Beneficial effects of dual TORC1/2 inhibition on chronic experimental colitis.

Adenosine Triphosphate/metabolism; Animals; Chronic Disease; Colitis/chemically induced/metabolism; Dextran Sulfate; Disease Models, Animal; Heart Transplantation; Humans; Inflammatory Bowel Diseases/metabolism; Janus Kinases/metabolism; Male; Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors; Mice; Mice, Inbred C57BL; Morpholines/pharmacology/therapeutic use; STAT Transcription Factors/metabolism; Signal Transduction; AZD8055; Chronic colitis; Inflammatory bowel disease; JAK/STAT; mTOR

Abstract :

[en] BACKGROUND AND AIM: AZD8055, a new immunosuppressive reagent, a dual TORC1/2 inhibitor, had been used successfully in animal models for heart transplantation. The aim of this study was to evaluate the effects and mechanisms of AZD8055 on chronic intestinal inflammation. METHODS: Dextran sulfate sodium (DSS) - induced chronic colitis was used to investigate the effects of AZD8055 on the development of colitis. Colitis activity was monitored by body weight assessment, colon length, histology and cytokine profile analysis. RESULTS: AZD8055 treatment significantly alleviated the severity of colitis, as assessed by colonic length and colonic damage. In addition, AZD8055 treatment decreased the colonic CD4+ T cell numbers and reduced both Th1 and Th17 cell activation and cytokine production. The percentages of Treg cells in the colon were also expanded by AZD8055 treatment. Furthermore, AZD8055 effectively inhibited mTOR downstream proteins and signal transducer and activator of transcription related proteins in CD4+ T cells of intestinal lamina propria. CONCLUSIONS: These findings increased our understanding of DSS-induced colitis and shed new lights on mechanisms of digestive tract chronic inflammation. Dual TORC1/2 inhibition showed potent anti-inflammatory and immune regulation effects by targeting critical signaling pathways. The results supported the strategy of using dual mTOR inhibitor to treat inflammatory bowel disease.

Research center :

National Natural Science of China (N° 81670503)

Disciplines :

Gastroenterology & hepatology

Author, co-author :

Hu, Shurong

Cheng, Mengmeng

Fan, Rong

Wang, Zhengting

Wang, Lei

Zhang, Tianyu

Zhang, Maochen

Louis, Edouard ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie

Zhong, Jie

Language :

English

Title :

Beneficial effects of dual TORC1/2 inhibition on chronic experimental colitis.

Publication date :

2019

Journal title :

International Immunopharmacology

ISSN :

1567-5769

eISSN :

1878-1705

Publisher :

Elsevier, Netherlands

Volume :

Pages :

88-100

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.sciencedirect.com/science/article/pii/S1567576918312190?via%3Dihub

Commentary :

Available on ORBi :

since 19 May 2020

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Bibliography

Ordás, I., Eckmann, L., Talamini, M., Baumgart, D.C., Sandborn, W.J., Ulcerative colitis. Lancet 380 (2012), 1606–1619, 10.1016/S0140-6736(12)60150-0.
Ishihara, S., Aziz, M.M., Yuki, T., Kazumori, H., Kinoshita, Y., Inflammatory bowel disease: review from the aspect of genetics. J. Gastroenterol. 44 (2009), 1097–1108, 10.1007/s00535-009-0141-8.
Kobayashi, T., Okamoto, S., Hisamatsu, T., Kamada, N., Chinen, H., Saito, R., Kitazume, M.T., Nakazawa, A., Sugita, A., Koganei, K., Isobe, K., Hibi, T., IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut 57 (2008), 1682–1689, 10.1136/gut.2007.135053.
Eastaff-Leung, N., Mabarrack, N., Barbour, A., Cummins, A., Barry, S., Foxp3+ regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease. J. Clin. Immunol. 30 (2010), 80–89, 10.1007/s10875-009-9345-1.
Imam, T., Park, S., Kaplan, M.H., Olson, M.R., Kaplan, M.H., Olson, M.R., Effector T helper cell subsets in inflammatory bowel diseases. Front. Immunol., 9, 2018, 10.3389/fimmu.2018.01212.
Nemoto, Y., Watanabe, M., The Th1, Th2, and Th17 paradigm in inflammatory bowel disease. Crohn's Disease and Ulcerative Colitis: From Epidemiology and Immunobiology to a Rational Diagnostic and Therapeutic Approach, 2012, 183–194, 10.1007/978-1-4614-0998-4_15.
Zenewicz, L.A., Antov, A., Flavell, R.A., CD4 T-cell differentiation and inflammatory bowel disease. Trends Mol. Med. 15 (2009), 199–207, 10.1016/j.molmed.2009.03.002.
Lohr, J., Knoechel, B., Wang, J.J., Villarino, A.V., Abbas, A.K., Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. J. Exp. Med. 203 (2006), 2785–2791, 10.1084/jem.20061341.
Zhu, J., Paul, W.E., Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol. Rev. 238 (2010), 247–262, 10.1111/j.1600-065X.2010.00951.x.
Murphy, K.M., Reiner, S.L., The lineage decisions of helper T cells. Nat. Rev. Immunol. 2 (2002), 933–944, 10.1038/nri954.
Manel, N., Unutmaz, D., Littman, D.R., The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat. Immunol. 9 (2008), 641–649, 10.1038/ni.1610.
Yang, X.O., Pappu, B.P., Nurieva, R., Akimzhanov, A., Kang, H.S., Chung, Y., Ma, L., Shah, B., Panopoulos, A.D., Schluns, K.S., Watowich, S.S., Tian, Q., Jetten, A.M., Dong, C., T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28 (2008), 29–39, 10.1016/j.immuni.2007.11.016.
Maul, J., Loddenkemper, C., Mundt, P., Berg, E., Giese, T., Stallmach, A., Zeitz, M., Duchmann, R., Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 128 (2005), 1868–1878, 10.1053/j.gastro.2005.03.043.
Bettelli, E., Korn, T., Oukka, M., Kuchroo, V.K., Induction and effector functions of TH17 cells. Nature 453 (2008), 1051–1057, 10.1038/nature07036.
Xu, X., Ye, L., Araki, K., Ahmed, R., MTOR, linking metabolism and immunity. Semin. Immunol. 24 (2012), 429–435, 10.1016/j.smim.2012.12.005.
Delgoffe, G.M., Powell, J.D., MTOR: taking cues from the immune microenvironment. Immunology 127 (2009), 459–465, 10.1111/j.1365-2567.2009.03125.x.
Atreya, I., Atreya, R., Neurath, M.F., NF-kappaB in inflammatory bowel disease. J. Intern. Med. 263 (2008), 591–596, 10.1111/j.1365-2796.2008.01953.x.
Dhingra, R., Gang, H., Wang, Y., Biala, A.K., Aviv, Y., Margulets, V., Tee, A., Kirshenbaum, L.A., Bidirectional regulation of nuclear factor-κb and mammalian target of rapamycin signaling functionally links bnip3 gene repression and cell survival of ventricular myocytes. Circ. Heart Fail. 6 (2013), 335–343, 10.1161/CIRCHEARTFAILURE.112.000061.
Buss, S.J., Muenz, S., Riffel, J.H., Malekar, P., Hagenmueller, M., Weiss, C.S., Bea, F., Bekeredjian, R., Schinke-Braun, M., Izumo, S., Katus, H.A., Hardt, S.E., Beneficial effects of mammalian target of rapamycin inhibition on left ventricular remodeling after myocardial infarction. J. Am. Coll. Cardiol. 54 (2009), 2435–2446, 10.1016/j.jacc.2009.08.031.
Okamoto, T., Ozawa, Y., Kamoshita, M., Osada, H., Toda, E., Kurihara, T., Nagai, N., Umezawa, K., Tsubota, K., The neuroprotective effect of rapamycin as a modulator of the mTOR-NF-KB axis during retinal inflammation. PLoS One, 11, 2016, e0146517, 10.1371/journal.pone.0146517.
C.G. Proud, mTORC1 signalling and mRNA translation, Biochem. Soc. Trans. 37 (2009) 227–231. doi: https://doi.org/10.1042/BST0370227.
Sarbassov, D.D., Guertin, D.A., Ali, S.M., Sabatini, D.M., Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307 (2005), 1098–1101, 10.1126/science.1106148.
Sarbassov, D.D., Ali, S.M., Sengupta, S., Sheen, J.H., Hsu, P.P., Bagley, A.F., Markhard, A.L., Sabatini, D.M., Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22 (2006), 159–168, 10.1016/j.molcel.2006.03.029.
Matsuda, C., Ito, T., Song, J., Mizushima, T., Tamagawa, H., Kai, Y., Hamanaka, Y., Inoue, M., Nishida, T., Matsuda, H., Sawa, Y., Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis. Clin. Exp. Immunol. 148 (2007), 348–359, 10.1111/j.1365-2249.2007.03345.x.
Rosborough, B.R., Raïch-Regué, D., Liu, Q., Venkataramanan, R., Turnquist, H.R., Thomson, A.W., Adenosine triphosphate-competitive mTOR inhibitors: a new class of immunosuppressive agents that inhibit allograft rejection. Am. J. Transplant. 14 (2014), 2173–2180, 10.1111/ajt.12799.
Morgan, M.E., Zheng, B., Koelink, P.J., van de Kant, H.J., Haazen, L.C., van Roest, M., Garssen, J., Folkerts, G., Kraneveld, A.D., New perspective on dextran sodium sulfate colitis: antigen-specific T cell development during intestinal inflammation. PLoS One, 8, 2013, e69936, 10.1371/journal.pone.0069936.
Melgar, S., Karlsson, L., Rehnström, E., Karlsson, A., Utkovic, H., Jansson, L., Michaëlsson, E., Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease. Int. Immunopharmacol. 8 (2008), 836–844, 10.1016/j.intimp.2008.01.036.
Morrissey, P.J., Charrier, K., Braddy, S., Liggitt, D., Watson, J.D., CD4 + T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J. Exp. Med. 178 (1993), 237–244.
Dieleman, L.A., Palmen, M.J., Akol, H., Bloemena, E., Pena, A.S., Meuwissen, S.G., Van Rees, E.P., Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin. Exp. Immunol. 114 (1998), 385–391.
Ustyugova, I.V., Zhi, L., Wu, M.X., Reciprocal regulation of the survival and apoptosis of Th17 and Th1 cells in the colon. Inflamm. Bowel Dis. 18 (2012), 333–343, 10.1002/ibd.21772.
Coskun, M., Salem, M., Pedersen, J., Nielsen, O.H., Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol. Res. 76 (2013), 1–8, 10.1016/j.phrs.2013.06.007.
Hu, S., Chen, M., Wang, Y., Wang, Z., Pei, Y., Fan, R., Liu, X., Wang, L., Zhou, J., Zheng, S., Zhang, T., Lin, Y., Zhang, M., Tao, R., Zhong, J., mTOR inhibition attenuates dextran sulfate sodium-induced colitis by suppressing T cell proliferation and balancing TH1/TH17/Treg profile. PLoS One, 11, 2016, e0154564, 10.1371/journal.pone.0154564.
Gaudio, E., Taddei, G., Vetuschi, A., Sferra, R., Frieri, G., Ricciardi, G., Caprilli, R., Dextran sulfate sodium (DSS) colitis in rats: clinical, structural, and ultrastructural aspects. Dig. Dis. Sci. 44 (1999), 1458–1475, 10.1023/A:1026620322859.
Saleiro, D., Platanias, L.C., Intersection of mTOR and STAT signaling in immunity. Trends Immunol. 36 (2015), 21–29, 10.1016/j.it.2014.10.006.
Durant, L., Watford, W.T., Ramos, H.L., Laurence, A., Vahedi, G., Wei, L., Takahashi, H., Sun, H.W., Kanno, Y., Powrie, F., O'Shea, J.J., Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32 (2010), 605–615, 10.1016/j.immuni.2010.05.003.
Laplante, M., Sabatini, D.M., MTOR signaling in growth control and disease. Cell 149 (2012), 274–293, 10.1016/j.cell.2012.03.017.
Zhang, D.M., Liu, J.S., Deng, L.J., Chen, M.F., Yiu, A., Cao, H.H., Tian, H.Y., Fung, K.P., Kurihara, H., Pan, J.X., Ye, W.C., Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway. Carcinogenesis 34 (2013), 1331–1342, 10.1093/carcin/bgt060.
Lauring, J., Park, B.H., Wolff, A.C., The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. J. Natl. Compr. Cancer Netw. 11 (2013), 670–678, 10.6004/jnccn.2013.0086.
Khare, V., Dammann, K., Asboth, M., Krnjic, A., Jambrich, M., Gasche, C., Overexpression of PAK1 promotes cell survival in inflammatory bowel diseases and colitis-associated cancer. Inflamm. Bowel Dis. 21 (2015), 287–296, 10.1097/MIB.0000000000000281.
Massey, D.C., Bredin, F., Parkes, M., Use of sirolimus (rapamycin) to treat refractory Crohn's disease. Gut 57 (2008), 1294–1296, 10.1136/gut.2008.157297.
Ogino, H., Nakamura, K., Iwasa, T., Ihara, E., Akiho, H., Motomura, Y., Akahoshi, K., Igarashi, H., Kato, M., Kotoh, K., Ito, T., Takayanagi, R., Regulatory T cells expanded by rapamycin in vitro suppress colitis in an experimental mouse model. J. Gastroenterol. 47 (2012), 366–376, 10.1007/s00535-011-0502-y.
Yin, H., Li, X., Zhang, B., Liu, T., Yuan, B., Ni, Q., Hu, S., Gu, H., Sirolimus ameliorates inflammatory responses by switching the regulatory T/T helper type 17 profile in murine colitis. Immunology 139 (2013), 494–502, 10.1111/imm.12096.
Kanwar, B., Wei, D., Hwang, A.B., Grenert, J.P., Williams, S.P., Franc, B., Mccune, J.M., In vivo imaging of mucosal CD4+ T cells using single photon emission computed tomography in a murine model of colitis. J. Immunol. Methods 329 (2008), 21–30, 10.1016/j.jim.2007.09.008.
Van Dop, W.A., Marengo, S., Anje, A., Ciraolo, E., Franco, I., Fiebo, J., Boeckxstaens, G.E., Hardwick, J.C., Hommes, D.W., Hirsch, E., Van Den Brink, G.R., The absence of functional PI3Kgamma prevents leukocyte recruitment and ameliorates DSS-induced colitis in mice. Immunol. Lett. 131 (2010), 33–39, 10.1016/j.imlet.2010.03.008.
te Velde, A.A., de Kort, F., Sterrenburg, E., Pronk, I., ten Kate, F.J., Hommes, D.W., Van Deventer, S.J., Comparative analysis of colonic gene expression of three experimental colitis models mimicking inflammatory bowel disease. Inflamm. Bowel Dis. 13 (2007), 325–330, 10.1002/ibd.20079.
Chresta, C.M., Davies, B.R., Hickson, I., Harding, T., Cosulich, S., Critchlow, S.E., Vincent, J.P., Ellston, R., Jones, D., Sini, P., James, D., Howard, Z., Dudley, P., Hughes, G., Smith, L., Maguire, S., Hummersone, M., Malagu, K., Menear, K., Jenkins, R., Jacobsen, M., Smith, G.C., Guichard, S., Pass, M., AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 70 (2010), 288–298, 10.1158/0008-5472.CAN-09-1751.
Araki, K., Ellebedy, A.H., Ahmed, R., TOR in the immune system. Curr. Opin. Cell Biol. 23 (2011), 707–715, 10.1016/j.ceb.2011.08.006.
Delgoffe, G.M., Kole, T.P., Zheng, Y., Zarek, P.E., Matthews, K.L., Xiao, B., Worley, P.F., Kozma, S.C., Powell, J.D., The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30 (2009), 832–844, 10.1016/j.immuni.2009.04.014.
Dieleman, L.A., Palmen, M.J., Akol, H., Bloemena, E., Peña, A.S., Meuwissen, S.G., Van Rees, E.P., Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin. Exp. Immunol. 114 (1998), 385–391, 10.1046/j.1365-2249.1998.00728.x.
Alex, P., Zachos, N.C., Nguyen, T., Gonzales, L., Chen, T.E., Conklin, L.S., Centola, M., Li, X., Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm. Bowel Dis. 15 (2009), 341–352, 10.1002/ibd.20753.
Fina, D., Sarra, M., Fantini, M.C., Rizzo, A., Caruso, R., Caprioli, F., Stolfi, C., Cardolini, I., Dottori, M., Boirivant, M., Pallone, F., MacDonald, T.T., Monteleone, G., Regulation of gut inflammation and Th17 cell response by Interleukin-21. Gastroenterology 134 (2008), 1038–1438, 10.1053/j.gastro.2008.01.041.
Takedatsu, H., Michelsen, K.S., Wei, B., Landers, C.J., Thomas, L.S., Dhall, D., Braun, J., Targan, S.R., TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-Helper 1 and T-Helper 17 activation. Gastroenterology 135 (2008), 552–567, 10.1053/j.gastro.2008.04.037.
Weigmann, B., Neurath, M.F., Oxazolone-induced colitis as a model of Th2 immune responses in the intestinal mucosa. Methods Mol. Biol. 1422 (2016), 253–261, 10.1007/978-1-4939-3603-8_23.
Yu, H., Pardoll, D., Jove, R., STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9 (2009), 798–809, 10.1038/nrc2734.
Reinecker, H.C., Steffen, M., Witthoeft, T., Pflueger, I., Schreiber, S., MacDermott, R.P., Raedler, A., Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin. Exp. Immunol. 94 (1993), 174–181, 10.1111/j.1365-2249.1993.tb05997.x.
Xu, Y., Li, Z., Yin, Y., Lan, H., Wang, J., Zhao, J., Feng, J., Li, Y., Zhang, W., Ghrelin inhibits the differentiation of T Helper 17 cells through mTOR/STAT3 signaling pathway. PLoS One, 10, 2015, e0117081, 10.1371/journal.pone.0117081.
He, Z., He, X., Chen, Z., Ke, J., He, X., Yuan, R., Cai, Z., Chen, X., Wu, X., Lan, P., Activation of the mTORC1 and STAT3 pathways promotes the malignant transformation of colitis in mice. Oncol. Rep. 32 (2014), 1873–1880, 10.3892/or.2014.3421.
Schreiber, S.L., Crabtree, G.R., The mechanism of action of cyclosporin A and FK506. Immunol. Today 13 (1992), 136–142, 10.1016/0167-5699(92)90111-J.
Choo, A.Y., Yoon, S.O., Kim, S.G., Roux, P.P., Blenis, J., Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc. Natl. Acad. Sci. 105 (2008), 17414–17419, 10.1073/pnas.0809136105.
O'Reilly, K.E., Rojo, F., She, Q.B., Solit, D., Mills, G.B., Smith, D., Lane, H., Hofmann, F., Hicklin, D.J., Ludwig, D.L., Baselga, J., Rosen, N., mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66 (2006), 1500–1508, 10.1158/0008-5472.CAN-05-2925.
Benjamin, D., Colombi, M., Moroni, C., Hall, M.N., Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat. Rev. Drug Discov. 10 (2011), 868–880, 10.1038/nrd3531.
Schreiber, K.H., Ortiz, D., Academia, E.C., Anies, A.C., Liao, C., Kennedy, B.K., Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging Cell 14 (2015), 265–273, 10.1111/acel.12313.
Chen, X., Liu, F., Song, X., Wang, Z., Dong, Z., Hu, Z., Lan, R., Guan, W., Zhou, T., Xu, X., Lei, H., Ye, Z., Peng, E., Du, L., Rapamycin regulates Akt and ERK phosphorylation through mTORC1 and mTORC2 signaling pathways. Mol. Carcinog. 610 (2010), 603–610, 10.1002/mc.20628.
Young, D.A., Nickerson-Nutter, C.L., mTOR—beyond transplantation. Curr. Opin. Pharmacol. 5 (2005), 418–423, 10.1016/j.coph.2005.03.004.
Fernandez, D., Bonilla, E., Mirza, N., Niland, B., Perl, A., Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 54 (2006), 2983–2988, 10.1002/art.22085.
Araki, Y., Mukaisyo, K., Sugihara, H., Fujiyama, Y., Hattori, T., Increased apoptosis and decreased proliferation of colonic epithelium in dextran sulfate sodium-induced colitis in mice. Oncol. Rep. 24 (2010), 869–874, 10.3892/or.
Iwamoto, M., Koji, T., Makiyama, K., Kobaysshi, N., Nakane, P.K., Apoptosis of crypt epithelial cells in ulcerative colitis. J. Pathol. 180 (1996), 152–159.
Sini, P., James, D., Chresta, C., Guichard, S., Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy 6 (2010), 553–554, 10.4161/auto.6.4.11671.
Gutierrez-Martinez, I.Z., Rubio, J.F., Piedra-Quintero, Z.L., Lopez-Mendez, O., Serrano, C., Reyes-Maldonado, E., Salinas-Lara, C., Betanzos, A., Shibayama, M., Silva-Olivares, A., Candelario-Martinez, A., Meraz-Rios, M.A., Schnoor, M., Villegas-Sepulveda, N., Nava, P., mTORC1 prevents epithelial damage during inflammation and inhibits colitis-associated colorectal cancer development. Transl. Oncol. 12 (2019), 24–35, 10.1016/j.tranon.2018.08.016.
Pott, J., Maloy, K.J., Epithelial autophagy controls chronic colitis by reducing TNF-induced apoptosis. Autophagy 14 (2018), 1460–1461, 10.1080/15548627.2018.1450021.
Pott, J., Kabat, A.M., Maloy, K.J., Intestinal epithelial cell autophagy is required to protect against TNF-induced apoptosis during chronic colitis in mice. Cell Host Microbe 23 (2018), 191–202, 10.1016/j.chom.2017.12.017.
Lin, X., Sun, Q., Zhou, L., He, M., Dong, X., Lai, M., Liu, M., Su, Y., Jia, C., Han, Z., Liu, S., Zheng, H., Jiang, Y., Ling, H., Li, M., Chen, J., Zou, Z., Bai, X., Colonic epithelial mTORC1 promotes ulcerative colitis through COX-2-mediated Th17 responses. Mucosal Immunol. 11 (2018), 1663–1673, 10.1038/s41385-018-0018-3.
Guan, Y., Zhang, L., Li, X., Zhang, X., Liu, S., Gao, N., Li, L., Gao, G., Wei, G., Chen, Z., Zheng, Y., Ma, X., Siwko, S., Chen, J.L., Liu, M., Li, D., Repression of mammalian target of rapamycin complex 1 inhibits intestinal regeneration in acute inflammatory bowel disease models. J. Immunol. 195 (2015), 339–346, 10.4049/jimmunol.1303356.
Gren, S.T., Grip, O., Role of monocytes and intestinal macrophages in Crohn's disease and ulcerative colitis. Inflamm. Bowel Dis. 22 (2016), 1992–1998, 10.1097/MIB.0000000000000824.
Bain, C.C., Mowat, A.M., Macrophages in intestinal homeostasis and inflammation. Immunol. Rev. 260 (2014), 102–117, 10.1111/imr.12192.
Medina-contreras, O., Parkos, C.A., Timothy, L., Medina-contreras, O., Geem, D., Laur, O., Williams, I.R., Lira, S.A., CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J. Clin. Invest. 121 (2011), 4787–4795, 10.1172/JCI59150.about.
Arranz, A., Doxaki, C., Vergadi, E., Martinez, Y., Torre, D., Vaporidi, K., Lagoudaki, E.D., Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc. Natl. Acad. Sci. 109 (2012), 9517–9522, 10.1073/pnas.1119038109.
Steinbach, E.C., Plevy, S.E., The role of macrophages and dendritic cells in the initiation of inflammation in IBD. Inflamm. Bowel Dis. 20 (2014), 166–175, 10.1097/MIB.0b013e3182a69dca.
Piedra-quintero, Z.L., Serrano, C., Villegas-sepúlveda, N., Maravillas-Montero, J.L., Romero-Ramírez, S., Shibayama, M., Medina-Contreras, O., Nava, P., Myosin 1F regulates M1-polarization by stimulating intercellular adhesion in macrophages. Front. Immunol., 9, 2019, 3118, 10.3389/fimmu.2018.03118.