Skip to main content
SpringerLink
Log in

Therapeutic regulation of cytokine signalling by inhibitors of p38 mitogen-activated protein kinase

  • Chapter
Novel Cytokine Inhibitors

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Over the last four years, selective inhibitors of the enzyme p38 mitogen-activated protein kinase (p38 MAPK) have emerged as potential new drugs for the treatment of inflammatory diseases, such as rheumatoid arthritis. Inhibition of the kinase activity of p38 MAPK is associated with the modulation of cytokine production, in particular tumor necrosis factor (TNF) and interleukin-1 (IL-1), and also the response of cells to these pro-inflammatory agents. This profile suggests that inhibitors of p38 MAPK may be disease-modifying, hence this enzyme has become the focus of considerable activity in the pharmaceutical industry. In this chapter we will review the chemistry and biology of p38 MAPK inhibitors and discuss how blocking the activity of p38 MAPK leads to an anti-inflammatory effect.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Han J, Lee J-D, Bibbs R, Ulevitch RJ (1994) A MAP Kinase targeted by endotoxin and hyperosmolarity in mammalian cells.Science265: 808–811

    Article  PubMed  CAS  Google Scholar 

  2. Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J (1994) Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27.Cell78: 1039–1049

    Article  PubMed  CAS  Google Scholar 

  3. Rouse J, Cohen P, Trigon S, Morange M, Alonso-Llamazares A, Zamanillo D, Hunt T, Nebreda AR (1994) A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins.Cell78: 1027–1037

    Article  PubMed  CAS  Google Scholar 

  4. Lee J, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW et al (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.Nature372: 739–746

    Article  PubMed  CAS  Google Scholar 

  5. Jiang Y, Chen C, Zhuangjie L, Guo W Gegner JA, Lin S, Han J (1996) Characterisation of the structure and function of a new mitogen-activated protein kinase (p38B).J Biol Chem271: 17920–17926

    Article  PubMed  CAS  Google Scholar 

  6. Li Z, Jiang Y, Ulevitch RJ, Han J (1996) the primary structure of p38γ: a new member of p38 group of MAP kinases.Biochem Biophy Res Commun228: 334–340

    Article  CAS  Google Scholar 

  7. Kumar S, McDonnell PC, Gum RJ, Hand AT, Lee JC, Young PR (1997) Novel homo-logues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibiton by pyridinyl imidazoles.Biochem Biophys Res Commun235: 533–538

    Article  PubMed  CAS  Google Scholar 

  8. Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ (1995) Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine.J Biol Chem270: 7420–7426

    Article  PubMed  CAS  Google Scholar 

  9. Doza YN, Cuenda A, Thomas GM, Cohen P, Nebreda AR (1995) Activation of the MAP kinase homologue RK requires the phosphorylation of Thr-180 and Tyr-182 and both residues are phosphorylated in chemically stressed KB cells.FEBS Lett364: 223–228

    Article  PubMed  CAS  Google Scholar 

  10. Cuenda A, Alonso G, Morrice N, Jones M, Meier R, Cohen P, Nebreda AR (1996) Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 stress-and cytokine-stimulated monocytes and epithelial cells.EMBO J15: 4156–4164

    PubMed  CAS  Google Scholar 

  11. Han J, Lee J-D, Jiang Y, Li Z, Feng L, Ulevitch R (1996) Characterisation of the structure and function of a novel MAP kinase kinase (MKK6).J Biol Chem271: 2886–2891

    Article  PubMed  CAS  Google Scholar 

  12. Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ (1996) MKK3 and MKK6regulated gene expression is mediated by p38 mitogen-activated protein kinase signal transduction pathway.Mol Cell Biol16: 1247–1255

    PubMed  CAS  Google Scholar 

  13. Derijard B, Raingeaud J, Barrett T, Wu I-H, Han J, Ulevitch RJ, Davis RJ (1995) Independent human MAP kinase signal transduction pathways defined by MEK and MKK isoforms.Science267: 682–685

    Article  PubMed  CAS  Google Scholar 

  14. Deacon K, Blank JL (1997) Characterisation of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3.J Biol Chem272: 14489–14496

    Article  PubMed  CAS  Google Scholar 

  15. Moriguchi M, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K et al (1996) A novel kinase cascade mediated by mitogen activated protein kinase kinase 6 and MKK3.J Biol Chem271: 13675–13679

    Article  PubMed  CAS  Google Scholar 

  16. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J-I, Cao Z, Matsumoto K (1999) The kinase TAK1 can activate the NIK-IicB as well as the MAP kinase cascade in the IL-1 signalling pathway.Nature398: 252–256

    Article  PubMed  CAS  Google Scholar 

  17. McLaughlin M, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR (1996) Identification of mitogen activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase.J Biol Chem271: 8488–8492

    Article  PubMed  CAS  Google Scholar 

  18. New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC, Han J (1998) PRAK, a novel protein kinase regulated by p38 MAP kinase. EMBO J 17: 3372–3384

    Article  PubMed  CAS  Google Scholar 

  19. Deak M, Clifton AD, Lucocq JM, Alessi DR (1998) Mitogen-and stress-activated protein kinase-1 (MSK-1) is directly activated by MAPK and SAPK/p38 and may mediate the activation of CREB.EMBO J17: 4426–4441

    Article  PubMed  CAS  Google Scholar 

  20. Waskiewicz AJ, Flynn A, Proud CG, Cooper JA (1997) Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2.EMBO J16: 1909–1920

    Article  PubMed  CAS  Google Scholar 

  21. Han J, Jiang Y, Li Z, Kravchenko V, Ulevitch RJ (1997) Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation.Nature386: 296–299

    Article  PubMed  CAS  Google Scholar 

  22. Janknecht R and Hunter T (1997) Convergence of MAP kinase pathways on a ternary complex factor Sap-1a. EMBO ϑ 16: 1620–1627

    Article  CAS  Google Scholar 

  23. Lee JC, Griswold D, Votta B, Hanna N (1988) Inhibition of monocyte Il-1 production by the anti-inflammatory compound, SK&F 86002.Int J Immunopharmacol10: 835–843

    Article  PubMed  CAS  Google Scholar 

  24. Lee JC, Badger AM, Griswold DE, Dunnington D, Truneh A, Votta B, White JR, Young PR, Bender PE (1993) Bicyclic imidazoles as a class of cytokine biosynthesis inhibitors.Ann NY Acad Sci696: 149–170

    Article  PubMed  CAS  Google Scholar 

  25. Griswold DE, Hillegrass LM, Meunier PC, DiMartino MJ, Hanna N (1988) The effect of inhibitors of eicosanoid metabolism in murine collagen-induced arthritis.Arthritis Rheum31: 1406–1412

    Article  PubMed  CAS  Google Scholar 

  26. Gallagher TF, Fier-Thompson SM, Garigipati RS, Sorenson ME, Smietana JM, Lee D, Bender PE, Lee JC, Laydon JT, Griswold DE et al (1995) 2,4,5-triarylimidazole inhibitors of IL-1 biosynthesis.Bioorg Med Chem Lett5: 1171–1176

    Article  CAS  Google Scholar 

  27. de Laszlo SE, Visco D, Agarwal L, Cahng L, Chin J, Croft G, Forsyth A, Flectcher D, Frantz B, Hacker C et al (1998) Pyrroles and other heterocycles as inhibitors of p38 kinase.Bioorg Med Chem Lett8: 2689–2694

    Article  PubMed  Google Scholar 

  28. Henry JR, Rupert KC, Dodd JH, Turchi IJ, Wadsworth SA, Cavender DE, Fahmy B, Olini GC, Davis JE, Pellegrino-Gensey JL et al (1998) 6-amino-2-(4-fluorophenyl)-4methoxy-3-(4-pyridyl)-1H-pyrrolo2,3-b]pyridine (RWJ 68354): a potent and selective p38 kinase inhibitor.J Med Chem41: 4196–4198

    Article  PubMed  CAS  Google Scholar 

  29. Aantanarayan A, Clare M, Geng L, Hanson G, Partis RA, Stealey MA, Weier RM (1998) 3(5)-heteroaryl substituted pyrazoles as p38 kinase inhibitors. GD Searle & Co patent application WO9852937

    Google Scholar 

  30. Jackson JR, Bolognese B, Hillegass L, Kassis S, Adams J, Griswold DE, Winkler JD (1998) Pharmacological effects of SB 220025, a selective inhibitor of p38 mitogen activated protein kinase, in angiogenesis and chronic inflammatory disease models.J Pharmacol Exp Ther284: 687–692

    PubMed  CAS  Google Scholar 

  31. LoGrasso PV, Frantz B, Rolando AM, O’Keefe SJ, Hermes JD, O’Neill EA (1997) Kinetic mechanism for p38 MAP kinase.Biochemistry36: 10422–10427

    Article  PubMed  CAS  Google Scholar 

  32. Young PR, Mclaughlin M, Kumar S, Kassis S, Doyle ML, McNulty D, Gallagher TF, Fisher S, McDonnell PC, Carr SA et al (1997) Pyridinylimidazole inhibitors of p38 mito-gen activated protein kinase bind in the ATP site. JBiol Chem272:12116–12121

    Article  PubMed  CAS  Google Scholar 

  33. Frantz B, Klatt MP, Parsons J, Rolando A, Williams H, Tocci MJ, O’Keefe SJ,O’Neill EA (1998) The activation of p38 mitogen activated protein kinase determines the efficiency of ATP competition for the pyridinylimidazole inhibitor binding.Biochemistry37: 13846–13853

    Article  PubMed  CAS  Google Scholar 

  34. Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young PR, Lee JC (1995) SB 203580 is as a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1.FEBS Lett364: 229–233

    Article  PubMed  CAS  Google Scholar 

  35. Clerk A, Sugden PH (1998) The p38 MAPK inhibitor, SB 203580, inhibits cardiac stress-activated protein kinases/c-jun N-terminal kinases (SAPKs/JNKs).FEBS Lett426: 93–96

    Article  PubMed  CAS  Google Scholar 

  36. Gum RJ, McLaughlin M, Kumar S, Wang Z, Bower MJ, Lee JC, Adams JL, Livi GP, Goldsmith EJ, Young PR (1998) Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket.J Biol Chem273; 15605–15610

    Article  PubMed  CAS  Google Scholar 

  37. Lisnock J, Tebben A, Frantz B, O’Neill EA, Croft G, O’Keefe SJ, Li B, Hacker C, de Laszlo S, Smith A et al (1998) Molecular basis for p38 protein kinase inhibitor specificity.Biochemistry37: 16573–16581

    Article  PubMed  CAS  Google Scholar 

  38. Eyers PA, Craxton M, Morrice N, Cohne P, Goedert M (1998) Conversion of SB 203580-sensitive MAP kinase family members to drug-sensitive forms by a single amino acid substitution.Chem Biol5: 321–328

    Article  PubMed  CAS  Google Scholar 

  39. Wilson KP, Fitzgibbon MJ, Caron PR, Griffith JP, Chen W, McCaffrey PG, Chambers SP, Su M (1996) Crystal structure of p38 mitogen activated protein kinase.J Biol Chem271: 27696–27700

    Article  PubMed  CAS  Google Scholar 

  40. Wang Z, Harkins PC, Ulevitch RJ, Han J, Cobb MH, Goldsmith EJ (1997) The structure of mitogen activated protein kinase p38 at 2.1-A resolution.Proc Natl Acad Sci USA94: 2327–2332

    Article  PubMed  CAS  Google Scholar 

  41. Tong L, Pay S, White DM, Rogers S, Crane KM, Cywin CL, Brown ML, Pargellis CA (1997) A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket.Nature Struct Biol4: 311–316

    Article  PubMed  CAS  Google Scholar 

  42. Wislon KP, McCaffrey PG, Hsiao K, Pazhanisamy S Galullo V, Bemis GW, Fitzgibbon MJ, Caron PR, Murcko MA, Su M (1997) The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase.Chem Biol4: 423–431

    Article  Google Scholar 

  43. Wang Z, Canagarajah BJ, Boehm JC, Kassisa S, Cobb MH, Young PR, Abdel-Meguid S, Adams JL, Goldsmith EJ (1998) Structural basis of inhibitor selectivity in MAP kinases.Structure6: 1117–1128

    Article  PubMed  CAS  Google Scholar 

  44. Badger AM, Bradbeer JM, Votta B, Lee JC, Adams JL, Griswold DE (1996) Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function.J Pharmacol Exp Ther279: 1453–1461

    PubMed  CAS  Google Scholar 

  45. Williams RO, Feldmann M, Maini RN (1992) Anti-tumour necrosis factor ameliorates joint disease in murine collagen-induced arthritis.Proc Natl Acad Sci USA89: 9784–9788

    Article  PubMed  CAS  Google Scholar 

  46. Van den Berg WB, Joosten LA, Helsen M, Van de Loo FA (1994) Amelioration of established murine collagen-induced arthritis with anti-IL-1 treatment.Clin Exp Immunol95: 237–243

    Article  PubMed  Google Scholar 

  47. Ridley SH, Sarsfield SJ, Lee JC, Bigg HF, Cawston TE, Taylor DJ, DeWitt DL, Saklatvala J (1997) Actions of IL-1 are selectively controlled by p38 mitogen activated protein kinase.J Immunol158: 3165–3173

    PubMed  CAS  Google Scholar 

  48. Miyazawa K, Mori A, Miyata H, Akahane M, Ajisawa Y, Okudaira H (1998) Regulation of interleukin-113-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by p38 mitogen activated protein kinase.J Biol Chem273: 24832–24838

    Article  PubMed  CAS  Google Scholar 

  49. Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman JC, Cohen P, Fiers W (1996) The p38/RK mitogen activated protein kinase pathway regulates interleukin-6 synthesis response to tumour necrosis factor.EMBO J15: 1914–1923

    PubMed  CAS  Google Scholar 

  50. Pouliot M, Baillargeon J, Lee JC, Cleland LG, James MJ (1997) Inhibition of prostaglandin endoperoxide synthase-2 expression in stimulated human monocytes by inhibitors of p38 mitogen activated protein kinase.J Immunol158: 4930–4937

    PubMed  CAS  Google Scholar 

  51. Dean JL, Brook M, Clark AR, Saklatvala J (1999) p38 mitogen activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharidetreated human monocytes.J Biol Chem274: 264–269

    Article  PubMed  CAS  Google Scholar 

  52. Ridley S, Dean JL, Sarsfield SJ, Brook M, Clark AR, Saklatvala J (1998) A p38 map kinase inhibitor regulates stability of interleukin-1-induced cyclooxygenase-2 mRNA.FEBS Lett439: 75–80

    Article  PubMed  CAS  Google Scholar 

  53. Seki N, Sudo Y, Yoshioka T, Sugihara S, Fujitsu T, Sakuma S, Ogawa T, Hamaoka T, Senoh H, Fujiwara H (1988) Type II collagen-induced murine arthritis. I. Induction and perpetuation of arthritis require synergy between humoral and cell-mediated immunity.J Immunol140: 1477–1484

    PubMed  CAS  Google Scholar 

  54. Craxton A, Shu G, Graves JD, Saklatvala J, Krebs EG, Clark EA (1998) p38 MAPK is required for CD40-induced gene expression and proliferation in B lymphocytes.J Immunol161: 3225–3236

    PubMed  CAS  Google Scholar 

  55. Schafer PH, Wang L, Wadsworth SA, Davis JE, Siekierka JJ (1999) T cell activation signals up-regulate p38 mitogen activated protein kinase activity and induce TNFα production in a manner distinct from LPS activation of monocytes.J Immunol162: 659–668

    PubMed  CAS  Google Scholar 

  56. Crawley JB, Rawlinson L, Lai FV, Page TH, Saklatvala J, Foxwell BM (1997) T cell proliferation in response to interleukins 2 and 7 requires p38 MAP kinase activation.J Biol Chem272: 15023–15027

    Article  PubMed  CAS  Google Scholar 

  57. Koprak S, Staruch MJ, Dumont FJ (1999) A specific inhibitor of p38 mitogen activated protein kinase affects differentially the production of various cytokines by activated human T cells: dependence on CD28 signalling and preferential inhibition of IL-10 production.Cell Immunol192: 87–95

    Article  PubMed  CAS  Google Scholar 

  58. Bonnefoy JY, Lecoanet-Henchoz S, Gauchat JF, Graber P,Aubry JP, Jeannin P, Plater- Zyberk C (1997) Structure and functions of CD23.Int Rev Immunol16: 113–128

    Article  PubMed  CAS  Google Scholar 

  59. Marshall LA, Hansbury MJ, Bolognese BJ, Gum RJ, Young PR, Mayer RJ (1998) Inhibitors of the p38 mitogen activated kinase modulate IL-4 induction of low affinity IgE receptor (CD23) in human monocytes.J Immnuol161: 6005–6013

    CAS  Google Scholar 

  60. Plater-Zyberk C, Bonnefoy JF (1995) Marked amelioration of established collagen-induced arthritis by treatment with antibodies to CD23in vivo. Nat Med1: 781–785

    CAS  Google Scholar 

  61. Kleinu S, Martinsson P, Gustaysson S, Heyman B (1999) Importance of CD23 for collagen-induced arthritis: delayed onset and reduced severity in CD23-deficient mice.J Immunol162: 4266–4270

    Google Scholar 

  62. Pritchett W, Hand A, Shields J, Dunnington D (1995) Mechanism of action of bicylic imidazoles defines a translational regulatory pathway for tumour necrosis factor alpha.J In Hamm45: 97–105

    Google Scholar 

  63. Kotlyarov A, Neininger A, Schubert C, Eckert R, Birchmeier C, Volk H-D, Gaestel M (1999) MAPKAP kinase-2 is essential for LPS-induced TNFα biosynthesis.Nat Cell Biol1: 94–97

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Celltech Chiroscience, 216 Bath Road, Slough Berkshire, SL1 4EN, UK

    Raymond J. Owens & Simon Lumb

Authors
  1. Raymond J. Owens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Simon Lumb
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Celltech Chiroscience, 216 Bath Road, Slough Berkshire, SL1 4EN, UK

    Gerry A. Higgs

  2. Cellular Microbiology Research Group Eastman Dental Institute, University College London, 256 Gray’s Inn Road, London, WC1X 8LD, UK

    Brian Henderson

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer Basel AG

About this chapter

Cite this chapter

Owens, R.J., Lumb, S. (2000). Therapeutic regulation of cytokine signalling by inhibitors of p38 mitogen-activated protein kinase. In: Higgs, G.A., Henderson, B. (eds) Novel Cytokine Inhibitors. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8450-1_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-8450-1_10

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9572-9

  • Online ISBN: 978-3-0348-8450-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation