An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance

References

1. BeatoM, KlugJ. Steroid hormone receptors: an update. Hum Reprod Update2000;6:225–36.10.1093/humupd/6.3.225Search in Google Scholar

2. BarnesPJ. Corticosteroids: the drugs To Beat. Eur J Pharmacol2006;533:2–14.10.1016/j.ejphar.2005.12.052Search in Google Scholar

3. NewtonR, LeighR, GiembyczMA. Pharmacological strategies for improving the efficacy and therapeutic ratio of glucocorticoids in inflammatory lung diseases. Pharmacol Ther2010;125:286–327.10.1016/j.pharmthera.2009.11.003Search in Google Scholar

4. BarnesPJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol2013;131:636–45.10.1016/j.jaci.2012.12.1564Search in Google Scholar

5. McDonoughAK, CurtisJR, SaagKG. The epidemiology of glucocorticoid- associated adverse events. Curr Opin Rheumatol2008;20:131–7.10.1097/BOR.0b013e3282f51031Search in Google Scholar

6. StahnC, ButtgereitF. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol2008;4:525–33.10.1038/ncprheum0898Search in Google Scholar

7. KleimanA, TuckermannJP. Glucocorticoid receptor action in beneficial and side effects of steroid therapy: lessons from conditional knockout mice. Mol Cell Endocrinol2007;275:98–108.10.1016/j.mce.2007.05.009Search in Google Scholar

8. PerrettiM, AhluwaliaA. The microcirculation and inflammation: site of action for glucocorticoids. Microcirculation2000;7:147–61.10.1111/j.1549-8719.2000.tb00117.xSearch in Google Scholar

9. McEwenBS, BironCA, BrunsonKW, BullochK, ChambersWH, DhabharFS, et al. The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Rev1997;23:79–133.10.1016/S0165-0173(96)00012-4Search in Google Scholar

10. HeroldMJ, McPhersonKG, ReichardtHM. Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci2006;63:60–72.10.1007/s00018-005-5390-ySearch in Google Scholar PubMed PubMed Central

11. McCollA, MichlewskaS, DransfieldI, RossiAG. Effects of glucocorticoids on apoptosis and clearance of apoptotic cells. Sci World J2007;7:1165–81.10.1100/tsw.2007.224Search in Google Scholar PubMed PubMed Central

12. SmoakKA, CidlowskiJA. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev2004;125:697–706.10.1016/j.mad.2004.06.010Search in Google Scholar PubMed

13. NissenRM, YamamotoKR. The glucocorticoid receptor inhibits NFκB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev2000;14:2321–9.10.1101/gad.827900Search in Google Scholar PubMed PubMed Central

14. ButtgereitF, BurmesterGR. Glucocorticoids. In: JohnHK, JohnHS, LeslieJC, PatienceHW.Primer on the rheumatic diseases. Springer, 13th ed. 2008:644–50.10.1007/978-0-387-68566-3_42Search in Google Scholar

15. Hafezi-MoghadamA, SimonciniT, YangZ, LimbourgFP, PlumierJC, RebsamenMC, et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med2002;8:473–9.10.1038/nm0502-473Search in Google Scholar

16. SolitoE, MullaA, MorrisJF, ChristianHC, FlowerRJ, BuckinghamJC, et al. Dexamethasone induces rapid serine-phosphorylation and membrane translocation of annexin 1 in a human folliculostellate cell line via a novel nongenomic mechanism involving the glucocorticoid receptor, protein kinase C, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase. Endocrinology2003;144:1164–74.10.1210/en.2002-220592Search in Google Scholar PubMed

17. WatsonCS, GametchuB. Membrane-initiated steroid actions and the proteins that mediate them. Proc Soc Exp Biol Med1999;220:9–19.10.3181/00379727-220-44338Search in Google Scholar

18. PerrettiM, D’AcquistoF. Annexin A1 and glucocorticoids as effectors of the resolution of inflammation. Nat Rev Immunol2009;9:62–70.10.1038/nri2470Search in Google Scholar PubMed

19. MeijsingSH, PufallMA, SoAY, BatesDL, ChenL, YamamotoKR. DNA binding site sequence directs glucocorticoid receptor structure and activity. Science2009;324:407–10.10.1126/science.1164265Search in Google Scholar PubMed PubMed Central

20. LonardDM, O’MalleyBW. Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Mol Cell2007;27:691–700.10.1016/j.molcel.2007.08.012Search in Google Scholar PubMed

21. BarnesPJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond1998;94:557–72.10.1042/cs0940557Search in Google Scholar PubMed

22. BeaulieuE, MorandEF. Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis. Nat Rev Rheumatol2011;7:340–8.10.1038/nrrheum.2011.59Search in Google Scholar

23. AyroldiE, RiccardiC. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J2009;23:3649–58.10.1096/fj.09-134684Search in Google Scholar

24. HeSH, ChenP, ChenHQ. Modulation of enzymatic activity of human mast cell tryptase and chymase by protease inhibitors. Acta Pharm Sin2003;24:923–9.Search in Google Scholar

25. SolitoE, de CoupadeC, ParenteL, FlowerRJ, Russo-MarieF. IL-6 stimulates annexin 1 expression and translocation and suggests a new biological role as class II acute phase protein. Cytokine1998;10:514–21.10.1006/cyto.1997.0325Search in Google Scholar

26. CroxtallJD, ChoudhuryQ, TokumotoH, FlowerRJ. Lipocortin-1 and the control of arachidonic acid release in cell signalling. Glucocorticoids (changed from glucorticoids) inhibit G protein dependent activation of cPLA2 activity. Biochem Pharmacol1995;50:465–74.10.1016/0006-2952(95)00156-TSearch in Google Scholar

27. GrutzG. New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J Leukoc Biol2005;77:3–15.10.1189/jlb.0904484Search in Google Scholar

28. RoffeE, RothfuchsAG, SantiagoHC, MarinoAP, Ribeiro-GomesFL, EckhausM, et al. IL-10 limits parasite burden and protects against fatal myocarditis in a mouse model of trypanosoma cruzi infection. J Immunol2012;188:649–60.10.4049/jimmunol.1003845Search in Google Scholar

29. AuphanN, DiDonatoJA, RosetteC, HelmbergA, KarinM. Immunosuppression by glucocorticoids: inhibition of NF-kappa-B activity through induction of I-kappa-B synthesis. Science1995;270:286–90.10.1126/science.270.5234.286Search in Google Scholar

30. AdcockIM. Molecular mechanisms of glucocorticosteroids actions. Pulm Pharmacol Ther2000;13:115–26.10.1006/pupt.2000.0243Search in Google Scholar

31. KarinM. New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?. Cell1998;93:487–90.10.1016/S0092-8674(00)81177-0Search in Google Scholar

32. RosenfeldMG, GlassCK. Coregulator codes of transcriptional regulation by nuclear receptors. J Biol Chem2001;276:36865–8.10.1074/jbc.R100041200Search in Google Scholar PubMed

33. PascualG, FongAL, OgawaS, GamlielA, LiAC, PerissiV, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature2005;437:759–63.10.1038/nature03988Search in Google Scholar

34. LueckeHF, YamamotoKR. The glucocorticoid receptor blocks P-TEFb recruitment by NFkappaB to effect promoter-specific transcriptional repression. Genes Dev2005;19:1116–27.10.1101/gad.1297105Search in Google Scholar

35. BarnesPJ, AdcockIM. Glucocorticoid resistance in inflammatory diseases. Lancet2009;373:1905–1917.10.1016/S0140-6736(09)60326-3Search in Google Scholar

36. HewM, ChungKF. Corticosteroid insensitivity in severe asthma: significance, mechanisms and aetiology. Intern Med J2010;40:323–34.10.1111/j.1445-5994.2010.02192.xSearch in Google Scholar PubMed

37. ChaudhuriR, LivingstonE, McMahonAD, ThomsonL, BorlandW, ThomsonNC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med2003;168:1308–11.10.1164/rccm.200304-503OCSearch in Google Scholar PubMed

38. OkamotoK, TanakaH, OgawaH, MakinoY, EguchiH, HayashiS, et al. Redox-dependent regulation of nuclear import of the glucocorticoid receptor. J Biol Chem1999;274:10363–71.10.1074/jbc.274.15.10363Search in Google Scholar PubMed

39. ItoK, HanazawaT, TomitaK, BarnesPJ, AdcockIM. Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration. Biochem Biophys Res Commun2004;315:240–5.10.1016/j.bbrc.2004.01.046Search in Google Scholar PubMed

40. HawrylowiczC, RichardsD, LokeTK, CorriganC, LeeT. A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid- resistant asthmatic patients. J Allergy Clin Immunol2002;109:369–70.10.1067/mai.2002.121455Search in Google Scholar PubMed

41. XystrakisE, KusumakarS, BoswellS, PeekE, UrryZ, RichardsDF, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest2006;116:146–55.10.1172/JCI21759Search in Google Scholar PubMed PubMed Central

42. JohnstonSL. Overview of virus-induced airway disease. Proc Am Thorac Soc2005;2:150–6.10.1513/pats.200502-018AWSearch in Google Scholar PubMed

43. BellattatoC, AdcockIM, ItoK, CaramoriG, CasolariP, CiacciaA, et al. Rhinovirus infection reduces glucocorticoid receptor nuclear translocation in airway epithelial cells. Eur Respir J2003;22:565S.Search in Google Scholar

44. WenzelSE, SzeflerSJ, LeungDY, SloanSI, RexMD, MartinRJ. Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med1997;156:737–43.10.1164/ajrccm.156.3.9610046Search in Google Scholar PubMed

45. CampsM, RuckleT, JiH, ArdissoneV, RintelenF, ShawJ, et al. Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med2005;11:936–43.10.1038/nm1284Search in Google Scholar

46. ZhangX, MoilanenE, AdcockIM, LindsayMA, KankaanrantaH. Divergent effect of mometasone on human eosinophil and neutrophil apoptosis. Life Sci2002;71:1523–34.10.1016/S0024-3205(02)01921-5Search in Google Scholar

47. LeungDY, BloomJW. Update on glucocorticoid action and resistance. J Allergy Clin Immunol2003;111:3–22.10.1067/mai.2003.97Search in Google Scholar

48. NimmagaddaSR, SzeflerSJ, SpahnJD, SursW, LeungDY. Allergen exposure decreases glucocorticoid receptor binding affinity and steroid responsiveness in atopic asthmatics. Am J Respir Crit Care Med1997;155:87–93.10.1164/ajrccm.155.1.9001294Search in Google Scholar

49. De IudicibusS, FrancaR, MartelossiS, VenturaA, DecortiG. Molecular mechanism of glucocorticoid resistance in inflammatory bowel disease. World J Gastroenterol2011;17:1095–108.10.3748/wjg.v17.i9.1095Search in Google Scholar

50. BarnesPJ, ItoK, AdcockIM. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet2004;363:731–3.10.1016/S0140-6736(04)15650-XSearch in Google Scholar

51. HewM, BhavsarP, TorregoA, MeahS, KhorasaniN, BarnesPJ, et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med2006;174:134–41.10.1164/rccm.200512-1930OCSearch in Google Scholar PubMed PubMed Central

52. ToY, ItoK, KizawaY, FaillaM, ItoM, KusamaT, et al. Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med2010;182:897–904.10.1164/rccm.200906-0937OCSearch in Google Scholar PubMed PubMed Central

53. KarhausenJ, HaaseVH, ColganSP. Inflammatory hypoxia: role of hypoxiainducible factor. Cell Cycle2005;4:256–8.Search in Google Scholar

54. MurataT, HoriM, SakamotoK, KarakiH, OzakiH. Dexamethasone blocks hypoxia-induced endothelial dysfunction in organ-cultured pulmonary arteries. Am J Respir Crit Care Med2004;170:647–55.10.1164/rccm.200309-1311OCSearch in Google Scholar PubMed

55. KodamaT, ShimizuN, YoshikawaN, MakinoY, OuchidaR, OkamotoK, et al. Role of the glucocorticoid receptor for regulation of hypoxia-dependent gene expression. J Biol Chem2003;278:33384–91.10.1074/jbc.M302581200Search in Google Scholar PubMed

56. WagnerAE, HuckG, StiehlDP, JelkmannW, Hellwig-BurgelT. Dexamethasone impairs hypoxia-inducible factor-1 function. Biochem Biophys Res Commun2008;372:336–40.10.1016/j.bbrc.2008.05.061Search in Google Scholar PubMed

57. LeungDY, MartinRJ, SzeflerSJ, SherER, YingS, KayAB, et al. Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med1995;18:33–40.10.1084/jem.181.1.33Search in Google Scholar PubMed PubMed Central

58. MatthewsJG, ItoK, BarnesPJ, AdcockIM. Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients. J Allergy Clin Immunol2004;113:1100–8.10.1016/j.jaci.2004.03.018Search in Google Scholar PubMed

59. IrusenE, MatthewsJG, TakahashiA, BarnesPJ, ChungKF, AdcockIM. P38 mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol2002;109:649–57.10.1067/mai.2002.122465Search in Google Scholar PubMed

60. IshiguroY. Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis. J Gastroenterol1999;34:66–74.10.1007/s005350050218Search in Google Scholar PubMed

61. RogerT, ChansonAL, Knaup-ReymondM, CalandraT. Macrophage migration inhibitory factor promotes innate immune responses by suppressing glucocorticoid-induced expression of mitogen-activated protein kinase phosphatase-1. Eur J Immunol2005;35:3405–13.10.1002/eji.200535413Search in Google Scholar PubMed

62. CarmichaelJ, PatersonIC, DiazP, CromptonGK, KayAB, GrantIB. Corticosteroid resistance in asthma. BMJ1981;282:1419–22.10.1136/bmj.282.6274.1419Search in Google Scholar PubMed PubMed Central

63. HakonarsonH, BjornsdottirUS, HalapiE, BradfieldJ, ZinkF, MouyM, et al. Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. Proc Natl Acad Sci USA2005;102:14789–94.10.1073/pnas.0409904102Search in Google Scholar PubMed PubMed Central

64. SalemS, HarrisT, MokJSL, LiMYS, KeenanCR, SchuligaMJ, et al. Transforming growth factor-b impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line. Br J Pharmacol2012;166:2036–48.10.1111/j.1476-5381.2012.01885.xSearch in Google Scholar PubMed PubMed Central

65. FranchimontD, MartensH, HagelsteinMT, LouisE, DeweW, ChrousosGP, et al. Tumor necrosis factors alpha decreases, and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential regulation of the glucocorticoid receptor. J Clin Endocrinol Metab1999;84:2834–9.10.1210/jc.84.8.2834Search in Google Scholar

66. SousaAR, LaneSJ, CidlowskiJA, StaynovDZ, LeeTH. Glucocorticoid resistance in asthma is associated with elevated in vivo expression of the glucocorticoid receptor beta-isoform. J Allergy Clin Immunol2000;105:943–50.10.1067/mai.2000.106486Search in Google Scholar PubMed

67. KozaciDL, ChernajovskyY, ChikanzaIC. The differential expression of corticosteroid receptor isoforms in corticosteroid-resistant and -sensitive patients with rheumatoid arthritis. Rheumatol2007;46:579–85.10.1093/rheumatology/kel276Search in Google Scholar

68. OriiF, AshidaT, NomuraM, MaemotoA, FujikiT, AyabeT, et al. Quantitative analysis for human glucocorticoid receptor alpha/beta mRNA in IBD. Biochem Biophys Res Commun2002;296:1286–94.10.1016/S0006-291X(02)02030-2Search in Google Scholar

69. FakhriS, TulicM, ChristodoulopoulosP, FukakusaM, FrenkielS, LeungDY, et al. Microbial superantigens induce glucocorticoid receptor beta and steroid resistance in a nasal explant model. Laryngoscope2004;114:887–92.10.1097/00005537-200405000-00019Search in Google Scholar PubMed

70. ItoK, BarnesPJ, AdcockIM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits IL-1β-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol2000;20:6891–903.10.1128/MCB.20.18.6891-6903.2000Search in Google Scholar PubMed PubMed Central

71. RedingtonAE. Fibrosis and airway remodelling. Clin Exp Allergy2000;30:42–5.10.1046/j.1365-2222.2000.00096.xSearch in Google Scholar PubMed

72. EbinaM, TakahashiT, ChibaT, MotomiyaM. Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma: a 3-D morphometric study. Am Rev Respir Dis1993;148:720–6.10.1164/ajrccm/148.3.720Search in Google Scholar PubMed

73. BonacciJV, SchuligaM, HarrisT, StewartAG. Collagen impairs glucocorticoid actions in airway smooth muscle through integrin signalling. Br J Pharmacol2006;149:365–73.10.1038/sj.bjp.0706881Search in Google Scholar PubMed PubMed Central

74. LiZ, JiaoX, WangC, JuX, LuY, YuanL, et al. Cyclin D1 induction of cellular migration requires p27(KIP1). Cancer Res2006;66:9986–94.10.1158/0008-5472.CAN-06-1596Search in Google Scholar PubMed

75. LokeTK, MallettKH, RatoffJ, O’ConnorBJ, YingS, MengQ, et al. Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients. J Allergy Clin Immunol2006;118:368–75.10.1016/j.jaci.2006.04.055Search in Google Scholar PubMed

76. LaneSJ, AdcockIM, RichardsD, HawrylowiczC, BarnesPJ, LeeTH. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T-lymphocytes. J Clin Invest1998;102:2156–64.10.1172/JCI2680Search in Google Scholar PubMed PubMed Central

77. FlasterH, BernhagenJ, CalandraT, BucalaR. The macrophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity. Mol Endocrinol2007;21:1267–80.10.1210/me.2007-0065Search in Google Scholar

78. IshiguroY, OhkawaraT, SakurabaH, YamagataK, HiragaH, YamaguchiS, et al. Macrophage migration inhibitory factor has a proinflammatory activity via the p38 pathway in glucocorticoid-resistant ulcerative colitis. Clin Immunol2006;120:335–41.10.1016/j.clim.2006.05.010Search in Google Scholar

79. FarrellRJ, MurphyA, LongA, DonnellyS, CherikuriA, O’TooleD, et al. High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy. Gastroenterol2000;118:279–88.10.1016/S0016-5085(00)70210-1Search in Google Scholar

80. FarrellRJ, KelleherD. Glucocorticoid resistance in inflammatory bowel disease. J Endocrinol2003;178:339–46.10.1677/joe.0.1780339Search in Google Scholar PubMed

81. TsujimuraS, SaitoK, NawataM, NakayamadaS, TanakaY. Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis. Ann Rheum Dis2008;67:380–8.10.1136/ard.2007.070821Search in Google Scholar PubMed

82. HawrylowiczCM. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med2005;202:1459–63.10.1084/jem.20052211Search in Google Scholar PubMed PubMed Central

83. StanczykJ, OspeltC, GayS. Is there a future for small molecule drugs in the treatment of rheumatic diseases?. Curr Opin Rheumatol2008;20:257–62.10.1097/BOR.0b013e3282fa13eeSearch in Google Scholar PubMed

84. CosioBG, TsaprouniL, ItoK, JazrawiE, AdcockIM, BarnesPJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med2004;200:689–95.10.1084/jem.20040416Search in Google Scholar PubMed PubMed Central

85. FoxJC, SpicerD, ItoK, BarnesPJ, FitzgeraldMF. Oral or inhaled corticosteroid combination therapy with low dose theophylline reverses corticosteroid insensitivity in a smoking mouse model. Proc Am Thorac Soc2007;2:A637.Search in Google Scholar

86. FaillaM, ToY, ItoM, AdcockIM, BarnesPJ, ItoK. Oxidative stress-induced PI3-kinase activation reduces HDAC activity and is inhibited by theophylline. Proc Am Thorac Soc2007;2:A45.Search in Google Scholar

87. RahmanI, AdcockIM. Oxidative stress and redox regulation of lung inflammation in COPD. Eur Respir J2006;28:219–42.10.1183/09031936.06.00053805Search in Google Scholar PubMed

88. NobiliS, LandiniI, GiglioniB, MiniE. Pharmacological strategies for overcoming multidrug resistance. Curr Drug Targets2006;7:861–79.10.2174/138945006777709593Search in Google Scholar PubMed

89. HuschtschaL, BartierW, RossC, TattersallM. Characteristics of cancer cell death after exposure to cytotoxic drugs in vitro. Br J Cancer1996;73:54–60.10.1038/bjc.1996.10Search in Google Scholar

90. FeaganBG, RochonJ, FedorakRN, Irvine EJ, Wild G, Sutherland L, et al. The North American Crohn’s study group. Methotrexate for the treatment of Crohn’s disease. N Engl J Med1995;332:292–7.10.1056/NEJM199502023320503Search in Google Scholar

91. StackW, WilliamsD, StevensonM, LoganR. Immunosuppressive therapy for ulcerative colitis: results of a nation-wide survey among consultant physician members of the British society of gastroenterology. Aliment Pharmacol Ther1999;13:569–75.10.1046/j.1365-2036.1999.00511.xSearch in Google Scholar

92. JewellD, TrueloveS. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. BMJ1974;114:627–30.10.1136/bmj.4.5945.627Search in Google Scholar

93. GordonF, LaiC, HamiltonM, AllisonM, SrivastavaE, FouweatherM, et al. A randomized placebo-controlled trial of a humanized monoclonal antibody to α4 integrin in active Crohn’s disease. Gastroenterology2001;121:268–174.10.1053/gast.2001.26260Search in Google Scholar

94. Van AsscheG, DalleI, NomanM, AerdenI, SwijsenC, AsnongK, et al. A pilot study on the use of the humanized anti- interleukin-2 receptor antibody daclizumab in active ulcerative colitis. Am J Gastroenterol2003;98:369–76.10.1016/S0002-9270(02)05907-5Search in Google Scholar

95. KitaharaK, KawaiS. Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis. Curr Opin Rheumatol2007;19:238–45.10.1097/BOR.0b013e328099af80Search in Google Scholar PubMed

96. DastidarSG, RajagopalD, RayA. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs2007;8:364–72.Search in Google Scholar

97. StadtmannA, ZarbockA. CXCR2: from bench to bedside. Front Immunol2012;3:263.10.3389/fimmu.2012.00263Search in Google Scholar PubMed PubMed Central

98. ChungKF. P38 mitogen-activated protein kinase pathways in asthma and COPD. Chest2011;139:1470–9.10.1378/chest.10-1914Search in Google Scholar PubMed

99. Fung-LeungWP. Phosphoinositide 3-kinase delta (PI3Kdelta) in leukocyte signaling and function. Cell Signal2011;23:603–8.10.1016/j.cellsig.2010.10.002Search in Google Scholar PubMed

100. MarwickJA, CaramoriG, CasolariP, MazzoniF, KirkhamPA, AdcockIM, et al. A role for phosphoinositol 3- kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol2010;125:1146–53.10.1016/j.jaci.2010.02.003Search in Google Scholar

101. BrusselleGG, JoosGF, BrackeKR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet2011;378:1015–26.10.1016/S0140-6736(11)60988-4Search in Google Scholar

102. PaceE, FerraroM, SienaL, MelisM, MontalbanoAM, JohnsonM, et al. Cigarette smoke increases toll-like receptor 4 and modifies lipopolysaccharide-mediated responses in airway epithelial cells. Immunol2008;124:401–11.10.1111/j.1365-2567.2007.02788.xSearch in Google Scholar PubMed PubMed Central

103. BasithS, ManavalanB, LeeG, KimSG, ChoiS. Toll-like receptor modulators: a patent review (2006–2010). Expert Opin Ther Pat2011;21:927–44.10.1517/13543776.2011.569494Search in Google Scholar PubMed

104. KwakJH, JungJK, LeeH. Nuclear factor-kappa B inhibitors; a patent review (2006–2010). Expert Opin Ther Pat2011;21:1897-910.10.1517/13543776.2011.638285Search in Google Scholar PubMed

105. BakkePS, ZhuG, GulsvikA, KongX, AgustiAG, CalverleyPM, et al. Candidate genes for COPD in two large data sets. Eur Respir J2011;37:255–63.10.1183/09031936.00091709Search in Google Scholar PubMed

106. BarnesPJ. Scientific rationale for combination inhalers with a long-acting b2-agonists and corticosteroids. Eur Respir J2002;19:182–91.10.1183/09031936.02.00283202Search in Google Scholar PubMed

107. UsmaniOS, ItoK, ManeechotesuwanK, ItoM, JohnsonM, BarnesPJ, et al. Glucocorticoid receptor nuclear translocation in airway cells following inhaled combination therapy. Am J Respir Crit Care Med2005;172:704–12.10.1164/rccm.200408-1041OCSearch in Google Scholar PubMed

108. GiembyczMA, KaurM, LeighR, NewtonRA. Holy grail of asthma management: toward understanding how long-acting beta(2)-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids. Br J Pharmacol2008;153:1090–104.10.1038/sj.bjp.0707627Search in Google Scholar PubMed PubMed Central

109. KobayashiY, MercadoN, Miller-LarssonA, BarnesPJ, ItoK. Increased corticosteroid sensitivity by a long acting beta2 agonist formoterol via beta2 adrenoceptor independent protein phosphatase 2a activation. Pulm Pharmacol Ther2012;25:201–7.10.1016/j.pupt.2012.02.005Search in Google Scholar PubMed