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Genetic Dissection of the Cellular Pathways and Signaling Mechanisms in Modeled Tumor Necrosis Factor–induced Crohn's-like Inflammatory Bowel Disease

Dimitris Kontoyiannis¹, George Boulougouris¹, Menelaos Manoloukos¹, Maria Armaka¹, Maria Apostolaki¹, Theresa Pizarro², Alexey Kotlyarov³, Irmgard Forster⁴, Richard Flavell⁵, Matthias Gaestel³, Philip Tsichlis⁶, Fabio Cominelli² and George Kollias¹

¹ Institute for Immunology, Biomedical Sciences Research Center "Al. Fleming," Vari 166-72, Greece
² Division of Gastroenterology and Hepatology, University of Virginia Health Sciences Center, Charlottesville, VA 22906
³ Institut of Biochemistry, Medical School Hannover, 30625 Hannover, Germany
⁴ Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, 80333 Munich, Germany
⁵ Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
⁶ Molecular Oncology Research Institute, Tufts, New England Medical Center, Boston, MA 02111

Address correspondence to George Kollias, Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming," 14-16 Al. Fleming Street, 166-72 Vari, Greece. Phone: +301 9656507; Fax: +301 9656563; E-mail: g.kollias{at}fleming.gr

Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (Tnf^ARE mouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon and requires the function of CD8⁺ T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell–derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor–deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow–derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase–deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

Key Words: MAPK/SAPK • targeted mutants • CD8⁺ lymphocytes • apoptosis • intestine

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