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MAP3K2 augments Th1 cell differentiation via IL-18 to promote T cell-mediated colitis

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Abstract

T cell-mediated immunity in the intestine is stringently controlled to ensure proper immunity against pathogenic microbes and to prevent autoimmunity, a known cause of inflammatory bowel disease. However, precisely how T cells regulate intestine immunity remains to be fully understood. In this study, we found that mitogen-activated protein kinase kinase kinase 2 (MAP3K2) is required for the CD4+ T cell-mediated inflammation in the intestine. Using a T cell transfer colitis model, we found that MAP3K2-deficient naïve CD4 T cells had a dramatically reduced ability to induce colitis compared to wild type T cells. In addition, significantly fewer IFN-γ- but more IL-17A-producing CD4+ T cells in the intestines of mice receiving MAP3K2-deficient T cells than in those from mice receiving wild type T cells was observed. Interestingly, under well-defined in vitro differentiation conditions, MAP3K2-deficient naïve T cells were not impaired in their ability to differentiate into Th1, Th17 and Treg. Furthermore, the MAP3K2-regulated colitis severity was mediated by Th1 but not Th17 cells in the intestine. At the molecular level, we showed that MAP3K2-mediated Th1 cell differentiation in the intestine was regulated by IL-18 and required specific JNK activation. Together, our study reveals a novel regulatory role of MAP3K2 in intestinal T cell immunity via the IL-18-MAP3K2-JNK axis and may provide a novel target for intervention in T cell-mediated colitis.

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References

  • Arthur, J.S.C., and Ley, S.C. (2013). Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 13, 679–692.

    Article  CAS  PubMed  Google Scholar 

  • Banerjee, A., Gugasyan, R., McMahon, M., and Gerondakis, S. (2006). Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. Proc Natl Acad Sci USA 103, 3274–3279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bevivino, G., and Monteleone, G. (2018). Advances in understanding the role of cytokines in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 12, 907–915.

    Article  CAS  PubMed  Google Scholar 

  • Castro-Dopico, T., Dennison, T.W., Ferdinand, J.R., Mathews, R.J., Fleming, A., Clift, D., Stewart, B.J., Jing, C., Strongili, K., Labzin, L. I., et al. (2019). Anti-commensal IgG drives intestinal inflammation and type 17 immunity in ulcerative colitis. Immunity 50, 1099–1114.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang, L., and Karin, M. (2001). Mammalian MAP kinase signalling cascades. Nature 410, 37–40.

    Article  CAS  PubMed  Google Scholar 

  • Chang, X., Liu, F., Wang, X., Lin, A., Zhao, H., and Su, B. (2011). The kinases MEKK2 and MEKK3 regulate transforming growth factor-β-mediated helper T cell differentiation. Immunity 34, 201–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng, J., Yang, J., Xia, Y., Karin, M., and Su, B. (2000). Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation. Mol Cell Biol 20, 2334–2342.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Simone, V., Pallone, F., Monteleone, G., and Stolfi, C. (2013). Role of TH 17 cytokines in the control of colorectal cancer. Oncoimmunology 2, e26617.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dong, C. (2006). Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol 6, 329–334.

    Article  CAS  PubMed  Google Scholar 

  • Dong, C. (2008). TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8, 337–348.

    Article  CAS  PubMed  Google Scholar 

  • Dong, C., and Flavell, R.A. (2000). Cell fate decision: T-helper 1 and 2 subsets in immune responses. Arthritis Res 2, 179–188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fantuzzi, G., Reed, D.A., and Dinarello, C.A. (1999). IL-12-induced IFN-γ is dependent on caspase-1 processing of the IL-18 precursor. J Clin Invest 104, 761–767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fukata, M., Breglio, K., Chen, A., Vamadevan, A.S., Goo, T., Hsu, D., Conduah, D., Xu, R., and Abreu, M.T. (2008). The myeloid differentiation factor 88 (MyD88) is required for CD4+ T cell effector function in a murine model of inflammatory bowel disease. J Immunol 180, 1886–1894.

    Article  CAS  PubMed  Google Scholar 

  • Garlanda, C., Dinarello, C.A., and Mantovani, A. (2013). The interleukin-1 family: back to the future. Immunity 39, 1003–1018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • González-Navajas, J.M., Fine, S., Law, J., Datta, S.K., Nguyen, K.P., Yu, M., Corr, M., Katakura, K., Eckman, L., Lee, J., et al. (2010). TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice. J Clin Invest 120, 570–581.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Greenblatt, M.B., Shin, D.Y., Oh, H., Lee, K.Y., Zhai, B., Gygi, S.P., Lotinun, S., Baron, R., Liu, D., Su, B., et al. (2016). MEKK2 mediates an alternative β-catenin pathway that promotes bone formation. Proc Natl Acad Sci USA 113, E1226–E1235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guilloteau, K., Paris, I., Pedretti, N., Boniface, K., Juchaux, F., Huguier, V., Guillet, G., Bernard, F.X., Lecron, J.C., and Morel, F. (2010). Skin Inflammation Induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α recapitulates some features of psoriasis. J Immunol 184, 5263–5270.

    Article  CAS  PubMed  Google Scholar 

  • Guo, Z., Clydesdale, G., Cheng, J., Kim, K., Gan, L., McConkey, D.J., Ullrich, S.E., Zhuang, Y., and Su, B. (2002). Disruption of Mekk2 in mice reveals an unexpected role for MEKK2 in modulating T-cell receptor signal transduction. Mol Cell Biol 22, 5761–5768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Honda, K., and Littman, D.R. (2016). The microbiota in adaptive immune homeostasis and disease. Nature 535, 75–84.

    Article  CAS  PubMed  Google Scholar 

  • Hu, D., Denney, J., Liang, M., Javer, A., Yang, X., Zhu, R., and Yin, D. (2013). Stimulatory Toll-like receptor 2 suppresses restraint stress-induced immune suppression. Cell Immunol 283, 18–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imanishi, T., Hara, H., Suzuki, S., Suzuki, N., Akira, S., and Saito, T. (2007). Cutting edge: TLR2 directly triggers Th1 effector functions. J Immunol 178, 6715–6719.

    Article  CAS  PubMed  Google Scholar 

  • Izcue, A., Coombes, J.L., and Powrie, F. (2009). Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27, 313–338.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, L.I., Huang, M., Wang, L., Fan, X., Wang, P., Wang, D., Fu, X., and Wang, J. (2013). Overexpression of MEKK2 is associated with colorectal carcinogenesis. Oncol Lett 6, 1333–1337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin, W., and Dong, C. (2013). IL-17 cytokines in immunity and inflammation. Emerg Microbes Infect 2, 1–5.

    Article  CAS  Google Scholar 

  • Jostins, L., Ripke, S., Weersma, R.K., Duerr, R.H., McGovern, D.P., Hui, K.Y., Lee, J.C., Philip Schumm, L., Sharma, Y., Anderson, C.A., et al. (2012). Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kabat, A.M., Srinivasan, N., and Maloy, K.J. (2014). Modulation of immune development and function by intestinal microbiota. Trends Immunol 35, 507–517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kallsen, K., Andresen, E., and Heine, H. (2012). Histone deacetylase (HDAC) 1 controls the expression of beta defensin 1 in human lung epithelial cells. PLoS ONE 7, e50000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamada, N., Hisamatsu, T., Honda, H., Kobayashi, T., Chinen, H., Takayama, T., Kitazume, M.T., Okamoto, S., Koganei, K., Sugita, A., et al. (2010). TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn’s disease. Inflamm Bowel Dis 16, 568–575.

    Article  PubMed  Google Scholar 

  • Kamada, N., Seo, S.U., Chen, G.Y., and Núñez, G. (2013). Role of the gut microbiota in immunity and inflammatory disease. Nat Rev Immunol 13, 321–335.

    Article  CAS  PubMed  Google Scholar 

  • Kaser, A., Zeissig, S., and Blumberg, R.S. (2010). Inflammatory bowel disease. Annu Rev Immunol 28, 573–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kesavan, K., Lobel-Rice, K., Sun, W., Lapadat, R., Webb, S., Johnson, G. L., and Garrington, T.P. (2004). MEKK2 regulates the coordinate activation of ERK5 and JNK in response to FGF-2 in fibroblasts. J Cell Physiol 199, 140–148.

    Article  CAS  PubMed  Google Scholar 

  • Khor, B., Gardet, A., and Xavier, R.J. (2011). Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kiesler, P., Fuss, I.J., and Strober, W. (2015). Experimental models of inflammatory bowel diseases. Cellul Mol Gastroenterol Hepatol 1, 154–170.

    Article  Google Scholar 

  • King, V.L., Lin, A.Y., Kristo, F., Anderson, T.J.T., Ahluwalia, N., Hardy, G. J., Owens Iii, A.P., Howatt, D.A., Shen, D., Tager, A.M., et al. (2009). Interferon-γ and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture. Circulation 119, 426–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi, T., Okamoto, S., Hisamatsu, T., Kamada, N., Chinen, H., Saito, R., Kitazume, M.T., Nakazawa, A., Sugita, A., Koganei, K., et al. (2008). IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn’s disease. Gut 57, 1682–1689.

    Article  CAS  PubMed  Google Scholar 

  • Komai-Koma, M., Jones, L., Ogg, G.S., Xu, D., and Liew, F.Y. (2004). TLR2 is expressed on activated T cells as a costimulatory receptor. Proc Natl Acad Sci USA 101, 3029–3034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • LaRosa, D.F., Stumhofer, J.S., Gelman, A.E., Rahman, A.H., Taylor, D.K., Hunter, C.A., and Turka, L.A. (2008). T cell expression of MyD88 is required for resistance to Toxoplasma gondii. Proc Natl Acad Sci USA 105, 3855–3860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, J.S., Tato, C.M., Joyce-Shaikh, B., Gulen, M.F., Cayatte, C., Chen, Y., Blumenschein, W.M., Judo, M., Ayanoglu, G., McClanahan, T.K., et al. (2015). Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43, 727–738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leppkes, M., Becker, C., Ivanov, I.I., Hirth, S., Wirtz, S., Neufert, C., Pouly, S., Murphy, A.J., Valenzuela, D.M., Yancopoulos, G.D., et al. (2009). RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136, 257–267.

    Article  CAS  PubMed  Google Scholar 

  • Liu, L., Sun, H., Wu, S., Tan, H., Sun, Y., Liu, X., Si, S., Xu, L., Huang, J., Zhou, W., et al. (2019). IL-17A promotes CXCR2-dependent angiogenesis in a mouse model of liver cancer. Mol Med Rep 20, 1065–1074.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ma, S., Cheng, Q., Cai, Y., Gong, H., Wu, Y., Yu, X., Shi, L., Wu, D., Dong, C., and Liu, H. (2014). IL-17A produced by γδ T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res 74, 1969–1982.

    Article  CAS  PubMed  Google Scholar 

  • Maloy, K.J., and Powrie, F. (2011). Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306.

    Article  CAS  PubMed  Google Scholar 

  • Martin, J.C., Chang, C., Boschetti, G., Ungaro, R., Giri, M., Grout, J.A., Gettler, K., Chuang, L.S., Nayar, S., Greenstein, A.J., et al. (2019). Single-cell analysis of Crohn’s disease lesions identifies a pathogenic cellular module associated with resistance to anti-TNF therapy. Cell 178, 1493–1508.e20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mazur, P.K., Reynoird, N., Khatri, P., Jansen, P.W.T.C., Wilkinson, A.W., Liu, S., Barbash, O., Van Aller, G.S., Huddleston, M., Dhanak, D., et al. (2014). SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510, 283–287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Micallef, M.J., Ohtsuki, T., Kohno, K., Tanabe, F., Ushio, S., Namba, M., Tanimoto, T., Torigoe, K., Fujii, M., Ikeda, M., et al. (1996). Interferon-γ-inducing factor enhances T helper 1 cytokine production by stimulated human T cells: synergism with interleukin-12 for interferon-γ production. Eur J Immunol 26, 1647–1651.

    Article  CAS  PubMed  Google Scholar 

  • Mirza, A.A., Kahle, M.P., Ameka, M., Campbell, E.M., and Cuevas, B.D. (2014). MEKK2 regulates focal adhesion stability and motility in invasive breast cancer cells. Biochim Biophys Acta 1843, 945–954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizoguchi, A. (2012). Animal models of inflammatory bowel disease. Prog Mol Biol Transl Sci 105, 263–320.

    Article  CAS  PubMed  Google Scholar 

  • Monteleone, G., Trapasso, F., Parrello, T., Biancone, L., Stella, A., Iuliano, R., Luzza, F., Fusco, A., and Pallone, F. (1999). Bioactive IL-18 expression is up-regulated in Crohn’s disease. J Immunol 163, 143–147.

    CAS  PubMed  Google Scholar 

  • Mosmann, T.R., Cherwinski, H., Bond, M.W., Giedlin, M.A., and Coffman, R.L. (1986). Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136, 2348–2357.

    CAS  PubMed  Google Scholar 

  • Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., and Cheroutre, H. (2007). Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260.

    Article  CAS  PubMed  Google Scholar 

  • Munk, R.B., Sugiyama, K., Ghosh, P., Sasaki, C.Y., Rezanka, L., Banerjee, K., Takahashi, H., Sen, R., and Longo, D.L. (2011). Antigen-independent IFN-γ production by human Naïve CD4+ T cells activated by IL-12 plus IL-18. PLoS ONE 6, e18553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muñoz, M., Eidenschenk, C., Ota, N., Wong, K., Lohmann, U., Kühl, A.A., Wang, X., Manzanillo, P., Li, Y., Rutz, S., et al. (2015). Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity 42, 321–331.

    Article  PubMed  CAS  Google Scholar 

  • Muzumdar, M.D., Tasic, B., Miyamichi, K., Li, L., and Luo, L. (2007). A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura, K., and Johnson, G.L. (2003). PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. J Biol Chem 278, 36989–36992.

    Article  CAS  PubMed  Google Scholar 

  • Neurath, M.F. (2014). Cytokines in inflammatory bowel disease. Nat Rev Immunol 14, 329–342.

    Article  CAS  PubMed  Google Scholar 

  • Novick, D., Kim, S., Kaplanski, G., and Dinarello, C.A. (2013). Interleukin-18, more than a Th1 cytokine. Semin Immunol 25, 439–448.

    Article  CAS  PubMed  Google Scholar 

  • Nowarski, R., Jackson, R., Gagliani, N., de Zoete, M.R., Palm, N.W., Bailis, W., Low, J.S., Harman, C.C.D., Graham, M., Elinav, E., et al. (2015). Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Connor Jr, W., Kamanaka, M., Booth, C.J., Town, T., Nakae, S., Iwakura, Y., Kolls, J.K., and Flavell, R.A. (2009). A protective function for interleukin 17A in T cell-mediated intestinal inflammation. Nat Immunol 10, 603–609.

    Article  CAS  Google Scholar 

  • Okamura, H., Nagata, K., Komatsu, T., Tanimoto, T., Nukata, Y., Tanabe, F., Akita, K., Torigoe, K., Okura, T., and Fukuda, S. (1995a). A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infect Immun 63, 3966–3972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okamura, H., Tsutsui, H., Komatsu, T., Yutsudo, M., Hakura, A., Tanimoto, T., Torigoe, K., Okura, T., Nukada, Y., Hattori, K., et al. (1995b). Cloning of a new cytokine that induces IFN-γ production by T cells. Nature 378, 88–91.

    Article  CAS  PubMed  Google Scholar 

  • Parronchi, P., Romagnani, P., Annunziato, F., Sampognaro, S., Becchio, A., Giannarini, L., Maggi, E., Pupilli, C., Tonelli, F., and Romagnani, S. (1997). Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn’s disease. Am J Pathol 150, 823–832.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peterson, L.W., and Artis, D. (2014). Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol 14, 141–153.

    Article  CAS  PubMed  Google Scholar 

  • Powrie, F., Leach, M.W., Mauze, S., Menon, S., Barcomb Caddle, L., and Coffman, R.L. (1994). Inhibition of Thl responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1, 553–562.

    Article  CAS  PubMed  Google Scholar 

  • Reynolds, J.M., and Dong, C. (2013). Toll-like receptor regulation of effector T lymphocyte function. Trends Immunol 34, 511–519.

    Article  CAS  PubMed  Google Scholar 

  • Reynolds, J.M., Martinez, G.J., Chung, Y., and Dong, C. (2012). Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc Natl Acad Sci USA 109, 13064–13069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda, M. (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155, 1151–1164.

    CAS  PubMed  Google Scholar 

  • Sanchez-Munoz, F., Dominguez-Lopez, A., and Yamamoto-Furusho, J.K. (2008). Role of cytokines in inflammatory bowel disease. World J Gastroenterol 14, 4280–4288.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sands, B.E., Anderson, F.H., Bernstein, C.N., Chey, W.Y., Feagan, B.G., Fedorak, R.N., Kamm, M.A., Korzenik, J.R., Lashner, B.A., Onken, J. E., et al. (2004). Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 350, 876–885.

    Article  CAS  PubMed  Google Scholar 

  • Sawada, S., Scarborough, J.D., Killeen, N., and Littman, D.R. (1994). A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell 77, 917–929.

    Article  CAS  PubMed  Google Scholar 

  • Schneider, C., O’Leary, C.E., von Moltke, J., Liang, H.E., Ang, Q.Y., Turnbaugh, P.J., Radhakrishnan, S., Pellizzon, M., Ma, A., and Locksley, R.M. (2018). A metabolite-triggered tuft cell-ILC2 circuit drives small intestinal remodeling. Cell 174, 271–284.e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Senda, T., Dogra, P., Granot, T., Furuhashi, K., Snyder, M.E., Carpenter, D. J., Szabo, P.A., Thapa, P., Miron, M., and Farber, D.L. (2019). Microanatomical dissection of human intestinal T-cell immunity reveals site-specific changes in gut-associated lymphoid tissues over life. Mucosal Immunol 12, 378–389.

    Article  CAS  PubMed  Google Scholar 

  • Siegmund, B. (2010). Interleukin-18 in intestinal inflammation: friend and foe? Immunity 32, 300–302.

    Article  CAS  PubMed  Google Scholar 

  • Sivakumar, P.V., Westrich, G.M., Kanaly, S., Garka, K., Born, T.L., Derry, J.M.J., and Viney, J.L. (2002). Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage. Gut 50, 812–820.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smillie, C.S., Biton, M., Ordovas-Montanes, J., Sullivan, K.M., Burgin, G., Graham, D.B., Herbst, R.H., Rogel, N., Slyper, M., Waldman, J., et al. (2019). Intra- and inter-cellular rewiring of the human colon during ulcerative colitis. Cell 178, 714–730.e22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soderholm, A.T., and Pedicord, V.A. (2019). Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity. Immunology 158, 267–280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Su, B., Cheng, J., Yang, J., and Guo, Z. (2001). MEKK2 is required for T-cell receptor signals in JNK activation and interleukin-2 gene expression. J Biol Chem 276, 14784–14790.

    Article  CAS  PubMed  Google Scholar 

  • Sun, M., He, C., Cong, Y., and Liu, Z. (2015a). Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol 8, 969–978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun, Y., Liu, W.Z., Liu, T., Feng, X., Yang, N., and Zhou, H.F. (2015b). Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J Recept Signal Transduct Res 35, 600–604.

    Article  CAS  PubMed  Google Scholar 

  • Ten Hove, T., Corbaz, A., Amitai, H., Aloni, S., Belzer, I., Graber, P., Drillenburg, P., van Deventer, S.J., Chvatchko, Y., and Te Velde, A.A. (2001). Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-α production in mice. Gastroenterology 121, 1372–1379.

    Article  CAS  PubMed  Google Scholar 

  • Torres, J., Mehandru, S., Colombel, J.F., and Peyrin-Biroulet, L. (2017). Crohn’s disease. Lancet 389, 1741–1755.

    Article  PubMed  Google Scholar 

  • Uhlig, H.H., and Powrie, F. (2018). Translating immunology into therapeutic concepts for inflammatory bowel disease. Annu Rev Immunol 36, 755–781.

    Article  CAS  PubMed  Google Scholar 

  • Ungaro, R., Mehandru, S., Allen, P.B., Peyrin-Biroulet, L., and Colombel, J.F. (2017). Ulcerative colitis. Lancet 389, 1756–1770.

    Article  PubMed  Google Scholar 

  • Ushio, S., Namba, M., Okura, T., Hattori, K., Nukada, Y., Akita, K., Tanabe, F., Konishi, K., Micallef, M., Fujii, M., et al. (1996). Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol 156, 4274–4279.

    CAS  PubMed  Google Scholar 

  • van Wijk, F., and Cheroutre, H. (2010). Mucosal T cells in gut homeostasis and inflammation. Expert Rev Clin Immunol 6, 559–566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, Y., Sedimbi, S., Löfbom, L., Singh, A.K., Porcelli, S.A., and Cardell, S.L. (2018). Unique invariant natural killer T cells promote intestinal polyps by suppressing TH1 immunity and promoting regulatory T cells. Mucosal Immunol 11, 131–143.

    Article  CAS  PubMed  Google Scholar 

  • Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M., and Murphy, K.M. (2006). Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688.

    Article  CAS  PubMed  Google Scholar 

  • Weber, A., Wasiliew, P., and Kracht, M. (2010). Interleukin-1 (IL-1) pathway. Sci Signal 3, cm1.

    Google Scholar 

  • Weisshof, R., Ungar, B., Blatt, A., Dahan, A., Pressman, S., Waterman, M., Kopylov, U., Ben-Horin, S., and Chowers, Y. (2016). Anti-infliximab antibodies with neutralizing capacity in patients with inflammatory bowel disease. Inflamm Bowel Dis 22, 1655–1661.

    Article  PubMed  Google Scholar 

  • Wen, M., Ma, X., Cheng, H., Jiang, W., Xu, X., Zhang, Y., Zhang, Y., Guo, Z., Yu, Y., Xu, H., et al. (2015). Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages. Nat Commun 6, 7167.

    Article  CAS  PubMed  Google Scholar 

  • Yue, F., Cheng, Y., Breschi, A., Vierstra, J., Wu, W., Ryba, T., Sandstrom, R., Ma, Z., Davis, C., Pope, B.D., et al. (2014). A comparative encyclopedia of DNA elements in the mouse genome. Nature 515, 355–364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaki, M.H., Boyd, K.L., Vogel, P., Kastan, M.B., Lamkanfi, M., and Kanneganti, T.D. (2010). The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32, 379–391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, D., Facchinetti, V., Wang, X., Huang, Q., Qin, J., and Su, B. (2006a). Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways. EMBO J 25, 97–107.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, Z., Zheng, M., Bindas, J., Schwarzenberger, P., and Kolls, J.K. (2006b). Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 12, 382–388.

    Article  PubMed  Google Scholar 

  • Zhou, S., Kurt-Jones, E.A., Cerny, A.M., Chan, M., Bronson, R.T., and Finberg, R.W. (2009). MyD88 intrinsically regulates CD4 T-cell responses. J Virol 83, 1625–1634.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81430033, 81871269, 91942311 and 31930035). We want to thank Dr. Fang Wang for kindly reading the manuscript and providing helpful comments. We also want to thank Dr. Lei Shen for assisting with T cell differentiation experiment.

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Authors and Affiliations

  1. Shanghai Institute of Immunology, Department of Immunology and Microbiology, and Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China

    Ningbo Wu, Dongping Chen, Hongxiang Sun, Jianmei Tan, Yuheng Han, Hongzhi Liu, Xinxing Ouyang, Xiao-Dong Yang, Xiaoyin Niu & Bing Su

  2. Shanghai JiaoTong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China

    Ningbo Wu, Dongping Chen, Hongxiang Sun, Jianmei Tan, Yuheng Han, Hongzhi Liu, Xiao-Dong Yang & Bing Su

  3. Department of Gastroenterology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China

    Yao Zhang, Tianyu Zhang, Jie Zhong & Zhengting Wang

Authors
  1. Ningbo Wu
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  2. Dongping Chen
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  3. Hongxiang Sun
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  4. Jianmei Tan
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  6. Tianyu Zhang
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  7. Yuheng Han
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  8. Hongzhi Liu
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  9. Xinxing Ouyang
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  10. Xiao-Dong Yang
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  11. Xiaoyin Niu
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  12. Jie Zhong
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  13. Zhengting Wang
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  14. Bing Su
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Corresponding authors

Correspondence to Zhengting Wang or Bing Su.

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Compliance and ethics The author(s) declare that they have no conflict of interest. All animal experiments were performed according to the guidelines for the use and care of laboratory animals as provided by Shanghai JiaoTong University School of Medicine Institutional Animal Care and Use Committees (IACUC).

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Wu, N., Chen, D., Sun, H. et al. MAP3K2 augments Th1 cell differentiation via IL-18 to promote T cell-mediated colitis. Sci. China Life Sci. 64, 389–403 (2021). https://doi.org/10.1007/s11427-020-1720-9

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  • DOI: https://doi.org/10.1007/s11427-020-1720-9

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