Protein kinase C and its inhibitors in the regulation of inflammation: Inducible nitric oxide synthase as an example

Basic and Clinical Pharmacology and Toxicology

Volumn 114, Issue 1, 2014, Pages 37-43

  Leppänen, Tiina ^a   Tuominen, Raimo K ^b   Moilanen, Eeva ^a  

^a TAMPERE UNIVERSITY OF TECHNOLOGY   (Finland)

^b UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

7 HYDROXYSTAUROSPORINE; APRINOCARSEN; AUROTHIOMALATE; BRYOSTATIN 1; DELCASERTIB; ENZASTAURIN; INDUCIBLE NITRIC OXIDE SYNTHASE; MIDOSTAURIN; PROTEIN KINASE C; PROTEIN KINASE C INHIBITOR; RUBOXISTAURIN; SOTRASTAURIN; TAMOXIFEN;

ANTIINFLAMMATORY ACTIVITY; ENZYME INHIBITION; ENZYME REGULATION; GENE EXPRESSION REGULATION; HUMAN; IMMUNE RESPONSE; INFLAMMATORY DISEASE; INNATE IMMUNITY; MACROPHAGE; NONHUMAN; PLEIOTROPY; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

ANIMALIA;

ANIMALS; ANTI-INFLAMMATORY AGENTS; DISEASE MODELS, ANIMAL; ENZYME INHIBITORS; HUMANS; INFLAMMATION; MACROPHAGES; MOLECULAR TARGETED THERAPY; NITRIC OXIDE; NITRIC OXIDE SYNTHASE TYPE II; PROTEIN KINASE C; SIGNAL TRANSDUCTION;

EID: 84890799799     PISSN: 17427835     EISSN: 17427843     Source Type: Journal    
DOI: 10.1111/bcpt.12139     Document Type: Review

References (80)

1. Gould CM, Newton AC. The life and death of protein kinase C. Curr Drug Targets 2008;9:614-25.
2. Steinberg SF. Structural basis of protein kinase C isoform function. Physiol Rev 2008;88:1341-78.
3. Huang FL, Yoshida Y, Cunha-Melo JR, Beaven MA, Huang KP. Differential down-regulation of protein kinase C isozymes. J Biol Chem 1989;264:4238-43.
4. Chen CC. Protein kinase C alpha, delta, epsilon and zeta in C6 glioma cells. TPA induces translocation and down-regulation of conventional and new PKC isoforms but not atypical PKC zeta. FEBS Lett 1993;332:169-73.
5. Yonezawa T, Kurata R, Kimura M, Inoko H. PKC delta and epsilon in drug targeting and therapeutics. Recent Pat DNA Gene Seq 2009;3:96-101.
6. Pfeifhofer C, Gruber T, Letschka T, Thuille N, Lutz-Nicoladoni C, Hermann-Kleiter N et al. Defective IgG2a/2b class switching in PKC alpha-/- mice. J Immunol 2006;176:6004-11.
7. Pierce A, Heyworth CM, Nicholls SE, Spooncer E, Dexter TM, Lord JM et al. An activated protein kinase C alpha gives a differentiation signal for hematopoietic progenitor cells and mimicks macrophage colony-stimulating factor-stimulated signaling events. J Cell Biol 1998;140:1511-8.
8. Leitges M, Schmedt C, Guinamard R, Davoust J, Schaal S, Stabel S et al. Immunodeficiency in protein kinase cbeta-deficient mice. Science 1996;273:788-91.
9. Saijo K, Mecklenbräuker I, Santana A, Leitger M, Schmedt C, Tarakhovsky A. Protein kinase C beta controls nuclear factor kappaB activation in B cells through selective regulation of the IkappaB kinase alpha. J Exp Med 2002;195:1647-52.
10. Mecklenbräuker I, Saijo K, Zheng NY, Leitges M, Tarakhovsky A. Protein kinase Cdelta controls self-antigen-induced B-cell tolerance. Nature 2002;416:860-5.
11. Miyamoto A, Nakayama K, Imaki H, Hirose S, Jiang Y, Abe M et al. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cdelta. Nature 2002;416:865-9.
12. Osada S, Mizuno K, Saido TC, Suzuki K, Kuroki T, Ohno S. A new member of the protein kinase C family, nPKC theta, predominantly expressed in skeletal muscle. Mol Cell Biol 1992;12:3930-8.
13. Hayashi K, Altman A. Protein kinase C theta (PKCtheta): a key player in T cell life and death. Pharmacol Res 2007;55:537-44.
14. Boschelli DH. Small molecule inhibitors of PKCtheta as potential antiinflammatory therapeutics. Curr Top Med Chem 2009;9:640-54.
15. Sun Z, Arendt CW, Ellmeier W, Schaeffer EM, Sunshine MJ, Gandhi L et al. PKC-theta is required for TCR-induced NF-kappaB activation in mature but not immature T lymphocytes. Nature 2000;404:402-7.
16. 2+ mobilization and NFAT cell activation in primary mouse T cells. J Exp Med 2003;197:1525-35.
17. Leitges M, Sanz L, Martin P, Duran A, Braun U, García JF et al. Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. Mol Cell 2001;8:771-80.
18. Martin P, Duran A, Minguet S, Gaspar ML, Diaz-Meco MT, Rennert P et al. Role of zeta PKC in B-cell signaling and function. EMBO J 2002;21:4049-57.
19. Martin P, Villares R, Rodriguez-Mascarenhas S, Zaballos A, Leitges M, Kovac J. Control of T helper 2 cell function and allergic airway inflammation by PKCzeta. Proc Natl Acad Sci USA 2005;102:9866-71.
20. Yang JQ, Leitges M, Duran A, Diaz-Meco MT, Moscat J. Loss of PKC lambda/iota impairs Th2 establishment and allergic airway inflammation in vivo. Proc Natl Acad Sci USA 2009;106:1099-104.
21. Lee MR, Duan W, Tan SL. Protein kinase C isozymes as potential therapeutic targets in immune disorders. Expert Opin Ther Targets 2008;12:535-52.
22. Aiello LP, Vignati L, Sheetz MJ, Zhi X, Girach A, Davis MD et al. Oral protein kinase c beta inhibition using ruboxistaurin: efficacy, safety, and causes of vision loss among 813 patients (1, 392 eyes) with diabetic retinopathy in the Protein Kinase C beta Inhibitor-Diabetic Retinopathy Study and the Protein Kinase C beta Inhibitor-Diabetic Retinopathy Study 2. Retina 2011;31:2084-94.
23. Rao S, Watkins D, Cunningham D, Dunlop D, Johnson P, Selby P et al. Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C alpha, in patients with previously treated low-grade non-Hodgkin's lymphoma. Ann Oncol 2004;15:1413-8.
24. Direct Inhibition of delta-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) Investigators, Bates E, Bode C, Costa M, Gibson CM, Granger C, Green C et al. Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation 2008;117:886-96.
25. Cousins MJ, Pickthorn K, Huang S, Critchley L, Bell G. The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (epsilonPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design. Pain Med 2013;14:533-40.
26. Moodie JE, Bisley EJ, Huang S, Pickthorn K, Bell G. A single-center, randomized, double-blind, active, and placebo-controlled study of KAI-1678, a novel PKC-epsilon inhibitor, in the treatment of acute postoperative orthopedic pain. Pain Med 2013;14:916-24.
27. Blackhall FH, Ranson M, Radford JA, Hancock BW, Soukop M, McGown AT et al. A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma. Br J Cancer 2001;84:465-9.
28. Evenou JP, Wagner J, Zenke G, Brinkmann V, Wagner K, Kovarik J et al. The potent protein kinase C-selective inhibitor AEB071 (sotrastaurin) represents a new class of immunosuppressive agents affecting early T-cell activation. J Pharmacol Exp Ther 2009;330:792-801.
29. Friman S, Arns W, Nashan B, Vincenti F, Banas B, Budde K et al. Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients. Am J Transplant 2011;11:1444-55.
30. Russ GR, Tedesco-Silva H, Kuypers DR, Cohney S, Langer RM, Witzke O et al. Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results. Am J Transplant 2013;13:1746-56.
31. Skvara H, Dawid M, Kleyn E, Wolff B, Meingassner JG, Knight H et al. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J Clin Invest 2008;118:3151-9.
32. Birchall AM, Bishop J, Bradshaw D, Cline A, Coffey J, Elliot LH et al. Ro 32-0432, a selective and orally active inhibitor of protein kinase C prevents T-cell activation. J Pharmacol Exp Ther 1994;268:922-9.
33. DiMartino M, Wolff C, Patil A, Nambi P. Effects of a protein kinase C inhibitor (PKCI) on the development of adjuvant-induced arthritis (AA) in rats. Inflamm Res 1995;44(Suppl. 2):S123-4.
34. Jacobson PB, Kuchera SL, Metz A, Schächtele C, Imre K, Schrier DJ. Anti-inflammatory properties of Gö 6850: a selective inhibitor of protein kinase C. J Pharmacol Exp Ther 1995;275:995-1002.
35. Salek-Ardakani S, So T, Halteman BS, Altman A, Croft M. Differential regulation of Th2 and Th1 lung inflammatory responses by protein kinase C theta. J Immunol 2004;173:6440-7.
36. Healy AM, Izmailova E, Fitzgerald M, Walker R, Hattersley M, Silva M et al. PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis. J Immunol 2006;177:1886-93.
37. Korhonen R, Lahti A, Kankaanranta H, Moilanen E. Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy 2005;4:471-9.
38. Tripathi P, Tripathi P, Kashyap L, Singh V. The role of nitric oxide in inflammatory reactions. FEMS Immunol Med Microbiol 2007;51:443-52.
39. Pautz A, Art J, Hahn S, Nowag S, Voss C, Kleinert H. Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 2010;23:75-93.
40. Singh D, Richards D, Knowles RG, Schwartz S, Woodcock A, Langley S et al. Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma. Am J Respir Crit Care Med 2007;176:988-93.
41. Hellio de Graverand MP, Clemmer RS, Redifer P, Brunell RM, Hayes CW, Brandt KD et al. A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Ann Rheum Dis 2013;72:187-95.
42. Severn A, Wakelam MJ, Liew FY. The role of protein kinase C in the induction of nitric oxide synthesis by murine macrophages. Biochem Biophys Res Commun 1992;188:997-1002.
43. Fujihara M, Connolly N, Ito N, Suzuki T. Properties of protein kinase C isoforms (betaII, iota, and zeta) in a macrophage cell line (J774) and their roles in LPS-induced nitric oxide production. J Immunol 1994;152:1898-906.
44. Paul A, Pendreigh RH, Plevin R. Protein kinase C and tyrosine kinase pathways regulate lipopolysaccharide-induced nitric oxide synthase activity in RAW 264.7 murine macrophages. Br J Pharmacol 1995;114:482-8.
45. Paul A, Doherty K, Plevin R. Differential regulation by protein kinase C isoforms of nitric oxide synthase induction in RAW 264.7 macrophages and rat aortic smooth muscle cells. Br J Pharmacol 1997;120:940-6.
46. Park YC, Jun CD, Kang HS, Kim HD, Kim HM, Chung HT. Role of intracellular calcium as a priming signal for the induction of nitric oxide synthesis in murine peritoneal macrophages. Immunology 1996;87:296-302.
47. Zhu Y, Zhu M, Lance P. iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Exp Cell Res 2012;318:2116-27.
48. Vuolteenaho K, Koskinen A, Kukkonen M, Nieminen R, Päivärinta U, Moilanen E. Leptin enhances synthesis of proinflammatory mediators in human osteoarthritic cartilage-mediator role of NO in leptin-induced PGE2, IL-6, and IL-8 production. Mediators Inflamm 2009;2009:345838.
49. Li S, Huang FL, Feng Q, Liu J, Fan SX, McKenna TM. Overexpression of protein kinase C alpha enhances lipopolysaccharide-induced nitric oxide formation in vascular smooth muscle cells. J Cell Physiol 1998;176:402-11.
50. Boncoeur É, Bouvet G, Migneault F, Tardif V, Ferraro P, Radzioch D et al. Induction of nitric oxide synthase expression by lipopolysaccharide is mediated by calcium-dependent PKCalpha-beta1 in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 2013;305:L175-84.
51. Chen CC, Wang JK, Lin SB. Antisense oligonucleotides targeting protein kinase C-alpha, -betaI, or -delta but not -eta inhibit lipopolysaccharide-induced nitric oxide synthase expression in RAW 264.7 macrophages: involvement of a nuclear factor kappaB-dependent mechanism. J Immunol 1998;161:6206-14.
52. St-Denis A, Chano F, Tremblay P, St-Pierre Y, Descoteaux A. Protein kinase C-alpha modulates lipopolysaccharide-induced functions in a murine macrophage cell line. J Biol Chem 1998;273:32787-92.
53. Kang J, Yang M, Jou I, Joe E. Identification of protein kinase C isoforms involved in interferon-gamma-induced expression of inducible nitric oxide synthase in murine BV2 microglia. Neurosci Lett 2001;299:205-8.
54. Coussens L, Rhee L, Parker PJ, Ullrich A. Alternative splicing increases the diversity of the human protein kinase C family. DNA 1987;6:389-94.
55. Kubo K, Ohno S, Suzuki K. Primary structures of human protein kinase C beta I and beta II differ only in their C-terminal sequences. FEBS Lett 1987;223:138-42.
56. Shinji H, Akagawa KS, Yoshida T. LPS induces selective translocation of protein kinase C-beta in LPS-responsive mouse macrophages, but not in LPS-nonresponsive mouse macrophages. J Immunol 1994;153:5760-71.
57. Salonen T, Sareila O, Jalonen U, Kankaanranta H, Tuominen R, Moilanen E. Inhibition of classical PKC isoenzymes downregulates STAT1 activation and iNOS expression in LPS-treated murine J774 macrophages. Br J Pharmacol 2006;147:790-9.
58. Wen J, Ribeiro R, Zhang Y. Specific PKC isoforms regulate LPS-stimulated iNOS induction in murine microglial cells. J Neuroinflammation 2011;8:38.
59. Carpenter L, Cordery D, Biden TJ. Protein kinase Cdelta activation by interleukin-1beta stabilizes inducible nitric-oxide synthase mRNA in pancreatic beta-cells. J Biol Chem 2001;276:5368-74.
60. Leppänen T, Korhonen R, Laavola M, Nieminen R, Tuominen RK, Moilanen E. Down-regulation of protein kinase Cdelta inhibits inducible nitric oxide synthase expression through IRF1. PLoS ONE 2013;8:e52741.
61. Salvemini D, Wang ZQ, Wyatt PS, Bourdon DM, Marino MH, Manning PT et al. Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br J Pharmacol 1996;118:829-38.
62. Morris CJ. Carrageenan-induced paw edema in the rat and mouse. Methods Mol Biol 2003;225:115-21.
63. Loram LC, Fuller A, Fick LG, Cartmell T, Poole S, Mitchell D. Cytokine profiles during carrageenan-induced inflammatory hyperalgesia in rat muscle and hind paw. J Pain 2007;8:127-36.
64. Bhatt KH, Pandey RK, Dahiya Y, Sodhi A. Protein kinase Cdelta and protein tyrosine kinase regulate peptidoglycan-induced nuclear factor-kappaB activation and inducible nitric oxide synthase expression in mouse peritoneal macrophages in vitro. Mol Immunol 2010;47:861-70.
65. Tepperman BL, Chang Q, Soper BD. Protein kinase C mediates lipopolysaccharide- and phorbol-induced nitric-oxide synthase activity and cellular injury in the rat colon. J Pharmacol Exp Ther 2000;295:1249-57.
66. Ginnan R, Guikema BJ, Singer HA, Jourd'heuil D. PKC-delta mediates activation of ERK1/2 and induction of iNOS by IL-1beta in vascular smooth muscle cells. Am J Physiol Cell Physiol 2006;290:C1583-91.
67. Castrillo A, Pennington DJ, Otto F, Parker PJ, Owen MJ, Boscá L. Protein kinase Cepsilon is required for macrophage activation and defense against bacterial infection. J Exp Med 2001;194:1231-42.
68. McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ et al. Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling. Proc Natl Acad Sci USA 2006;103:9196-201.
69. Díaz-Guerra MJ, Bodelón OG, Velasco M, Whelan R, Parker PJ, Boscá L. Up-regulation of protein kinase C-epsilon promotes the expression of cytokine-inducible nitric oxide synthase in RAW 264.7 cells. J Biol Chem 1996;271:32028-33.
70. Jones E, Adcock IM, Ahmed BY, Punchard NA. Modulation of LPS stimulated NF-kappaB mediated nitric oxide production by PKCepsilon and JAK2 in RAW macrophages. J Inflamm (Lond) 2007;4:23.
71. Pham TN, Brown BL, Dobson PR, Richardson VJ. Protein kinase C-eta (PKC-eta) is required for the development of inducible nitric oxide synthase (iNOS) positive phenotype in human monocytic cells. Nitric Oxide 2003;9:123-34.
72. Pham TN, Rahman P, Tobin YM, Khraishi MM, Hamilton SF, Alderdice C et al. Elevated serum nitric oxide levels in patients with inflammatory arthritis associated with co-expression of inducible nitric oxide synthase and protein kinase C-eta in peripheral blood monocyte-derived macrophages. J Rheumatol 2003;30:2529-34.
73. Heale CE, Fåhræus-Van Ree GE, Rahman P, Richardson VJ. Progressive and concordant expression of PKC-eta and iNOS phenotypes in monocytes from patients with rheumatoid arthritis: association with disease severity. J Histochem Cytochem 2007;55:495-503.
74. Pham TN, Rahman P, Richardson VJ. Divergent effects of infliximab and anakinra therapies on macrophage phenotype from patients with refractory rheumatoid arthritis. Int J Immunopathol Pharmacol 2010;23:491-501.
75. Teixeira VH, Jacq L, Moore J, Lasbleiz S, Hilliquin P, Resende Oliveira C et al. Association and expression study of PRKCH gene in a French Caucasian population with rheumatoid arthritis. J Clin Immunol 2008;28:115-21.
76. Chen CC, Wang JK, Chen WC, Lin SB. Protein kinase C eta mediates lipopolysaccharide-induced nitric-oxide synthase expression in primary astrocytes. J Biol Chem 1998;273:19424-30.
77. Fields AP, Regala RP. Protein kinase C iota: human oncogene, prognostic marker and therapeutic target. Pharmacol Res 2007;55:487-97.
78. LaVallie ER, Chockalingam PS, Collins-Racie LA, Freeman BA, Keohan CC, Leitges M et al. Protein kinase Czeta is up-regulated in osteoarthritic cartilage and is required for activation of NF-kappaB by tumor necrosis factor and interleukin-1 in articular chondrocytes. J Biol Chem 2006;281:24124-37.
79. Chockalingam PS, Varadarajan U, Sheldon R, Fortier E, LaVallie ER, Morris EA et al. Involvement of protein kinase Czeta in interleukin-1beta induction of ADAMTS-4 and type 2 nitric oxide synthase via NF-kappaB signaling in primary human osteoarthritic chondrocytes. Arthritis Rheum 2007;56:4074-83.
80. Banan A, Zhang L, Fields JZ, Farhadi A, Talmage DA, Keshavarzian A. PKC-zeta prevents oxidant-induced iNOS upregulation and protects the microtubules and gut barrier integrity. Am J Physiol Gastrointest Liver Physiol 2002;283:G909-22.