Antiinflammatory Effects of Dexamethasone Are Partly Dependent on Induction of Dual Specificity Phosphatase 1

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2006 Aug 2

PMID 16880258

Citations 183

Authors

Sonya M Abraham

Toby Lawrence

Anna Kleiman

Paul Warden

Mino Medghalchi

Jan Tuckermann

Jeremy Saklatvala

Andrew R Clark

Affiliations

Soon will be listed here.

Abstract

Glucocorticoids (GCs), which are used in the treatment of immune-mediated inflammatory diseases, inhibit the expression of many inflammatory mediators. They can also induce the expression of dual specificity phosphatase 1 (DUSP1; otherwise known as mitogen-activated protein kinase [MAPK] phosphatase 1), which dephosphorylates and inactivates MAPKs. We investigated the role of DUSP1 in the antiinflammatory action of the GC dexamethasone (Dex). Dex-mediated inhibition of c-Jun N-terminal kinase and p38 MAPK was abrogated in DUSP1-/- mouse macrophages. Dex-mediated suppression of several proinflammatory genes (including tumor necrosis factor, cyclooxygenase 2, and interleukin 1alpha and 1beta) was impaired in DUSP1-/- mouse macrophages, whereas other proinflammatory genes were inhibited by Dex in a DUSP1-independent manner. In vivo antiinflammatory effects of Dex on zymosan-induced inflammation were impaired in DUSP1-/- mice. Therefore, the expression of DUSP1 is required for the inhibition of proinflammatory signaling pathways by Dex in mouse macrophages. Furthermore, DUSP1 contributes to the antiinflammatory effects of Dex in vitro and in vivo.

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References

Swantek J, Cobb M, Geppert T . Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is required for lipopolysaccharide stimulation of tumor necrosis factor alpha (TNF-alpha) translation: glucocorticoids inhibit TNF-alpha translation by blocking JNK/SAPK. Mol Cell Biol. 1997; 17(11):6274-82. PMC: 232478. DOI: 10.1128/MCB.17.11.6274. View

Dorfman K, Carrasco D, Gruda M, Ryan C, Lira S, Bravo R . Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts. Oncogene. 1996; 13(5):925-31. View

Sousa A, Lane S, Soh C, Lee T . In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation. J Allergy Clin Immunol. 1999; 104(3 Pt 1):565-74. DOI: 10.1016/s0091-6749(99)70325-8. View

Mavropoulos A, Sully G, Cope A, Clark A . Stabilization of IFN-gamma mRNA by MAPK p38 in IL-12- and IL-18-stimulated human NK cells. Blood. 2004; 105(1):282-8. DOI: 10.1182/blood-2004-07-2782. View

Nimah M, Zhao B, Denenberg A, Bueno O, Molkentin J, Wong H . Contribution of MKP-1 regulation of p38 to endotoxin tolerance. Shock. 2004; 23(1):80-7. DOI: 10.1097/01.shk.0000145206.28812.60. View

Zhao Q, Shepherd E, Manson M, Nelin L, Sorokin A, Liu Y . The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. J Biol Chem. 2004; 280(9):8101-8. DOI: 10.1074/jbc.M411760200. View

Schacke H, Rehwinkel H, Asadullah K . Dissociated glucocorticoid receptor ligands: compounds with an improved therapeutic index. Curr Opin Investig Drugs. 2005; 6(5):503-7. View

Ogawa S, Lozach J, Benner C, Pascual G, Tangirala R, Westin S . Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell. 2005; 122(5):707-21. PMC: 1430687. DOI: 10.1016/j.cell.2005.06.029. View

Salojin K, Owusu I, Millerchip K, Potter M, Platt K, Oravecz T . Essential role of MAPK phosphatase-1 in the negative control of innate immune responses. J Immunol. 2006; 176(3):1899-907. DOI: 10.4049/jimmunol.176.3.1899. View

10.

Hammer M, Mages J, Dietrich H, Servatius A, Howells N, Cato A . Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. J Exp Med. 2005; 203(1):15-20. PMC: 2118077. DOI: 10.1084/jem.20051753. View

11.

Zhao Q, Wang X, Nelin L, Yao Y, Matta R, Manson M . MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J Exp Med. 2005; 203(1):131-40. PMC: 2118076. DOI: 10.1084/jem.20051794. View

12.

Chi H, Barry S, Roth R, Wu J, Jones E, Bennett A . Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci U S A. 2006; 103(7):2274-9. PMC: 1413743. DOI: 10.1073/pnas.0510965103. View

13.

Tuckermann J, Reichardt H, Arribas R, RICHTER K, Schutz G, Angel P . The DNA binding-independent function of the glucocorticoid receptor mediates repression of AP-1-dependent genes in skin. J Cell Biol. 1999; 147(7):1365-70. PMC: 2174255. DOI: 10.1083/jcb.147.7.1365. View

14.

Camps M, Nichols A, Arkinstall S . Dual specificity phosphatases: a gene family for control of MAP kinase function. FASEB J. 2000; 14(1):6-16. View

15.

Newton R . Molecular mechanisms of glucocorticoid action: what is important?. Thorax. 2000; 55(7):603-13. PMC: 1745805. DOI: 10.1136/thorax.55.7.603. View

16.

Lasa M, Brook M, Saklatvala J, Clark A . Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38. Mol Cell Biol. 2001; 21(3):771-80. PMC: 86669. DOI: 10.1128/MCB.21.3.771-780.2001. View

17.

Adcock I, Caramori G . Cross-talk between pro-inflammatory transcription factors and glucocorticoids. Immunol Cell Biol. 2001; 79(4):376-84. DOI: 10.1046/j.1440-1711.2001.01025.x. View

18.

Lawrence T, Gilroy D, Colville-Nash P, Willoughby D . Possible new role for NF-kappaB in the resolution of inflammation. Nat Med. 2001; 7(12):1291-7. DOI: 10.1038/nm1201-1291. View

19.

Reichardt H, Tuckermann J, Gottlicher M, Vujic M, Weih F, Angel P . Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor. EMBO J. 2001; 20(24):7168-73. PMC: 125338. DOI: 10.1093/emboj/20.24.7168. View

20.

Bantel H, Schmitz M, Raible A, Gregor M, Schulze-Osthoff K . Critical role of NF-kappaB and stress-activated protein kinases in steroid unresponsiveness. FASEB J. 2002; 16(13):1832-4. DOI: 10.1096/fj.02-0223fje. View