nach oben

Digestive Diseases and Sciences

Erschienen in:

01.07.2012 | Original Article

Inhibition of Pim-1 Kinase Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

verfasst von: Yue-Ming Shen, Yan Zhao, Ya Zeng, Lu Yan, Bo-Lin Chen, Ai-Min Leng, Yi-Bin Mu, Gui-Ying Zhang

Erschienen in: Digestive Diseases and Sciences | Ausgabe 7/2012

Einloggen, um Zugang zu erhalten

Abstract

Background

Pim-1 kinase is involved in the control of cell growth, differentiation and apoptosis. Recent evidence suggests that Pim kinases play a role in immune regulation and inflammation. However, the role of Pim-1 kinase in inflammatory bowel diseases (IBD) remains unclear.

Aims

The aims of this study were to explore the role of Pim-1 kinase in the pathology of IBD and to assess whether inhibiting Pim-1 kinase may be of therapeutic benefit as a treatment regimen for IBD.

Methods

Colitic mouse model was established by the induction of dextran sodium sulfate. The expression of Pim-1 in the colonic samples of control and colitic mice was examined. Furthermore, the mice were treated with Pim-1inhibitor (PIM-Inh), then the body weight and colon inflammation were evaluated, and the production of cytokines including IFN-γ, IL-4, TGF-β and IL-17 in colon tissues was determined by ELISA. The expression of T cell master transcription factors T-bet, ROR-γt, GATA-3 and Foxp3 and Nuclear factor κB (NF-κB) and inducible nitric oxide synthase in colon tissues was detected by real-time PCR and western blot. Finally, the effect of LPS on Pim-1 expression and the effects of PIM-Inh on LPS-induced upregualtion of p65 and TNF-α in RAW264.7 cells were examined by real-time PCR and western blot.

Results

Pim-1 expression was correlated with the degree of mucosal inflammation in vivo, and it was significantly induced by LPS in vitro. PIM-Inh had protective effects on acute colitis in vivo. Mechanistically, PIM-Inh reduced the proinflammatory immune response through the inhibition of the overactivation of macrophages and the down-regulation of excessive Th1- and Th17-type immune responses. Furthermore, PIM-Inh could skew T cell differentiation towards a Treg phenotype.

Conclusions

Pim-1 kinase is involved in mucosal injury/inflammation and Pim-1 kinase inhibitor may provide a novel therapeutic approach for IBD.

Fiocchi C. The immune system in inflammatory bowel disease. Acta Gastroenterol Belg. 1997;60:156–162.PubMed

Wen Z, Fiocchi C. Inflammatory bowel disease: autoimmune or immune-mediated pathogenesis? Clin Dev Immunol. 2004;11:195–204.PubMedCrossRef

Mahida YR. The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. Inflamm Bowel Dis. 2000;6:21–33.PubMedCrossRef

Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in inflammatory bowel disease. World J Gastroenterol. 2008;14:4280–4288.PubMedCrossRef

Seiderer J, Elben I, Diegelmann J, et al. Role of the novel Th17 cytokine il-17f in inflammatory bowel disease (ibd): upregulated colonic il-17f expression in active crohn’s disease and analysis of the il17f p.his161arg polymorphism in ibd. Inflamm Bowel Dis. 2008;14:437–445.PubMedCrossRef

Boden EK, Snapper SB. Regulatory t cells in inflammatory bowel disease. Curr Opin Gastroenterol. 2008;24:733–741.PubMedCrossRef

Groux H, Powrie F. Regulatory t cells and inflammatory bowel disease. Immunol Today. 1999;20:442–445.PubMedCrossRef

Daniel C, Sartory N, Zahn N, Geisslinger G, Radeke HH, Stein JM. Fty720 ameliorates th1-mediated colitis in mice by directly affecting the functional activity of cd4 + cd25 + regulatory t cells. J Immunol. 2007;178:2458–2468.PubMed

Ogino H, Nakamura K, Ihara E, Akiho H, Takayanagi R. Cd4 + cd25 + regulatory t cells suppress th17-responses in an experimental colitis model. Dig Dis Sci. 2011;56:376–386.PubMedCrossRef

10.

Yoshimitsu M, Hayamizu K, Egi H, et al. The neutrophil/th1 lymphocyte balance and the therapeutic effect of granulocyte colony-stimulating factor in tnbs-induced colitis of rat strains. J Interferon Cytokine Res. 2006;26:291–300.PubMedCrossRef

11.

Wang Z, Bhattacharya N, Weaver M, et al. Pim-1: a serine/threonine kinase with a role in cell survival, proliferation, differentiation and tumorigenesis. J Vet Sci. 2001;2:167–179.PubMed

12.

Wingett D, Stone D, Davis WC, Magnuson NS. Expression of the pim-1 protooncogene: differential inducibility between alpha/beta- and gamma/delta-t cells and b cells. Cell Immunol. 1995;162:123–130.PubMedCrossRef

13.

Owaki T, Asakawa M, Morishima N, et al. Stat3 is indispensable to il-27-mediated cell proliferation but not to il-27-induced th1 differentiation and suppression of proinflammatory cytokine production. J Immunol. 2008;180:2903–2911.PubMed

14.

Aho TL, Lund RJ, Ylikoski EK, Matikainen S, Lahesmaa R, Koskinen PJ. Expression of human pim family genes is selectively up-regulated by cytokines promoting t helper type 1, but not t helper type 2, cell differentiation. Immunology. 2005;116:82–88.PubMedCrossRef

15.

Bachmann M, Moroy T. The serine/threonine kinase pim-1. Int J Biochem Cell Biol. 2005;37:726–730.PubMedCrossRef

16.

Fox CJ, Hammerman PS, Thompson CB. The pim kinases control rapamycin-resistant t cell survival and activation. J Exp Med. 2005;201:259–266.PubMedCrossRef

17.

Cheney IW, Yan S, Appleby T, et al. Identification and structure-activity relationships of substituted pyridones as inhibitors of pim-1 kinase. Bioorg Med Chem Lett. 2007;17:1679–1683.PubMedCrossRef

18.

Naito Y, Katada K, Takagi T, et al. Rosuvastatin, a new hmg-coa reductase inhibitor, reduces the colonic inflammatory response in dextran sulfate sodium-induced colitis in mice. Int J Mol Med. 2006;17:997–1004.PubMed

19.

Takagi T, Naito Y, Uchiyama K, et al. Carbon monoxide liberated from carbon monoxide-releasing molecule exerts an anti-inflammatory effect on dextran sulfate sodium-induced colitis in mice. Dig Dis Sci. 2011;56:1663–1671.PubMedCrossRef

20.

Hausmann M, Obermeier F, Paper DH, et al. In vivo treatment with the herbal phenylethanoid acteoside ameliorates intestinal inflammation in dextran sulphate sodium-induced colitis. Clin Exp Immunol. 2007;148:373–381.PubMedCrossRef

21.

Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140:1756–1767.PubMedCrossRef

22.

Park SG, Mathur R, Long M, et al. T regulatory cells maintain intestinal homeostasis by suppressing gammadelta t cells. Immunity. 2010;33:791–803.PubMedCrossRef

23.

Andresen L, Jorgensen VL, Perner A, Hansen A, Eugen-Olsen J, Rask-Madsen J. Activation of nuclear factor kappab in colonic mucosa from patients with collagenous and ulcerative colitis. Gut. 2005;54:503–509.PubMedCrossRef

24.

Wei J, Feng J. Signaling pathways associated with inflammatory bowel disease. Recent Pat Inflamm Allergy Drug Discov. 2010;4:105–117.PubMedCrossRef

25.

Wang S, Liu Z, Wang L, Zhang X. Nf-kappab signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 2009;6:327–334.PubMedCrossRef

26.

De Plaen IG, Liu SX, Tian R, et al. Inhibition of nuclear factor-kappab ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis. Pediatr Res. 2007;61:716–721.PubMedCrossRef

27.

Nihira K, Ando Y, Yamaguchi T, Kagami Y, Miki Y, Yoshida K. Pim-1 controls nf-kappab signalling by stabilizing rela/p65. Cell Death Differ. 2010;17:689–698.PubMedCrossRef

28.

Zemskova M, Sahakian E, Bashkirova S, Lilly M. The pim1 kinase is a critical component of a survival pathway activated by docetaxel and promotes survival of docetaxel-treated prostate cancer cells. J Biol Chem. 2008;283:20635–20644.PubMedCrossRef

29.

Kim K, Kim JH, Youn BU, Jin HM, Kim N. Pim-1 regulates rankl-induced osteoclastogenesis via nf-kappab activation and nfatc1 induction. J Immunol. 2010;185:7460–7466.PubMedCrossRef

30.

Liu ZJ, Yadav PK, Su JL, Wang JS, Fei K. Potential role of th17 cells in the pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2009;15:5784–5788.PubMedCrossRef

31.

Nielsen OH, Kirman I, Rudiger N, Hendel J, Vainer B. Upregulation of interleukin-12 and -17 in active inflammatory bowel disease. Scand J Gastroenterol. 2003;38:180–185.PubMedCrossRef

32.

Wang LJ, Cao Y, Shi HN. Helminth infections and intestinal inflammation. World J Gastroenterol. 2008;14:5125–5132.PubMedCrossRef

33.

Watanabe T, Yamori M, Kita T, Chiba T, Wakatsuki Y. Cd4 + cd25 + t cells regulate colonic localization of cd4 t cells reactive to a microbial antigen. Inflamm Bowel Dis. 2005;11:541–550.PubMedCrossRef

34.

Asseman C, Fowler S, Powrie F. Control of experimental inflammatory bowel disease by regulatory t cells. Am J Respir Crit Care Med. 2000;162:S185–S189.PubMed

35.

Fantini MC, Becker C, Tubbe I, et al. Transforming growth factor beta induced foxp3 + regulatory t cells suppress th1 mediated experimental colitis. Gut. 2006;55:671–680.PubMedCrossRef

36.

Zhu N, Ramirez LM, Lee RL, Magnuson NS, Bishop GA, Gold MR. Cd40 signaling in b cells regulates the expression of the pim-1 kinase via the nf-kappa b pathway. J Immunol. 2002;168:744–754.PubMed

37.

Peperzak V, Veraar EA, Keller AM, Xiao Y, Borst J. The pim kinase pathway contributes to survival signaling in primed cd8 + t cells upon cd27 costimulation. J Immunol. 2010;185:6670–6678.PubMedCrossRef

38.

Mikkers H, Nawijn M, Allen J, et al. Mice deficient for all pim kinases display reduced body size and impaired responses to hematopoietic growth factors. Mol Cell Biol. 2004;24:6104–6115.PubMedCrossRef

39.

Jackson LJ, Pheneger JA, Pheneger TJ, et al. The role of pim kinases in human and mouse cd4 + t cell activation and inflammatory bowel disease. Cell Immunol. 2012;272:200–213.PubMedCrossRef

40.

Komine O, Hayashi K, Natsume W, et al. The runx1 transcription factor inhibits the differentiation of naive cd4 + t cells into the th2 lineage by repressing gata3 expression. J Exp Med. 2003;198:51–61.PubMedCrossRef

41.

Aho TL, Sandholm J, Peltola KJ, Ito Y, Koskinen PJ. Pim-1 kinase phosphorylates runx family transcription factors and enhances their activity. BMC Cell Biol. 2006;7:21.PubMedCrossRef

42.

Chen LS, Redkar S, Bearss D, Wierda WG, Gandhi V. Pim kinase inhibitor, sgi-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood. 2009;114:4150–4157.PubMedCrossRef

43.

Chen LS, Redkar S, Taverna P, Cortes JE, Gandhi V. Mechanisms of cytotoxicity to pim kinase inhibitor, sgi-1776, in acute myeloid leukemia. Blood. 2011;118:693–702.PubMedCrossRef

Titel: Inhibition of Pim-1 Kinase Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice
verfasst von: Yue-Ming Shen
Yan Zhao
Ya Zeng
Lu Yan
Bo-Lin Chen
Ai-Min Leng
Yi-Bin Mu
Gui-Ying Zhang
Publikationsdatum: 01.07.2012
Verlag: Springer US
Erschienen in: Digestive Diseases and Sciences / Ausgabe 7/2012
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-012-2106-7

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Echinokokkose medikamentös behandeln oder operieren?

06.05.2024 DCK 2024 Kongressbericht

Die Therapie von Echinokokkosen sollte immer in spezialisierten Zentren erfolgen. Eine symptomlose Echinokokkose kann – egal ob von Hunde- oder Fuchsbandwurm ausgelöst – konservativ erfolgen. Wenn eine Op. nötig ist, kann es sinnvoll sein, vorher Zysten zu leeren und zu desinfizieren.

Aquatherapie bei Fibromyalgie wirksamer als Trockenübungen

03.05.2024 Fibromyalgiesyndrom Nachrichten

Bewegungs-, Dehnungs- und Entspannungsübungen im Wasser lindern die Beschwerden von Patientinnen mit Fibromyalgie besser als das Üben auf trockenem Land. Das geht aus einer spanisch-brasilianischen Vergleichsstudie hervor.

Wo hapert es noch bei der Umsetzung der POMGAT-Leitlinie?

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Das Risiko für Vorhofflimmern in der Bevölkerung steigt

02.05.2024 Vorhofflimmern Nachrichten

Das Risiko, im Lauf des Lebens an Vorhofflimmern zu erkranken, ist in den vergangenen 20 Jahren gestiegen: Laut dänischen Zahlen wird es drei von zehn Personen treffen. Das hat Folgen weit über die Schlaganfallgefährdung hinaus.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Chronische Unterbauch- und Viszeralschmerzen in der Praxis managen"

Springer Medizin

Abstract

Background

Aims

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 7/2012

Epstein-Barr Virus Infection Is Common in Inflamed Gastrointestinal Mucosa

Nutrition, Intestinal Permeability, and Blood Ethanol Levels Are Altered in Patients with Nonalcoholic Fatty Liver Disease (NAFLD)

Neutrophil Infiltration of the Colon Is Independent of the FPR1 yet FPR1 Deficient Mice Show Differential Susceptibilities to Acute Versus Chronic Induced Colitis

Portal Vein Thrombosis After EUS-Guided Pancreatic Cyst Ablation

Adenovirus-Mediated Dual Gene Expression of Human Interleukin-10 and Hepatic Growth Factor Exerts Protective Effect Against CCl4-Induced Hepatocyte Injury in Rats