Digestive Diseases and Sciences

, Volume 51, Issue 8, pp 1443–1453 | Cite as

No Evidence for an Involvement of the P38 and JNK Mitogen-Activated Protein in Inflammatory Bowel Diseases

  • Georgia Malamut
  • Candice Cabane
  • Laurent Dubuquoy
  • Mathilde Malapel
  • Benoit Dérijard
  • Jérôme Gay
  • Cyrus Tamboli
  • Jean-Frédéric Colombel
  • Pierre Desreumaux
Original Paper


Involvement of mitogen-activated protein (MAPK) in inflammatory bowel disease (IBD) remains enigmatic. We sought to evaluate the expression and activity of p38 and JNK MAPK in IBD and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis; and the effects of a p38 inhibitor, SB203580, in TNBS colitis. P 38 and JNK were quantified in colonic mucosa of 28 IBD patients and 19 controls and in 77 TNBS or control mice treated or not with SB203580. Colitis severity was assessed by survival, macroscopic and microscopic scoring, and molecular markers. Expression and activity of p38 and JNK were similar in IBD patients and controls and not modified by inflammation. In mice, p38 and JNK expression or activity did not increase following the induction of colitis. SB203580 decreased the p38 activity but displayed no clinical nor biological therapeutic effect. In conclusion, these results minimize the role of p38 and JNK in inflammatory colitis and the interest of p38 as a therapeutic target in IBD.

Key Words

Inflammatory bowel disease Intestinal inflammation P38 MAPK JNK MAPK TNBS Colitis SB203580 



We enjoyed the support of grant from the Fondation pour la Recherche Médicale (FRM).


  1. 1.
    Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96PubMedCrossRefGoogle Scholar
  2. 2.
    Barnes PJ, Karin M (1997) Nuclear factor-kappa B: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 15:1066–1071CrossRefGoogle Scholar
  3. 3.
    Chen Z, Gibson TB, Robinson F, Silvestro M, Pearson G, Xu B, Wright A, Vanderbilt A, Cobb MH (2001) MAP kinases. Chem Rev 101:2449–2476PubMedCrossRefGoogle Scholar
  4. 4.
    Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22:153–183PubMedCrossRefGoogle Scholar
  5. 5.
    Kumar S, Boehm J, Lee JC (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2:717–726PubMedCrossRefGoogle Scholar
  6. 6.
    Hale KK, Trollinger D, Rihanek M, Manthey CL (1999) Differential expression and activation of p38 mitogen-activated protein kinase alpha, beta, gamma, and delta in inflammatory cell lineages. J Immunol 162:4246–4252PubMedGoogle Scholar
  7. 7.
    Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869PubMedGoogle Scholar
  8. 8.
    Chen CY, Del Gatto-Konczak F, Wu Z, Karin M (1998) Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. Science 280:1945–1949PubMedCrossRefGoogle Scholar
  9. 9.
    Waetzig GH, Seegert D, Rosenstiel P, Nikolaus S, Schreiber S (2002) P38 Mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease. J Immunol 168:5342–5351PubMedGoogle Scholar
  10. 10.
    Badger AM, Bradbeer JN, 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 Ther 279:1453–1461PubMedGoogle Scholar
  11. 11.
    Song GY, Chung CS, Jarrar D, Chaudry IH, Ayala A (2001) Evolution of an immune suppressive macrophage phenotype as a product of P38 MAPK activation in polymicrobial sepsis. Shock 15:42–48PubMedGoogle Scholar
  12. 12.
    ten Hove T, van den Blink B, Pronk I, Drillenburg P, Peppelenbosch MP, van Deventer SJ (2002) Dichotomal role of inhibition of p38 MAPK with SB 203580 in experimental colitis. Gut 50:507–512PubMedCrossRefGoogle Scholar
  13. 13.
    Hommes D, van den Blink B, Plasse T, Bartelsman J, Xu C, Macpherson B, Tytgat G, Peppelenbosch M, Van Deventer S (2002) Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn’s disease. Gastroenterology 122:7–14PubMedCrossRefGoogle Scholar
  14. 14.
    Sandborn WJ, Faubion WA (2004) Biologics in inflammatory bowel diseases: how much progress have we made? Gut 53:1366–1373PubMedCrossRefGoogle Scholar
  15. 15.
    Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K, Derijard B, Desvergne B, Wahli W, Chambon P, Leibowitz MD, Colombel JF, Auwerx J (2001) Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J Exp Med 193:827–838Google Scholar
  16. 16.
    Philippe D, Dubuquoy L, Groux H, Brun V, Chuoi-Mariot MT, Gaveriaux-Ruff C, Colombel JF, Kieffer BL, Desreumaux P (2003) Anti-inflammatory properties of the mu opioid receptor support its use in the treatment of colon inflammation. J Clin Invest 111:1329–1338PubMedGoogle Scholar
  17. 17.
    Griswold DE, Hillegass LM, O’Leary-Bartus J, Lee JC, Laydon JT, Torphy TJ (1996) Evaluation of human cytokine production and effects of pharmacological agents in a heterologous system in vivo. J Immunol Methods 195:1–5PubMedCrossRefGoogle Scholar
  18. 18.
    Appleyard CB, Wallace JL (1995) Reactivation of hapten-induced colitis and its prevention by anti-inflammatory drugs. Am J Physiol Gastrointest Liver Physiol 269:G119–G125Google Scholar
  19. 19.
    McCafferty DM, Wallace JL, Sharkey KA (1997) Effects of chemical sympathectomy and sensory nerve ablation on experimental colitis in the rat. Am J Physiol Gastrointest Liver Physiol 272:G272–G280Google Scholar
  20. 20.
    Ameho CK, Adjei AA, Harrison EK, Takeshita K, Morioka T, Arakaki Y, Ito E, Suzuki I, Kulkarni AD, Kawajiri A, Yamamoto S (1997) Prophylactic effect of dietary glutamine supplementation on interleukin 8 and tumour necrosis factor alpha production in trinitrobenzene sulphonic acid induced colitis. Gut 41:487–493PubMedCrossRefGoogle Scholar
  21. 21.
    Yeow K, Phillips B, Dani C, Cabane C, Amri EZ, Derijard B (2001) Inhibition of myogenesis enables adipogenic trans-differentiation in the C2C12 myogenic cell line. FEBS Lett 506:157–162PubMedCrossRefGoogle Scholar
  22. 22.
    Derijard B, Hibi M, Wu IH, Barrett T, Su B, Deng T, Barrett T, Deng T, Karin M, Davis RJ (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025–1037PubMedCrossRefGoogle Scholar
  23. 23.
    Dickens M, Rogers JS, Cavanagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL, Davis RJ (1997) A cytoplasmic inhibitor of the JNK signal transduction pathway. Science 277:693–696PubMedCrossRefGoogle Scholar
  24. 24.
    Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS (2001) c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108:73–81PubMedGoogle Scholar
  25. 25.
    Desreumaux P, Brandt E, Gambiez L, Emilie D, Geboes K, Klein O, Ectors N, Cortot A, Capron M, Colombel JF (1997) Distinct cytokine patterns in early and chronic ileal lesions of Crohn’s disease. Gastroenterology 113:118–126PubMedCrossRefGoogle Scholar
  26. 26.
    Dohi T, Fujihashi K, Kiyono H, Elson CO, McGhee JR (2002) Mice deficient in Th1- and Th2-type cytokines develop distinct forms of hapten-induced colitis. Gastroenterology 119:724–733CrossRefGoogle Scholar
  27. 27.
    Arulampalam V, Pettersson S (2002) Uncoupling the p38 MAPK kinase in IBD: a double edged sword? Gut 50:446–447PubMedCrossRefGoogle Scholar
  28. 28.
    Kumar S, McDonnell PC, Gum RJ, Hand AT, Lee JC, Young PR (1997) Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles. Biochem Biophys Res Commun 235:533–538PubMedCrossRefGoogle Scholar
  29. 29.
    Tong L, Pav S, White DM, Rogers S, Crane KM, Cywin CL, Brown M, Pargellis CA (1997) A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket. Nat Struct Biol 4:311–316PubMedCrossRefGoogle Scholar
  30. 30.
    Warny M, Keates AC, Keates S, Castagliuolo I, Zacks JK, Aboudola S, Qamar A, Pothoulakis C, LaMont JT, Kelly CP (2000) P38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest 105:1147–1156PubMedCrossRefGoogle Scholar
  31. 31.
    Hollenbach E, Neumann M, Vieth M, Roessner A, Malfertheiner P, Naumann M (2004) Inhibition of p38 MAP kinase and RICK/NF-κB-signaling suppresses inflammatory bowel disease. FASEB 18:1550–1552Google Scholar
  32. 32.
    Borsch-Haubold AG, Pasquet S, Watson SP (1998) Direct inhibition of cyclooxygenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase. J Biol Chem 273:28766–28772Google Scholar
  33. 33.
    Morteau O, Morham SG, Sellon R, Dieleman LA, Langenbach R, Smithies O, Sartor RB (2000) Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2. J Clin Invest 105:469–478PubMedCrossRefGoogle Scholar
  34. 34.
    Guo X, Gerl RE, Schrader JW (2003) Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. J Biol Chem 278:22237–22242PubMedCrossRefGoogle Scholar
  35. 35.
    Foey AD, Parry SL, Williams LM, Feldmann M, Foxwell BM, Brennan FM (1998) Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-alpha: role of the p38 and p42/44 mitogen-activated protein kinases. J Immunol 160:920–928PubMedGoogle Scholar
  36. 36.
    Bamba S, Andoh A, Yasui H, Makino J, Kim S, Fujiyama Y (2003) Regulation of IL-11 expression in intestinal myofibroblasts: role of c-Jun AP-1- and MAPK-dependent pathways. Am J Physiol Gastrointest Liver Physiol 285:G529–G538PubMedGoogle Scholar
  37. 37.
    Parrello T, Monteleone G, Cucchiara S, Monteleone I, Sebkova L, Doldo P, Luzza F, Pallone F (2000) Up-regulation of the IL-12 receptor beta 2 chain in Crohn’s disease. J Immunol 165:7234–7239PubMedGoogle Scholar
  38. 38.
    Stallmach A, Marth T, Weiss B, Wittig BM, Hombach A, Schmidt C, Neurath M, Zeitz M, Zeuzem S, Abken H (2004) An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn’s disease and experimental colitis in vivo. Gut 53:339–345PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Georgia Malamut
    • 1
  • Candice Cabane
    • 2
  • Laurent Dubuquoy
    • 1
  • Mathilde Malapel
    • 1
  • Benoit Dérijard
    • 3
  • Jérôme Gay
    • 1
  • Cyrus Tamboli
    • 1
  • Jean-Frédéric Colombel
    • 1
  • Pierre Desreumaux
    • 3
  1. 1.INSERM 0114LilleFrance
  2. 2.UMR 6548-Centre National de la Recherche ScientifiqueNiceFrance
  3. 3.Service de GastroentérologieLilleFrance

Personalised recommendations