, Volume 17, Issue 2, pp 113–129 | Cite as

Inhibitors of p38 Mitogen-Activated Protein Kinase

Potential as Anti-inflammatory Agents in Asthma?
Drug Mechanisms and Targets


Asthma is an inflammatory disease of the airways, which in patients with mild to moderate symptoms is adequately controlled by either β2-adrenoceptor agonists or corticosteroids, or a combination of both. Despite this, there are classes of patients that fail to respond to these treatments. In addition, there is a general trend towards increasing morbidity and mortality due to asthma, which suggests that there is a need for new and improved treatments. The p38 mitogen-activated protein kinases (MAPKs) represent a point of convergence for multiple signalling processes that are activated in inflammation and that impact on a diverse range of events that are important in inflammation. Small molecule pyridinyl imidazole inhibitors of p38 MAPK have proved to be highly effective in reducing various parameters of inflammation, in particular cytokine expression. Like corticosteroids, inhibitors of p38 MAPK appear to be able to repress gene expression at multiple levels, for example, by transcriptional, posttranscriptional and translational repression, and this raises the possibility of a similarly broad spectrum of anti-inflammatory activities. Indeed these molecules have proved to be effective in numerous in vitro and in vivo models of inflammation and septicaemia, which suggests that such compounds may be effective as therapeutic agents against inflammatory disorders. Despite these very promising indications of the possible therapeutic use of p38 MAPK inhibitors, a number of events that are p38-dependent are in fact also beneficial to the resolution or modulation of diseases such as asthma. We conclude that the overall effect of p38 MAPK inhibition would be beneficial in inflammatory diseases such as rheumatoid arthritis and asthma. However, these drugs may result in a complex phenotype that will require careful evaluation. Currently, a number of second or third generation inhibitors of p38 MAPK are being tested in phase I and phase II clinical trials.


Asthma Chronic Obstructive Pulmonary Disease Airway Smooth Muscle cAMP Response Element Binding Elastin mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Neil Holden is funded by the MRC and Novartis Pharmaceuticals UK Ltd.


  1. 1.
    Chiappara G, Gagliardo R, Siena A, et al. Airway remodelling in the pathogenesis of asthma. Curr Opin Allergy Clin Immunol 2001; 1: 85–93PubMedGoogle Scholar
  2. 2.
    Foster PS, Hogan SP, Yang M, et al. Interleukin-5 and eosinophils as therapeutic targets for asthma. Trends Mol Med 2002; 8: 162–7PubMedCrossRefGoogle Scholar
  3. 3.
    Hartert TV, Peebles Jr RS. Epidemiology of asthma: the year in review. Curr Opin Pulm Med 2000; 6: 4–9PubMedCrossRefGoogle Scholar
  4. 4.
    Barnes PJ. Therapeutic strategies for allergic diseases. Nature 1999; 402(6760): B31–8PubMedCrossRefGoogle Scholar
  5. 5.
    Bryan SA, Leckie MJ, Hansel TT, et al. Novel therapy for asthma. Expert Opin Investig Drugs 2000; 9: 25–42PubMedCrossRefGoogle Scholar
  6. 6.
    Barnes PJ. The role of inflammation and anti-inflammatory medication in asthma. Respir Med 2002; 96 Suppl. A: S9–15PubMedGoogle Scholar
  7. 7.
    Sears MR. The evolution of beta2-agonists. Respir Med 2001; 95 Suppl. B: S2–6PubMedCrossRefGoogle Scholar
  8. 8.
    Barnes PJ. Inhaled glucocorticoids for asthma. N Engl J Med 1995; 332: 868–75PubMedCrossRefGoogle Scholar
  9. 9.
    Hancox RJ, Taylor DR. Long-acting beta-agonist treatment in patients with persistent asthma already receiving inhaled corticosteroids. BioDrugs 2001; 15: 11–24PubMedCrossRefGoogle Scholar
  10. 10.
    Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonists and corticosteroids. Eur Respir J 2002; 19: 182–91PubMedCrossRefGoogle Scholar
  11. 11.
    Lane SJ, Lee TH. Mechanisms of corticosteroid resistance in asthmatic patients. Int Arch Allergy Immunol 1997; 113: 193–5PubMedCrossRefGoogle Scholar
  12. 12.
    Barnes PJ, Woolcock AJ. Difficult asthma. Eur Respir J 1998; 12: 1209–18PubMedCrossRefGoogle Scholar
  13. 13.
    Griswold DE, Marshall PJ, Webb EF, et al. SK&F 86002: a structurally novel anti-inflammatory agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid. Biochem Pharmacol 1987; 36: 3463–70PubMedCrossRefGoogle Scholar
  14. 14.
    DiMartino MJ, Griswold DE, Berkowitz BA, et al. Pharmacologic characterization of the anti-inflammatory properties of a new dual inhibitor of lipoxygenase and cyclooxygenase. Agents Actions 1987; 20: 113–23PubMedCrossRefGoogle Scholar
  15. 15.
    Griswold DE, Hillegass LM, Meunier PC, et al. Effect of inhibitors of eicosanoid metabolism in murine collagen-induced arthritis. Arthritis Rheum 1988; 31: 1406–12PubMedCrossRefGoogle Scholar
  16. 16.
    Lee JC, Griswold DE, Votta B, et al. Inhibition of monocyte IL-1 production by the anti-inflammatory compound, SK&F 86002. Int J Immunopharmacol 1988; 10: 835–43PubMedCrossRefGoogle Scholar
  17. 17.
    Lee JC, Laydon JT, McDonnell PC, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 1994; 372: 739–46PubMedCrossRefGoogle Scholar
  18. 18.
    Cuenda A, Rouse J, Doza YN, et al. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Lett 1995; 364: 229–33PubMedCrossRefGoogle Scholar
  19. 19.
    Raingeaud J, Gupta S, Rogers JS, et al. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem 1995; 270: 7420–6PubMedCrossRefGoogle Scholar
  20. 20.
    Griswold DE, Hillegass LM, O’Leary-Bartus J, et al. Evaluation of human cytokine production and effects of pharmacological agents in a heterologous system in vivo. J Immunol Methods 1996; 195: 1–5PubMedCrossRefGoogle Scholar
  21. 21.
    Badger AM, Griswold DE, Kapadia R, et al. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum 2000; 43: 175–83PubMedCrossRefGoogle Scholar
  22. 22.
    Underwood DC, Osborn RR, Kotzer CJ, et al. SB 239063, apotentp38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence. J Pharmacol Exp Ther 2000; 293: 281–8PubMedGoogle Scholar
  23. 23.
    Liverton NJ, Butcher JW, Claiborne CF, et al. Design and synthesis of potent, selective, and orally bioavailable tetrasubstituted imidazole inhibitors of p38 mitogen-activated protein kinase. J Med Chem 1999; 42: 2180–90PubMedCrossRefGoogle Scholar
  24. 24.
    Haddad JJ. VX-745: Vertex Pharmaceuticals. Curr Opin Investig Drugs 2001; 2: 1070–6PubMedGoogle Scholar
  25. 25.
    Henry JR, Rupert KC, Dodd JH, et al. 6-Amino-2-(4-fluorophenyl)-4-methoxy-3-(4-pyridyl)-lH-pyrrolo[2,3-b]pyridine(RWJ 68354): apotent and selective p38 kinase inhibitor. J Med Chem 1998; 41: 4196–8PubMedCrossRefGoogle Scholar
  26. 26.
    Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001; 81: 807–69PubMedGoogle Scholar
  27. 27.
    Buchsbaum RJ, Connolly BA, Feig LA, et al. Interaction of Rac exchange factors Tiaml and Ras-GRFl with a scaffold for the p38 mitogen-activated protein kinase cascade. Mol Cell Biol 2002; 22: 4073–85PubMedCrossRefGoogle Scholar
  28. 28.
    Han J, Lee JD, Bibbs L, et al. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 1994; 265: 808–11PubMedCrossRefGoogle Scholar
  29. 29.
    Rouse J, Cohen P, Trigon S, et al. A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 1994; 78: 1027–37PubMedCrossRefGoogle Scholar
  30. 30.
    Freshney NW, Rawlinson L, Guesdon F, et al. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 1994; 78: 1039–49PubMedCrossRefGoogle Scholar
  31. 31.
    Zervos AS, Faccio L, Gatto JP, et al. Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. Proc Natl Acad Sci U S A 1995; 92: 10531–4PubMedCrossRefGoogle Scholar
  32. 32.
    Jiang Y, Chen C, Li Z, et al. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem 1996; 271: 17920–6PubMedCrossRefGoogle Scholar
  33. 33.
    Mertens S, Craxton M, Goedert M. SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. FEBS Lett 1996; 383: 273–6PubMedCrossRefGoogle Scholar
  34. 34.
    Lechner C, Zahalka MA, Giot JF, et al. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A 1996; 93: 4355–9PubMedCrossRefGoogle Scholar
  35. 35.
    Li Z, Jiang Y, Ulevitch RJ, et al. The primary structure of p38 gamma: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun 1996; 228: 334–40PubMedCrossRefGoogle Scholar
  36. 36.
    Goedert M, Cuenda A, Craxton M, et al. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBOJ 1997; 16: 3563–71CrossRefGoogle Scholar
  37. 37.
    Cuenda A, Cohen P, Buee-Scherrer V, et al. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBOJ 1997; 16: 295–305CrossRefGoogle Scholar
  38. 38.
    Jiang Y, Gram H, Zhao M, et al. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem 1997; 272: 30122–8PubMedCrossRefGoogle Scholar
  39. 39.
    Young PR, McLaughlin MM, Kumar S, et al. Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site. J Biol Chem 1997; 272: 12116–21PubMedCrossRefGoogle Scholar
  40. 40.
    Derijard B, Raingeaud J, Barrett T, et al. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science 1995; 267: 682–5PubMedCrossRefGoogle Scholar
  41. 41.
    Raingeaud J, Whitmarsh AJ, Barrett T, et al. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol 1996; 16: 1247–55PubMedGoogle Scholar
  42. 42.
    Cuenda A, Alonso G, Morrice N, et al. Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. EMBO J 1996; 15: 4156–64PubMedGoogle Scholar
  43. 43.
    McDermott EP, O’Neill LA. Ras participates in the activation of p38 MAPK by interleukin-1 by associating with IRAK, IRAK2, TRAF6, and TAK-1. J Biol Chem 2002; 277: 7808–15PubMedCrossRefGoogle Scholar
  44. 44.
    Wesselborg S, Bauer MK, Vogt M, et al. Activation of transcription factor NF-kappaB and p38 mitogen-activated protein kinase is mediated by distinct and separate stress effector pathways. J Biol Chem 1997; 272: 12422–9PubMedCrossRefGoogle Scholar
  45. 45.
    Marinissen MJ, Chiariello M, Gutkind JS. Regulation of gene expression by the small GTPase Rho through the ERK6 (p38 gamma) MAP kinase pathway. Genes Dev 2001; 15: 535–3PubMedCrossRefGoogle Scholar
  46. 46.
    Yamauchi J, Tsujimoto G, Kaziro Y, et al. Parallel regulation of mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 in Gq-signaling cascade. J Biol Chem 2001; 276: 23362–72PubMedCrossRefGoogle Scholar
  47. 47.
    Marinissen MJ, Chiariello M, Pallante M, et al. A network of mitogen-activated protein kinases links G protein-coupled receptors to the c-jun promoter: a role for c-Jun NH2-terminal kinase, p38s, and extracellular signal-regulated kinase 5. Mol Cell Biol 1999; 19: 4289–301PubMedGoogle Scholar
  48. 48.
    Diener K, Wang XS, Chen C, et al. Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. Proc Natl Acad Sci U S A 1997; 94: 9687–92PubMedCrossRefGoogle Scholar
  49. 49.
    Yuasa T, Ohno S, Kehrl JH, et al. Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38: germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. J Biol Chem 1998; 273: 22681–92PubMedCrossRefGoogle Scholar
  50. 50.
    Graves JD, Gotoh Y, Draves KE, et al. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J 1998; 17: 2224–34PubMedCrossRefGoogle Scholar
  51. 51.
    Stokoe D, Campbell DG, Nakielny S, et al. MAPKAP kinase-2: a novel protein kinase activated by mitogen-activated protein kinase. EMBO J 1992; 11: 3985–94PubMedGoogle Scholar
  52. 52.
    McLaughlin MM, Kumar S, McDonnell PC, etal. Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem 1996; 271: 8488–92PubMedCrossRefGoogle Scholar
  53. 53.
    Stokoe D, Engel K, Campbell DG, et al. Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins. FEBS Lett 1992; 313: 307–13PubMedCrossRefGoogle Scholar
  54. 54.
    New L, Jiang Y, Zhao M, et al. PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J 1998; 17: 3372–84PubMedCrossRefGoogle Scholar
  55. 55.
    Deak M, Clifton AD, Lucocq LM, et al. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 1998; 17: 4426–41PubMedCrossRefGoogle Scholar
  56. 56.
    Wiggin GR, Soloaga A, Foster JM, et al. MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts. Mol Cell Biol 2002; 22: 2871–81PubMedCrossRefGoogle Scholar
  57. 57.
    Fukunaga R, Hunter T. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J 1997; 16: 1921–33PubMedCrossRefGoogle Scholar
  58. 58.
    Waskiewicz AJ, Flynn A, Proud CG, et al. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 1997; 16: 1909–20PubMedCrossRefGoogle Scholar
  59. 59.
    Pyronnet S, Imataka H, Gingras AC, et al. Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnkl to phosphorylate eIF4E. EMBO J 1999; 18: 270–9PubMedCrossRefGoogle Scholar
  60. 60.
    Waskiewicz AJ, Johnson JC, Penn B, et al. Phosphorylation of the cap-binding protein eukaryotic translation initiation factor 4E by protein kinase Mnkl in vivo. Mol Cell Biol 1999; 19: 1871–80PubMedGoogle Scholar
  61. 61.
    Werz O, Szellas D, Steinhilber D. Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). J Biol Chem 2002; 277: 14793–800PubMedCrossRefGoogle Scholar
  62. 62.
    Waterman WH, Molski TF, Huang CK, et al. Tumour necrosis factor-alpha-induced phosphorylation and activation of cytosolic phospholipase A2 are abrogated by an inhibitor of the p38 mitogen-activated protein kinase cascade in human neutrophils. Biochem J 1996; 319: 17–20PubMedGoogle Scholar
  63. 63.
    Hefner Y, Borsch-Haubold AG, Murakami M, et al. Serine 727 phosphorylation and activation of cytosolic phospholipase A2 by MNK1-related protein kinases. J Biol Chem 2000; 275: 37542–51PubMedCrossRefGoogle Scholar
  64. 64.
    Newton R, Cambridge L, Hart LA, et al. The MAP kinase inhibitors, PD098059, UO126 and SB203580, inhibit IL-lbeta-dependent PGE2 release via mechanistically distinct processes. Br J Pharmacol 2000; 130: 1353–61PubMedCrossRefGoogle Scholar
  65. 65.
    Boehm JC, Smietana JM, Sorenson ME, et al. 1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. J Med Chem 1996; 39: 3929–37PubMedCrossRefGoogle Scholar
  66. 66.
    Newton R. Molecular mechanisms of glucocorticoid action: what is important? Thorax 2000; 55: 603–13PubMedCrossRefGoogle Scholar
  67. 67.
    Rolli M, Kotlyarov A, Sakamoto KM, et al. Stress-induced stimulation of early growth response gene-1 by p38/stress-activated protein kinase 2 is mediated by a cAMP-responsive promoter element in a MAPKAP kinase 2-independent manner. J Biol Chem 1999; 274: 19559–64PubMedCrossRefGoogle Scholar
  68. 68.
    Zhu T, Lobie PE. Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone: resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis. J Biol Chem 2000; 275: 2103–14PubMedCrossRefGoogle Scholar
  69. 69.
    Han J, Jiang Y, Li Z, et al. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Nature 1997; 386: 296–9PubMedCrossRefGoogle Scholar
  70. 70.
    Wang XZ, Ron D. Stress-induced phosphorylation and activation of the transcription factor CHOP (GADD153) by p38 MAP Kinase. Science 1996; 272:1347–9PubMedCrossRefGoogle Scholar
  71. 71.
    Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336: 1066–71PubMedCrossRefGoogle Scholar
  72. 72.
    Barnes PJ. Pathophysiology of asthma. In: Barnes PJ, Rodger IW, Thomson NC, editors. Asthma: basic mechanisms and clinical management. San Diego: Academic Press, 1998: 487–506Google Scholar
  73. 73.
    Hazzalin CA, Cano E, Cuenda A, et al. p38/RK is essential for stress-induced nuclear responses: JNK/SAPKs and c-Jun/ATF-2 phosphorylation are insufficient. Curr Biol 1996; 6: 1028–31PubMedCrossRefGoogle Scholar
  74. 74.
    Chiariello M, Marinissen MJ, Gutkind JS. Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. Mol Cell Biol 2000; 20: 1747–58PubMedCrossRefGoogle Scholar
  75. 75.
    Janknecht R, Hunter T. Convergence of MAP kinase pathways on the ternary complex factor Sap-la. EMBO J 1997; 16: 1620–7PubMedCrossRefGoogle Scholar
  76. 76.
    Chung KC, Kim SM, Rhang S, et al. Expression of immediate early gene pip92 during anisomycin-induced cell death is mediated by the JNK- and p38-dependent activation of Elk1. Eur J Biochem 2000; 267: 4676–84PubMedCrossRefGoogle Scholar
  77. 77.
    Beyaert R, Cuenda A, Vanden Berghe W, et al. The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J 1996; 15: 1914–23PubMedGoogle Scholar
  78. 78.
    Berghe WV, Plaisance S, Boone E, et al. p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappa B p65 transactivation mediated by tumor necrosis factor. J Biol Chem 1998; 273: 3285–90CrossRefGoogle Scholar
  79. 79.
    Carter AB, Knudtson KL, Monick MM, et al. The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression: the role of TATA-binding protein (TBP). J Biol Chem 1999; 274: 30858–63PubMedCrossRefGoogle Scholar
  80. 80.
    Madrid LV, Mayo MW, Reuther JY, et al. Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem 2001; 276: 18934–40PubMedCrossRefGoogle Scholar
  81. 81.
    Thomson S, Clayton AL, Hazzalin CA, et al. The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 asapotentialhistoneH3/HMG-14kinase. EMBOJ 1999; 18: 4779–93CrossRefGoogle Scholar
  82. 82.
    Saccani S, Pantano S, Natoli G. p38-dependent marking of inflammatory genes for increased NF-kappa B recruitment. Nat Immunol 2002; 3: 69–75PubMedCrossRefGoogle Scholar
  83. 83.
    Bergmann M, Hart L, Lindsay M, et al. IkappaBalpha degradation and nuclear factor-kappaB DNA binding are insufficient for interleukin-1beta and tumor necrosis factor-alpha induced kappaB-dependent transcription: requirement for an additional activation pathway. J Biol Chem 1998; 273: 6607–10PubMedCrossRefGoogle Scholar
  84. 84.
    Haq R, Halupa A, Beattie BK, et al. Regulation of erythropoietin-induced STAT serine phosphorylation by distinct mitogen-activated protein kinases. J Biol Chem 2002; 277: 17359–6PubMedCrossRefGoogle Scholar
  85. 85.
    Visconti R, Gadina M, Chiariello M, et al. Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood 2000; 96: 1844–52PubMedGoogle Scholar
  86. 86.
    Kovarik P, Stoiber D, Eyers PA, et al. Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. Proc Natl Acad Sci U S A 1999; 96:13956–61PubMedCrossRefGoogle Scholar
  87. 87.
    Adcock IM, Lane SJ, Brown CR, et al. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. J Exp Med 1995; 182:1951–8PubMedCrossRefGoogle Scholar
  88. 88.
    Irusen E, Matthews JG, Takahashi A, et al. p38 mitogen-activated protein kinaseinduced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol 2002; 109: 649–57PubMedCrossRefGoogle Scholar
  89. 89.
    Olivera DL, Laydon JT, Hillegass L, et al. Effects of pyridinyl imidazole compounds on murine TNF-alpha production. Agents Actions 1993; 39: C55–7PubMedCrossRefGoogle Scholar
  90. 90.
    Young P, McDonnell P, Dunnington D, et al. Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level. Agents Actions 1993; 39: C67–9PubMedCrossRefGoogle Scholar
  91. 91.
    Jacobson A, Peltz SW. Interrelationships of the pathways of mRNA decay and translation in eukaryotic cells. Annu Rev Biochem 1996; 65: 693–739PubMedCrossRefGoogle Scholar
  92. 92.
    Kleijn M, Scheper GC, Voorma HO, et al. Regulation of translation initiation factors by signal transduction. Eur J Biochem 1998; 253: 531–44PubMedCrossRefGoogle Scholar
  93. 93.
    Rhoads RE. Signal transduction pathways that regulate eukaryotic protein synthesis. J Biol Chem 1999; 274: 30337–40PubMedCrossRefGoogle Scholar
  94. 94.
    Shaw G, Kamen R. A conserved AU sequence from the 3′untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 1986; 46: 659–67PubMedCrossRefGoogle Scholar
  95. 95.
    Huarte J, Stutz A, O’Connell ML, et al. Transient translational silencing by reversible mRNA deadenylation. Cell 1992; 69: 1021–30PubMedCrossRefGoogle Scholar
  96. 96.
    Kruys V, Marinx O, Shaw G, et al. Translational blockade imposed by cytokine-derived UA-rich sequences. Science 1989; 245: 852–5PubMedCrossRefGoogle Scholar
  97. 97.
    Rajagopalan LE, Malter JS. Modulation of granulocyte-macrophage colony-stimulating factor mRNA stability in vitro by the adenosine-uridine binding factor. J Biol Chem 1994; 269: 23882–8PubMedGoogle Scholar
  98. 98.
    Rajagopalan LE, Burkholder JK, Turner J, et al. Granulocyte-macrophage colony-stimulating factor mRNA stabilization enhances transgenic expression in normal cells and tissues. Blood 1995; 86: 2551–8PubMedGoogle Scholar
  99. 99.
    Caput D, Beutler B, Hartog K, et al. Identification of a common nucleotide sequence in the 3′- untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci U S A 1986; 83: 1670–4PubMedCrossRefGoogle Scholar
  100. 100.
    Yang L, Yang YC. Regulation of interleukin (IL)-11 gene expression in IL-1 induced primate bone marrow stromal cells. J Biol Chem 1994; 269: 32732–9PubMedGoogle Scholar
  101. 101.
    Han J, Brown T, Beutler B. Endotoxin-responsive sequences control cachectin/ tumor necrosis factor biosynthesis at the translational level. J Exp Med 1990; 171:465–75PubMedCrossRefGoogle Scholar
  102. 102.
    Han J, Huez G, Beutler B. Interactive effects of the tumor necrosis factor promoter and 3′- untranslated regions. J Immunol 1991; 146: 1843–8PubMedGoogle Scholar
  103. 103.
    Crawford EK, Ensor JE, Kalvakolanu I, et al. The role of 3′poly(A) tail metabolism in tumor necrosis factor-alpha regulation. J Biol Chem 1997; 272: 21120–7PubMedCrossRefGoogle Scholar
  104. 104.
    Gueydan C, Droogmans L, Chalon P, et al. Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA. J Biol Chem 1999; 274: 2322–6PubMedCrossRefGoogle Scholar
  105. 105.
    Kern JA, Warnock LJ, McCafferty JD. The 3′untranslated region of IL-1beta regulates protein production. J Immunol 1997; 158: 1187–93PubMedGoogle Scholar
  106. 106.
    Henics T, Sanfridson A, Hamilton BJ, et al. Enhanced stability of interleukin-2 mRNA in MLA 144 cells: possible role of cytoplasmic AU-rich sequence-binding proteins. J Biol Chem 1994; 269: 5377–83PubMedGoogle Scholar
  107. 107.
    Dean JL, Wait R, Mahtani KR. The 3′untranslated region of tumor necrosis factor alpha mRNA is a target of the mRNA-stabilizing factor HuR. Mol Cell Biol 2001; 21: 721–30PubMedCrossRefGoogle Scholar
  108. 108.
    Chen CY, Del Gatto-Konczak F, Wu Z, et al. Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. Science 1998; 280: 1945–9PubMedCrossRefGoogle Scholar
  109. 109.
    Winzen R, Kracht M, Ritter B, et al. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. EMBO J 1999; 18: 4969–80PubMedCrossRefGoogle Scholar
  110. 110.
    Ristimaki A, Garfinkel S, Wessendorf J, et al. Induction of cyclooxygenase-2 by interleukin-1 alpha: evidence for post-transcriptional regulation. J Biol Chem 1994; 269: 11769–75PubMedGoogle Scholar
  111. 111.
    Newton R, Seybold S, Liu SF, et al. Alternate COX-2 transcripts are differentially regulated: implications for post-transcriptional control. Biochem Biophys Res Commun 1997; 234: 85–9PubMedCrossRefGoogle Scholar
  112. 112.
    Barrios RM, Tiraloche G, Chadee K. Lipopolysaccharide modulates cyclooxygenase-2 transcriptionally and posttranscriptionally in human macrophages independently from endogenous IL-1 beta and TNF-alpha. J Immunol 1999; 163: 963–9Google Scholar
  113. 113.
    Brook M, Sully G, Clark AR, et al. Regulation of tumour necrosis factor alpha mRNA stability by the mitogen-activated protein kinase p38 signalling cascade. FEBS Lett 2000; 483: 57–61PubMedCrossRefGoogle Scholar
  114. 114.
    Rutault K, Hazzalin CA, Mahadevan LC. Combinations of ERK and p38 MAPK inhibitors ablate tumor necrosis factor-alpha (TNF-alpha) mRNA induction: evidence for selective destabilization of TNF-alpha transcripts. J Biol Chem 2001; 276: 6666–74PubMedCrossRefGoogle Scholar
  115. 115.
    Ming XF, Stoecklin G, Lu M, et al. Parallel and independent regulation of interleukin-3 mRNA turnover by phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase. Mol Cell Biol 2001; 21: 5778–89PubMedCrossRefGoogle Scholar
  116. 116.
    Dean JL, Brook M, Clark AR, et al. p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharidetreated human monocytes. J Biol Chem 1999; 274: 264–9PubMedCrossRefGoogle Scholar
  117. 117.
    Lasa M, Brook M, Saklatvala J, et al. Dexamethasone destabilizes cyclooxygenase 2 mRNA by inhibiting mitogen-activated protein kinase p38. Mol Cell Biol 2001; 21:771–80PubMedCrossRefGoogle Scholar
  118. 118.
    Kucich U, Rosenbloom JC, Abrams WR, et al. Transforming growth factor-beta stabilizes elastin mRNA by a pathway requiring active Smads, protein kinase C-delta, and p38. Am J Respir Cell Mol Biol 2002; 26: 183–8PubMedGoogle Scholar
  119. 119.
    Kotlyarov A, Neininger A, Schubert C, et al. MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol 1999; 1: 94–7PubMedCrossRefGoogle Scholar
  120. 120.
    Neininger A, Kontoyiannis D, Kotlyarov A, et al. MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. J Biol Chem 2002; 277:3065–8PubMedCrossRefGoogle Scholar
  121. 121.
    Kontoyiannis D, Kotlyarov A, Carballo E, et al. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. EMBO J 2001; 20: 3760–70PubMedCrossRefGoogle Scholar
  122. 122.
    Carballo E, Lai WS, Blackshear PJ. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 1998; 281: 1001–5PubMedCrossRefGoogle Scholar
  123. 123.
    Lai WS, Carballo E, Strum JR, et al. Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol 1999; 19: 4311–23PubMedGoogle Scholar
  124. 124.
    Carballo E, Lai WS, Blackshear PJ. Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood 2000; 95: 1891–9PubMedGoogle Scholar
  125. 125.
    Knauf U, Tschopp C, Gram H. Negative regulation of protein translation by mitogen-activated protein kinase-interacting kinases 1 and 2. Mol Cell Biol 2001; 21: 5500–11PubMedCrossRefGoogle Scholar
  126. 126.
    Cuesta R, Laroia G, Schneider RJ. Chaperone hsp27 inhibits translation during heat shock by binding eIF4G and facilitating dissociation of cap-initiation complexes. Genes Dev 2000; 14: 1460–70PubMedGoogle Scholar
  127. 127.
    Chen G, Hitomi M, Han J, et al. The p38 pathway provides negative feedback for Ras proliferative signaling. J Biol Chem 2000; 275: 38973–80PubMedCrossRefGoogle Scholar
  128. 128.
    Westermarck J, Li SP, Kallunki T, et al. p38 mitogen-activated protein kinase-dependent activation of protein phosphatases 1 and 2A inhibits MEK1 and MEK2 activity and collagenase 1 (MMP-1) gene expression. Mol Cell Biol 2001; 21: 2373–83PubMedCrossRefGoogle Scholar
  129. 129.
    Niiro H, Otsuka T, Ogami E, et al. MAP kinase pathways as a route for regulatory mechanisms of IL-10 and IL-4 which inhibit COX-2 expression in human monocytes. Biochem Biophys Res Commun 1998; 250: 200–5PubMedCrossRefGoogle Scholar
  130. 130.
    Lim W, Ma W, Gee K, et al. Distinct role of p38 and c-Jun N-terminal kinases in IL-10-dependent and IL-10-independent regulation of the costimulatory molecule B7.2 in lipopolysaccharide-stimulated human monocytic cells. J Immunol 2002; 168: 1759–69PubMedGoogle Scholar
  131. 131.
    Lee JC, Kumar S, Griswold DE, et al. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 2000; 47: 185–201PubMedCrossRefGoogle Scholar
  132. 132.
    Giembycz MA, Lindsay MA. Pharmacology of the eosinophil. Pharmacol Rev 1999; 51: 213–339PubMedGoogle Scholar
  133. 133.
    Kampen GT, Stafford S, Adachi T, et al. Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases. Blood 2000; 95: 1911–7PubMedGoogle Scholar
  134. 134.
    Kankaanranta H, De Souza PM, Barnes PJ, et al. SB 203580, an inhibitor of p38 mitogen-activated protein kinase, enhances constitutive apoptosis of cytokine-deprived human eosinophils. J Pharmacol Exp Ther 1999; 290: 621–8PubMedGoogle Scholar
  135. 135.
    Lynch OT, Giembycz MA, Barnes PJ, et al. Pharmacological comparison of LTB(4)-induced NADPH oxidase activation in adherent and non-adherent guinea-pig eosinophils. Br J Pharmacol 2001; 134: 797–806PubMedCrossRefGoogle Scholar
  136. 136.
    Adachi T, Choudhury BK, Stafford S, et al. The differential role of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase in eosinophil functions. J Immunol 2000; 165: 2198–204PubMedGoogle Scholar
  137. 137.
    Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999; 54: 825–57PubMedCrossRefGoogle Scholar
  138. 138.
    Matsumoto K, Hashimoto S, Gon Y, et al. Proinflammatory cytokine-induced and chemical mediator-induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein kinase-dependent pathway. J Allergy Clin Immunol1998; 101: 825–31PubMedCrossRefGoogle Scholar
  139. 139.
    Hashimoto S, Matsumoto K, Gon Y, et al. p38 MAP kinase regulates TNF alpha-, IL-1 alpha- and PAF-induced RANTES and GM-CSF production by human bronchial epithelial cells. Clin Exp Allergy 2000; 30: 48–55PubMedCrossRefGoogle Scholar
  140. 140.
    Laan M, Lotvall J, Chung KF, et al. IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases. Br J Pharmacol 2001; 133: 200–6PubMedCrossRefGoogle Scholar
  141. 141.
    Yoon J-H, Lee W-J, Song KS. Both ERK1/2 and p38 map kinase are essential for cytokine-induced MUC5AC gene expression in airway epithelial cells [abstract]. Am J Respir Crit Care Med 2002; 165: A428Google Scholar
  142. 142.
    Lazaar AL, Panettieri Jr RA. Airway smooth muscle as an immunomodulatory cell: a new target for pharmacotherapy? Curr Opin Pharmacol 2001; 1: 259–64PubMedCrossRefGoogle Scholar
  143. 143.
    Page K, Hershenson MB. Mitogen-activated signaling and cell cycle regulation in airway smooth muscle. Front Biosci 2000; 5: D258–67PubMedCrossRefGoogle Scholar
  144. 144.
    Hedges JC, Dechert MA, Yamboliev IA, et al. A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration. J Biol Chem 1999; 274: 24211–9PubMedCrossRefGoogle Scholar
  145. 145.
    Page K, Li J, Hershenson MB. p38 MAP kinase negatively regulates cyclin D1 expression in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2001; 280: L955–64PubMedGoogle Scholar
  146. 146.
    Rice AB, Ingram JI, Bonner JC. p38 map kinase regulates growth factor-stimulated mitogenesis of pulmonary myofibroblasts in vitro [abstract]. Am J Respir Crit Care Med 2002; 165: A617Google Scholar
  147. 147.
    Hirst SJ, Hallsworth MP, Peng Q, et al. Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain. Am J Respir Crit Care Med 2002; 165: 1161–71PubMedGoogle Scholar
  148. 148.
    Radi ZA, Kehrli ME, Ackermann MR. Cell adhesion molecules, leukocyte trafficking, and strategies to reduce leukocyte infiltration. J Vet Intern Med 2001; 15: 516–29PubMedCrossRefGoogle Scholar
  149. 149.
    Hashimoto S, Matsumoto K, Gon Y, et al. p38 mitogen-activated protein kinase regulates IL-8 expression in human pulmonary vascular endothelial cells. Eur Respir J 1999; 13: 1357–64PubMedGoogle Scholar
  150. 150.
    Hashimoto S, Gon Y, Matsumoto K, et al. Selective inhibitor of p38 mitogen-activated protein kinase inhibits lipopolysaccharide-induced interleukin-8 expression in human pulmonary vascular endothelial cells. J Pharmacol Exp Ther 2000; 293: 370–5PubMedGoogle Scholar
  151. 151.
    Goebeler M, Kilian K, Gillitzer R, et al. The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-alpha-induced expression of monocyte-chemoattractant protein-1 in endothelial cells. Blood 1999; 93: 857–65PubMedGoogle Scholar
  152. 152.
    Gao F, Yue TL, Shi DW, et al. p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation. Cardiovasc Res 2002; 53: 414–22PubMedCrossRefGoogle Scholar
  153. 153.
    Wang Q, Doerschuk CM. The p38 mitogen-activated protein kinase mediates cytoskeletal remodeling in pulmonary microvascular endothelial cells upon intracellular adhesion molecule-1 ligation. J Immunol 2001; 166: 6877–84PubMedGoogle Scholar
  154. 154.
    Ridley SH, Sarsfield SJ, Lee JC, et al. Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. J Immunol 1997; 158: 3165–73PubMedGoogle Scholar
  155. 155.
    Pawankar R. Mast cells as orchestrators of the allergic reaction: the IgE-IgE receptor mast cell network. Curr Opin Allergy Clin Immunol 2001; 1: 3–6PubMedGoogle Scholar
  156. 156.
    Ishizuka T, Okajima F, Ishiwara M, et al. Sensitized mast cells migrate toward the antigen: a response regulated by p38 mitogen-activated protein kinase and Rho-associated coiled-coil-forming protein kinase. J Immunol 2001; 167: 2298–304PubMedGoogle Scholar
  157. 157.
    Feoktistov I, Goldstein AE, Biaggioni I. Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. Mol Pharmacol 1999; 55: 726–34PubMedGoogle Scholar
  158. 158.
    Mori A, Kaminuma O, Miyazawa K, et al. p38 mitogen-activated protein kinase regulates human T cell IL-5 synthesis. J Immunol 1999; 163: 4763–71PubMedGoogle Scholar
  159. 159.
    Staples KJ, Bergmann M, Tomita K, et al. Adenosine 3′, 5′-cyclic monophosphate (cAMP)-dependent inhibition of IL-5 from human T lymphocytes is not mediated by the cAMP-dependent protein kinase A. J Immunol 2001; 167: 2074–80PubMedGoogle Scholar
  160. 160.
    Chen CH, Zhang DH, LaPorte JM, et al. Cyclic AMP activates p38 mitogen-activated protein kinase in Th2 cells: phosphorylation of GATA-3 and stimulation of Th2 cytokine gene expression. J Immunol 2000; 165: 5597–605PubMedGoogle Scholar
  161. 161.
    Bacharier LB, Geha RS. Molecular mechanisms of IgE regulation. J Allergy Clin Immunol 2000; 105: S547–58PubMedCrossRefGoogle Scholar
  162. 162.
    Brady K, Fitzgerald S, Ingvarsson S. CD40 employs p38 MAP kinase in IgE isotype switching. Biochem Biophys Res Commun 2001; 289: 276–81PubMedCrossRefGoogle Scholar
  163. 163.
    Hawrylowicz CM, Lee TH. Monocytes, macrophage and dendritic cells. In: Barnes PJ, Rodger IW, Thomson NC, editors. Asthma: basic mechanisms and clinical management. San Diego, USA: Academic Press, 1998: 127–40Google Scholar
  164. 164.
    Ayala JM, Goyal S, Liverton NJ, et al. Serum-induced monocyte differentiation and monocyte chemotaxis are regulated by the p38 MAP kinase signal transduction pathway. J Leukoc Biol 2000; 67: 869–75PubMedGoogle Scholar
  165. 165.
    Nick JA, Young SK, Brown KK, et al. Role of p38 mitogen-activated protein kinase in a murine model of pulmonary inflammation. J Immunol 2000; 164: 2151–9PubMedGoogle Scholar
  166. 166.
    Meja KK, Seldon PM, Nasuhara Y, et al. p38 MAP kinase and MKK-1 co-operate in the generation of GM-CSF from LPS-stimulated human monocytes by an NF-kappa B-independent mechanism. Br J Pharmacol 2000; 131: 1143–53PubMedCrossRefGoogle Scholar
  167. 167.
    Williams JA, Pontzer CH, Shacter E. Regulation of macrophage interleukin-6 (IL-6) and IL-10 expression by prostaglandin E2: the role of p38 mitogen-activated protein kinase. J Interferon Cytokine Res 2000; 20: 291–8PubMedCrossRefGoogle Scholar
  168. 168.
    Kang BY, Chung SW, Cho D, et al. Involvement of p38 mitogen-activated protein kinase intheinduction of interleukin-12 p40 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid. Biochem Pharmacol 2002; 63: 1901–10PubMedCrossRefGoogle Scholar
  169. 169.
    Jatakanon A, Uasuf C, Maziak W, et al. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999; 160: 1532–9PubMedGoogle Scholar
  170. 170.
    Tonnel AB, Gosset P, Molet S, et al. Interactions between endothelial cells and effector cells in allergic inflammation. Ann N Y Acad Sci 1996; 796: 9–20PubMedCrossRefGoogle Scholar
  171. 171.
    Fong CY, Pang L, Holland E, et al. TGF-beta1 stimulates IL-8 release, COX-2 expression, and PGE(2) release in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2000; 279: L201–7PubMedGoogle Scholar
  172. 172.
    Underwood DC, Osborn RR, Bochnowicz S, et al. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol 2000; 279: L895–902PubMedGoogle Scholar
  173. 173.
    Drost EM, MacNee W. Potential role of IL-8, platelet-activating factor and TNF-alpha in the sequestration of neutrophils in the lung: effects on neutrophil deformability, adhesion receptor expression, and chemotaxis. Eur J Immunol 2002; 32: 393–403PubMedCrossRefGoogle Scholar
  174. 174.
    Cara DC, Kaur J, Forster M, et al. Role of p38 mitogen-activated protein kinase in chemokine-induced emigration and chemotaxis in vivo. J Immunol 2001; 167: 6552–8PubMedGoogle Scholar
  175. 175.
    Smolen JE, Petersen TK, Koch C, et al. L-selectin signaling of neutrophil adhesion and degranulation involves p38 mitogen-activated protein kinase. J Biol Chem 2000; 275: 15876–84PubMedCrossRefGoogle Scholar
  176. 176.
    Barnes PJ. Neurogenic inflammation in the airways. Respir Physiol 2001; 125: 145–54PubMedCrossRefGoogle Scholar
  177. 177.
    Barnes PJ. Airway neuropeptides and their role in inflammation. In: Holgate ST, Butcher JW, editors. Inflammatory mechanisms in asthma. New York, NY: Marcel Dekker Inc., 1998: 537–70Google Scholar
  178. 178.
    Fiebich BL, Schleicher S, Butcher RD, et al. The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-kappa B. J Immunol 2000; 165: 5606–11PubMedGoogle Scholar
  179. 179.
    Cuesta MC, Quintero L, Pons H, et al. Substance P and calcitonin gene-related peptide increase IL-1 beta, IL-6 and TNF alpha secretion from human peripheral blood mononuclear cells. Neurochem Int 2002; 40: 301–6PubMedCrossRefGoogle Scholar
  180. 180.
    Wadsworth SA, Cavender DE, Beers SA, et al. RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J Pharmacol Exp Ther 1999; 291:680–7PubMedGoogle Scholar
  181. 181.
    Haddad EB, Birrell M, McCluskie K, et al. Role of p38 MAP kinase in LPS-induced airway inflammation in the rat. Br J Pharmacol 2001; 132: 1715–24PubMedCrossRefGoogle Scholar
  182. 182.
    Escott KJ, Belvisi MG, Birrell MA, et al. Effect of the p38 kinase inhibitor, SB 203580, on allergic airway inflammation in the rat. Br J Pharmacol 2000; 131: 173–6PubMedCrossRefGoogle Scholar
  183. 183.
    Salmon M, Davis AN, Carpenter DC, et al. Inhibition of antigen-induced airway inflammation and remodeling in sensitised brown-Norway rats by SB 239063, a potent and selective P38 MAP kinase inhibitor [abstract]. Am J Respir Crit Care Med 2003; 165: A538Google Scholar
  184. 184.
    Taube C, Nick J, Takeda K, et al. Treatment with M39 a p38 MAPK inhibitor decreases early neutrophil inflammation and airway hyperresponsiveness (AHR) in a murine model [abstract]. Am J Respir Crit Care Med 2002; 165: A729Google Scholar
  185. 185.
    Salmon M, Killian DJ, Carpenter DC, et al. Activation of the p38 map kinase pathway following ozone exposure of mice: effect of SB 239063 a potent and selective inhibitor of p38 MAP kinase [abstract]. Am J Respir Crit Care Med 2002; 165: A84Google Scholar
  186. 186.
    Ward KW, Prokscht JW, Azzaranot LM, et al. Preclinical pharmacokinetics of SB-203580, a potent inhibitor of p38 mitogen-activated protein kinase. Xenobiotica 2001; 31: 783–97PubMedCrossRefGoogle Scholar
  187. 187.
    Ward KW, Proksch JW, Salyers KL, et al. SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase: I. preclinical pharmacokinetics. Xenobiotica 2002; 32: 221–33PubMedCrossRefGoogle Scholar
  188. 188.
    Ward KW, Proksch JW, Gorycki PD, et al. SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase: II. in vitro and in vivo metabolism studies and pharmacokinetic extrapolation to man. Xenobiotica 2002; 32: 235–50PubMedCrossRefGoogle Scholar
  189. 189.
    Tamura K, Sudo T, Senftleben U, et al. Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell 2000; 102: 221–31PubMedCrossRefGoogle Scholar
  190. 190.
    Mudgett JS, Ding J, Guh-Siesel L, et al. Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. Proc Natl Acad Sci U S A 2000; 97: 10454–9PubMedCrossRefGoogle Scholar
  191. 191.
    Maruyama M, Sudo T, Kasuya Y, et al. Immunolocalization of p38 MAP kinase in mouse brain. Brain Res 2000; 887: 350–8PubMedCrossRefGoogle Scholar
  192. 192.
    Lehner MD, Schwoebel F, Kotlyarov A, et al. Mitogen-activated protein kinaseactivated protein kinase 2-deficient mice show increased susceptibility to Listeria monocytogenes infection. J Immunol 2002; 168: 4667–73PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Department of Biological SciencesUniversity of WarwickCoventryUK
  2. 2.Thoracic Medicine, National Heart & Lung InstituteImperial College Faculty of MedicineLondonUK

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