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Erschienen in: Digestive Diseases and Sciences 8/2006

01.08.2006 | Original Paper

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

verfasst von: Georgia Malamut, Candice Cabane, Laurent Dubuquoy, Mathilde Malapel, Benoit Dérijard, Jérôme Gay, Cyrus Tamboli, Jean-Frédéric Colombel, Pierre Desreumaux

Erschienen in: Digestive Diseases and Sciences | Ausgabe 8/2006

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Abstract

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.
Literatur
1.
2.
Zurück zum Zitat Barnes PJ, Karin M (1997) Nuclear factor-kappa B: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 15:1066–1071CrossRef Barnes PJ, Karin M (1997) Nuclear factor-kappa B: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 15:1066–1071CrossRef
3.
Zurück zum Zitat Chen Z, Gibson TB, Robinson F, Silvestro M, Pearson G, Xu B, Wright A, Vanderbilt A, Cobb MH (2001) MAP kinases. Chem Rev 101:2449–2476PubMedCrossRef Chen Z, Gibson TB, Robinson F, Silvestro M, Pearson G, Xu B, Wright A, Vanderbilt A, Cobb MH (2001) MAP kinases. Chem Rev 101:2449–2476PubMedCrossRef
4.
Zurück zum Zitat 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 22:153–183PubMedCrossRef 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 22:153–183PubMedCrossRef
5.
Zurück zum Zitat Kumar S, Boehm J, Lee JC (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2:717–726PubMedCrossRef Kumar S, Boehm J, Lee JC (2003) p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2:717–726PubMedCrossRef
6.
Zurück zum Zitat 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 162:4246–4252PubMed 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 162:4246–4252PubMed
7.
Zurück zum Zitat Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869PubMed Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869PubMed
8.
Zurück zum Zitat 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 280:1945–1949PubMedCrossRef 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 280:1945–1949PubMedCrossRef
9.
Zurück zum Zitat 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 168:5342–5351PubMed 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 168:5342–5351PubMed
10.
Zurück zum Zitat 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 279:1453–1461PubMed 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 279:1453–1461PubMed
11.
Zurück zum Zitat 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 15:42–48PubMed 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 15:42–48PubMed
12.
Zurück zum Zitat 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 50:507–512PubMedCrossRef 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 50:507–512PubMedCrossRef
13.
Zurück zum Zitat 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 122:7–14PubMedCrossRef 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 122:7–14PubMedCrossRef
14.
Zurück zum Zitat Sandborn WJ, Faubion WA (2004) Biologics in inflammatory bowel diseases: how much progress have we made? Gut 53:1366–1373PubMedCrossRef Sandborn WJ, Faubion WA (2004) Biologics in inflammatory bowel diseases: how much progress have we made? Gut 53:1366–1373PubMedCrossRef
15.
Zurück zum Zitat 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 193:827–838 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 193:827–838
16.
Zurück zum Zitat 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 111:1329–1338PubMed 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 111:1329–1338PubMed
17.
Zurück zum Zitat 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 195:1–5PubMedCrossRef 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 195:1–5PubMedCrossRef
18.
Zurück zum Zitat 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–G125 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–G125
19.
Zurück zum Zitat 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–G280 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–G280
20.
Zurück zum Zitat 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 41:487–493PubMedCrossRef 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 41:487–493PubMedCrossRef
21.
Zurück zum Zitat 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 506:157–162PubMedCrossRef 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 506:157–162PubMedCrossRef
22.
Zurück zum Zitat 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 76:1025–1037PubMedCrossRef 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 76:1025–1037PubMedCrossRef
23.
Zurück zum Zitat 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 277:693–696PubMedCrossRef 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 277:693–696PubMedCrossRef
24.
Zurück zum Zitat 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 108:73–81PubMed 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 108:73–81PubMed
25.
Zurück zum Zitat 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 113:118–126PubMedCrossRef 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 113:118–126PubMedCrossRef
26.
Zurück zum Zitat 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 119:724–733CrossRef 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 119:724–733CrossRef
27.
Zurück zum Zitat Arulampalam V, Pettersson S (2002) Uncoupling the p38 MAPK kinase in IBD: a double edged sword? Gut 50:446–447PubMedCrossRef Arulampalam V, Pettersson S (2002) Uncoupling the p38 MAPK kinase in IBD: a double edged sword? Gut 50:446–447PubMedCrossRef
28.
Zurück zum Zitat 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 235:533–538PubMedCrossRef 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 235:533–538PubMedCrossRef
29.
Zurück zum Zitat 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 4:311–316PubMedCrossRef 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 4:311–316PubMedCrossRef
30.
Zurück zum Zitat 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 105:1147–1156PubMedCrossRef 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 105:1147–1156PubMedCrossRef
31.
Zurück zum Zitat 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 18:1550–1552 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 18:1550–1552
32.
Zurück zum Zitat 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 273:28766–28772 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 273:28766–28772
33.
Zurück zum Zitat 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 105:469–478PubMedCrossRef 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 105:469–478PubMedCrossRef
34.
Zurück zum Zitat 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 278:22237–22242PubMedCrossRef 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 278:22237–22242PubMedCrossRef
35.
Zurück zum Zitat 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 160:920–928PubMed 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 160:920–928PubMed
36.
Zurück zum Zitat 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–G538PubMed 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–G538PubMed
37.
Zurück zum Zitat 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 165:7234–7239PubMed 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 165:7234–7239PubMed
38.
Zurück zum Zitat 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 53:339–345PubMedCrossRef 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 53:339–345PubMedCrossRef
Metadaten
Titel
No Evidence for an Involvement of the P38 and JNK Mitogen-Activated Protein in Inflammatory Bowel Diseases
verfasst von
Georgia Malamut
Candice Cabane
Laurent Dubuquoy
Mathilde Malapel
Benoit Dérijard
Jérôme Gay
Cyrus Tamboli
Jean-Frédéric Colombel
Pierre Desreumaux
Publikationsdatum
01.08.2006
Verlag
Springer US
Erschienen in
Digestive Diseases and Sciences / Ausgabe 8/2006
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-006-9116-2

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