Chester, and C.V. Paya Casein kinase II phosphorylates I kappa B alpha at S-283, S-289, S-293, and T-291 and is required for its degradation Mol Cell Biol 16 3 1996 899 906
57. E.M. Schwarz, D. Van Antwerp, and I.M. Verma Constitutive phosphorylation of IkappaBalpha by casein kinase II occurs preferentially at serine 293: requirement for degradation of free IkappaBalpha Mol Cell Biol 16 7 1996 3554 3559
58. J. Shen, P. Channavajhala, D.C. Seldin, and G.E. Sonenshein Phosphorylation by the protein kinase CK2 promotes calpain-mediated degradation of IkappaBalpha J Immunol 167 9 2001 4919 4925
59. S. Ali, N.N. Singh, H. Yildirim, and D.P. Ramji Requirement for nuclear factor kappa B signalling in the interleukin-1-induced expression of the CCAAT/enhancer binding protein-delta gene in hepatocytes Int J Biochem Cell Biol 42 1 2010 113 119
60. R. Romieu-Mourez, E. Landesman-Bollag, D.C. Seldin, and G.E. Sonenshein Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells Cancer Res 62 22 2002 6770 6778
61. T.A. Lodie, R. Savedra Jr., D.T. Golenbock, C.P. Van Beveren, R.A. Maki, and M.J. Fenton Stimulation of macrophages by lipopolysaccharide alters the phosphorylation state, conformation, and function of PU.1 via activation of casein kinase II J Immunol 158 4 1997 1848 1856
62. F. Chen, Y. Lu, D.C. Kuhn, M. Maki, X. Shi, and S.C. Sun Calpain contributes to silica-induced I kappa B-alpha degradation and nuclear factor-kappa B activation Arch Biochem Biophys 342 2 1997 383 388
63. G.S. Kim, J.E. Jung, K. Niizuma, and P.H. Chan CK2 is a novel negative regulator of NADPH oxidase and a neuroprotectant in mice after cerebral ischemia J Neurosci 29 47 2009 14779 14789
64. O. Kutuk, and H. Basaga Aspirin prevents apoptosis and NF-kappaB activation induced by H2O2 in hela cells Free Radic Res 37 12 2003 1267 1276
65. J. Zhang, G. Johnston, B. Stebler, and E.T. Keller Hydrogen peroxide activates NFkappaB and the interleukin-6 promoter through NFkappaB-inducing kinase Antioxid Redox Signal 3 3 2001 493 504
66. V.N. Ivanov, G. Deng, E.R. Podack, and T.R. Malek Pleiotropic effects of Bcl-2 on transcription factors in T cells: potential role of NF-kappa B p50-p50 for the anti-apoptotic function of Bcl-2 Int Immunol 7 11 1995 1709 1720
67. J.A. Royds, S.K. Dower, E.E. Qwarnstrom, and C.E. Lewis Response of tumour cells to hypoxia: role of p53 and NFkB Mol Pathol 51 2 1998 55 61
68. Z. Yu, D. Zhou, A.J. Bruce-Keller, M.S. Kindy, and M.P. Mattson Lack of the p50 subunit of nuclear factor-kappaB increases the vulnerability of hippocampal neurons to excitotoxic injury J Neurosci 19 20 1999 8856 8865
69. W. El-Kholy, P.E. Macdonald, J.H. Lin, J. Wang, J.M. Fox, and P.E. Light The phosphatidylinositol 3-kinase inhibitor LY294002 potently blocks K(V) currents via a direct mechanism FASEB J 17 6 2003 720 722
70. M.F. Ethier, and J.M. Madison LY294002, but not wortmannin, increases intracellular calcium and inhibits calcium transients in bovine and human airway smooth muscle cells Cell Calcium 32 1 2002 31 38
71. S. Straube, and A.B. Parekh Effects of phosphatidylinositol kinase inhibitors on the activation of the store-operated calcium current ICRAC in RBL-1 cells Pflugers Arch 442 3 2001 391 395
72. A. Welling, F. Hofmann, and J.W. Wegener Inhibition of L-type Cav1.2 Ca2+ channels by 2,(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) and 2-[1-(3-dimethyl-aminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) maleimide (Go6983) Mol Pharmacol 67 2 2005 541 544