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Severe Crohn's Disease Semapimod Induces Clinical Remission in Specific Inhibition of C-Raf Activity By Specific Inhibition of c-Raf Activity by Semapimod Induces Clinical Remission in Severe Crohn's Disease This information is current as Mark Löwenberg, Auke Verhaar, Bernt van den Blink, Fibo of September 24, 2021. ten Kate, Sander van Deventer, Maikel Peppelenbosch and Daniel Hommes J Immunol 2005; 175:2293-2300; ; doi: 10.4049/jimmunol.175.4.2293 http://www.jimmunol.org/content/175/4/2293 Downloaded from References This article cites 68 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/175/4/2293.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Specific Inhibition of c-Raf Activity by Semapimod Induces Clinical Remission in Severe Crohn’s Disease1 Mark Lo¨wenberg,2*‡ Auke Verhaar,* Bernt van den Blink,* Fibo ten Kate,† Sander van Deventer,* Maikel Peppelenbosch,§ and Daniel Hommes‡ There is a substantial need for novel treatment strategies in Crohn’s disease (CD), a chronic relapsing inflammatory disease of the gut. In an earlier study, we reported clinical efficacy of a 2-wk treatment with semapimod (CNI-1493) in 12 patients with therapy resistant CD. The aim of this study was to identify the cellular target underlying semapimod action. In vitro experiments with murine macrophages showed impaired MAPK signaling and decreased cytokine production due to semapimod treatment. In vitro kinase assays revealed c-Raf as a direct molecular target of semapimod, and semapimod did not affect b-Raf enzymatic activity. demonstrated increased expression (6 ؍ Immunohistochemistry performed on paired colon biopsies obtained from CD patients (n of phospho-MEK, the substrate of Raf. Strikingly, phospho-MEK levels were significantly decreased in patients with a good Downloaded from clinical response to semapimod, but no decrease in phospho-MEK expression was observed in a clinically nonresponsive patient. In conclusion, this study identifies c-Raf as a molecular target of semapimod action and suggests that decreased c-Raf activity correlates with clinical benefit in CD. Our observations indicate that c-Raf inhibitors are prime candidates for the treatment of CD. The Journal of Immunology, 2005, 175: 2293–2300. nhibitors of intracellular signaling pathways have proven ef- small molecule semapimod resulted in a reduction of disease ac- http://www.jimmunol.org/ fective in a wide range of experimental inflammatory disor- tivity and induction of clinical remissions (14). Although it has I ders, including experimental colitis (1). Small molecules tar- been demonstrated that semapimod interferes with the phosphor- geting these signaling cascades are generally considered as a ylation of both p38 and JNK (14), the exact underlying molecular promising novel strategy for the clinical management of inflam- mechanism of semapimod action remains to be characterized. The matory bowel diseases (i.e., Crohn’s disease (CD)3 and ulcerative identification of the molecular target of semapimod has important colitis). In particular, pharmaceutical intervention of the MAPK clinical relevance because it may prompt synthesis of a novel class pathways of intracellular signaling mediators attracts widespread of anti-inflammatory compounds. In this study we have identified interest (2–6). Three major MAPK cascades have been identified: macrophages as the target cells of semapimod action, and we char- ERK, JNK, and p38 MAPK, and these pathways are critically in- acterized c-Raf as the molecular target. Reduced expression of by guest on September 24, 2021 volved in inflammatory pathology, including CD (6–8). Selective phospho-MEK, a downstream target of c-Raf, in colon biopsies MAPK inhibitors targeting the p38 MAPK, ERK, and JNK path- correlated with clinical benefit in semapimod-treated CD patients. way demonstrated anti-inflammatory effects in preclinical models In contrast, no reduced phospho-MEK was observed in mucosal (1, 9–13). Despite the fact that the impact of MAPK pathways on biopsies obtained from a nonresponder. These results indicate that inflammatory pathology is profound, the molecular details of these c-Raf activity is a critical mediator of disease progression in CD, signaling cascades in the pathogenesis of inflammatory disorders and identify c-Raf as a novel therapeutic target for the clinical and their possible therapeutic value remain to be elucidated. In management of CD. view of the redundancy of MAPK pathways and the extensive cross-talk between these and other routes of signal transduction Materials and Methods (e.g., NF-␬B), such information is of great importance. We have Abs and reagents reported that treatment of therapy resistant CD patients with the Phospho-specific Abs directed against p38Thr180/Tyr182, ERK1/2Thr202/Tyr204, MEK1/2Ser217/221, c-RafSer338, stress-activated protein kinase/JNKThr183/Tyr185, p21-activated protein kinase (PAK)1/2Thr423/402, SEK1/MAPK kinase *Laboratory of Experimental Internal Medicine, †Department of Pathology, and ‡De- (MKK)4Thr261, MKK3/pMKK6Ser189/207, as well as Abs specific for MKK4, partment of Gastroenterology and Hepatology, Academic Medical Center, Amster- MKK3, and PAK were purchased from Cell Signaling Technology. Abs rec- dam, The Netherlands; and §Department of Cell Biology, University of Groningen, ognizing p38, ERK, JNK, MEK, b-Raf, c-Raf, and phospho-JNKThr183/Tyr185 Groningen, The Netherlands were from Santa Cruz Biotechnology. HRP-conjugated goat anti-rabbit, goat Received for publication January 25, 2005. Accepted for publication May 18, 2005. anti-mouse, and rabbit anti-goat were from DakoCytomation, and semapimod The costs of publication of this article were defrayed in part by the payment of page (CNI-1493) was acquired from Cytokine PharmaSciences (batch date 3/13/ charges. This article must therefore be hereby marked advertisement in accordance 2004; lot no. 08610302). The anti-CD68 mAb was from DakoCytomation, and with 18 U.S.C. Section 1734 solely to indicate this fact. anti-CD14 mAb was obtained from BD Biosciences. Anti-human CD3 (CD3⑀ mouse) was kindly provided by Dr. A. te Velde (Academic Medical Center, 1 This work is supported in part by grants from The Netherlands Organization for Health Research and Development (to D.H.), and from the Dutch Digestive Disease Amsterdam, The Netherlands). Anti-CD28 was from Sanquin. The c-Raf and Foundation (to M.P.). This study was performed with a grant kindly provided by b-Raf kinase kits were obtained from Upstate Biotechnology. Cytokine PharmaSciences (King of Prussia, PA). CD4 purification and cell sorting 2 Address correspondence and reprint requests to Dr. Mark Lo¨wenberg, Laboratory of Experimental Internal Medicine, Academic Medical Center, Meibergdreef 9, NL- PBMC were isolated from whole blood of healthy volunteers by Ficoll- 1105 AZ Amsterdam, The Netherlands. E-mail address: [email protected] Isopaque density gradient centrifugation (Amersham Biosciences). The 3 Abbreviations used in this paper: CD, Crohn’s disease; DC, dendritic cell; CRP, monocytes present in the PBMC pellet were removed by an adherence C-reactive protein; CBA, cytokine bead array; CDAI, Crohn’s Disease Activity In- procedure: cells were plated out in 6-well plates (Cellstar; Greiner Bio- dex; MKK, MAPK kinase; PAK, p21-activated protein kinase. One) at a final concentration of 5 ϫ 106 cells/well for 1.5 h at 37°C, and Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 2294 SEMAPIMOD-INDUCED INHIBITION OF c-Raf ACTIVITY subsequently, nonadherent cells were harvested for magnetic cell sorting. Protifar in TBST (0.05 M Tris, 150 mM NaCl, and 0.05% Tween 20). CD4ϩ T cells were purified by depletion of non-CD4ϩ T cells (negative Primary and secondary HRP-conjugated Abs were diluted in 1% Protifar in selection) using the MACS system. Non-CD4ϩ cells were indirectly mag- TBST, and proteins were visualized using the Lumi-Light substrate netically labeled with a mix of biotin-conjugated mAbs (against CD8, (Roche). Blots were incubated in stripping buffer (62.5 mM Tris-HCl (pH CD14, CD16, CD19, CD36, CD56, CD123, TCR ␥␦, and glycophorin A) 6.8), 100 mM 2-ME, and 2% SDS) for1hat50°C and subsequently bound to MicroBeads conjugated to a monoclonal anti-biotin Ab, as sec- reprobed with appropriate Abs to evaluate for equal loading. In addition, T ondary labeling agent (Miltenyi Biotec). The magnetically labeled non- cells (overnight cultured in 6-well plates, 3 ϫ 106 cells/well) pretreated CD4ϩ T cells were depleted by retaining them on a MACS Column in the with semapimod (1 h, 0.1 and 1 ␮M) and subsequently activated with magnetic field of the autoMACS Separator (Miltenyi Biotec), whereas the anti-CD3/anti-CD28 Abs (15 min) were analyzed on Western blot using ϩ unlabeled fraction of CD4 Th cells passed through the column. The sam- phosphospecific Abs. ple purity was assessed by FACS (BD Biosciences) with PE-conjugated CD4 and FITC-conjugated CD3 mAbs (BD Biosciences) (purity Ͼ95% ϩ ϩ CD3 CD4 ; data not shown). Raf in vitro kinase assays Generation of dendritic cells (DC) Raf in vitro kinase assays were used according to the instructions of the DC generation from PBMC (obtained form healthy volunteers) was per- manufacturer (Upstate Biotechnology). Truncated constitutively active Raf (b-Raf and c-Raf) was diluted in a Mg/ATP mixture and reaction formed as previously described (15, 16).
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